Christian Lachance

Selective Neuromicrovascular Endothelial Cell Death by 8-Iso-Prostaglandin F2α Possible Role in Ischemic Brain Injury

Background and Purpose— Free radical-induced peroxidation is an important factor in the genesis of hypoxic-ischemic encephalopathy, including that of the preterm infant. Isoprostanes are major peroxidation products. Since microvascular dysfunction seems to contribute to ischemic encephalopathies, we studied the cytotoxicity of 8-iso-prostaglandin F2&agr; (PGF2&agr;) on cerebral microvascular cells. Methods— Microvascular endothelial, astroglial, and smooth muscle cells from newborn brain were cultured. The cytotoxicity of 8-iso-PGF2&agr; on these cells was determined by MTT assays and lactate dehydrogenase (LDH) release, propidium iodide incorporation, and DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]). In addition, effects of intraventricular injections of 8-iso-PGF2&agr; and possible involvement of thromboxane in 8-iso-PGF2&agr;-induced cytotoxicity were determined. Results— 8-Iso-PGF2&agr; induced time- and concentration-dependent endothelial cell death (EC50=0.1 nmol/L) but exerted little effect on smooth muscle and astroglial cells; endothelial cell death seemed mostly of oncotic nature (propidium iodide incorporation and LDH release). Cell death was associated with increased endothelial thromboxane A2 (TXA2) formation and was prevented by TXA2 synthase inhibitors (CGS12970 and U63557A); TXA2 mimetics U46619 and I-BOP also caused endothelial cell death. Intraventricular injection of 8-iso-PGF2&agr; induced periventricular damage, which was attenuated by CGS12970 pretreatment. Conclusions— These data disclose a novel action of 8-iso-PGF2&agr; involving TXA2 in oxidant stress-induced cerebral microvascular injury and brain damage.

Myocardial, erythropoitic, and metabolic adaptations to anemia of prematurity

We determined the effects of anemia of prematurity on myocardial, metabolic, and erythropoietic functions. Twelve anemic (hemoglobin range, 65 to 78 gm/L) infants without symptoms (gestational age, (mean +/- SD) 28 +/- 2 weeks; birth weight, 1178 +/- 326 gm) were studied at a postconceptional age of 35 +/- 1.6 weeks. All measurements were done before and 36 to 48 hours after a transfusion of packed erythrocytes. Cardiac output, heart rate, and myocardial function were assessed. Oxygen consumption, carbon dioxide production, resting energy expenditure, arterial oxygen pressure for 50% hemoglobin saturation, and the concentrations of erythropoietin and 2,3-diphosphoglycerate were also determined. After transfusion, increased hemoglobin level (75 +/- 4 to 150 +/- 16 gm/L) and decreased oxyhemoglobin affinity (20.8 +/- 1.7 to 23.6 +/- 2.1 gm/L; p < 0.05) caused a decrease in plasma erythropoietin concentration (from 21.1 +/- 6.2 to 5.8 +/- 1.5 mU/ml; p < 0.01). There was a decrease in heart rate (from 155 +/- 10 beats/min to 146 +/- 7 beats/min) and cardiac output (from 281 +/- 73 ml/kg per minute to 199 +/- 62 ml/kg per minute; p < 0.05). Myocardial function indexes, weight gain, and metabolic demands were normal before and after transfusion. These results suggest that oxygenation is adequately maintained in symptom-free infants with anemia of prematurity.

Antiperoxide activity of sodium metabisulfite: A double-edged sword

Sulfites are chemical substances that are used widely in the pharmaceutical industry to reduce or prevent oxidation. Sodium metabisulfite (Na2S2O5) is still present in several parenteral amino acid solutions. Since intravenous lipid emulsions are contaminated by hydroperoxides, we evaluated whether metabisulfite had an antioxidant activity against hydroperoxides. In vitro, Na2S2O5 inhibited the oxidant activity of H2O2, tert-butyl-, and cumene hydroperoxides. The antioxidant capacity of metabisulfite was supported in vivo by the lower (P < 0.01) excretion of malondialdehyde, a stable end product of lipid peroxidation, in babies receiving metabisulfite in their parenteral nutrition. However, for concentrations outside the range found in solutions for parenteral nutrition, the reduction of hydroperoxides by Na2S2O5 could transform this compound into an oxidant, like a sulfite radical. It is suggested that metabisulfite has antiperoxide properties that, under specific conditions, contribute to the generation of toxic oxidants.

On the citation lifecycle of papers with delayed recognition

Delayed recognition is a concept applied to articles that receive very few to no citations for a certain period of time following publication, before becoming actively cited. To determine whether such a time spent in relative obscurity had an effect on subsequent citation patterns, we selected articles that received no citations before the passage of ten full years since publication, investigated the subsequent yearly citations received over a period of 37 years and compared them with the citations received by a group of papers without such a latency period. Our study finds that papers with delayed recognition do not exhibit the typical early peak, then slow decline in citations, but that the vast majority enter decline immediately after their first – and often only – citation. Middling papers’ citations remain stable over their lifetime, whereas the more highly cited papers, some of which fall into the “sleeping beauty” subtype, show non-stop growth in citations received. Finally, papers published in different disciplines exhibit similar behavior and did not differ significantly.

Prediction of developmental performance in preterm infants at two years of corrected age: contribution of the neurological assessment at term age.

BACKGROUND The population of preterm infants is increasing and resources available for follow-up are limited. Early markers are needed to identify children who will show major as well as more subtle neurodevelopmental impairments. Such a challenge could be achieved with the Amiel-Tison Neurological Assessment at Term (ATNAT). AIMS This study assesses the usefulness of the ATNAT in the prediction of developmental problems at two years of corrected age (CA) in infants born between 29 and 37 weeks of gestation. METHOD Inclusion criteria were: gestational age between 29(0/7) and 36(6/7) weeks inclusively, birth weight below 2500g and minimal 24-hour stay in the Neonatal Intensive Care Unit of Sainte-Justine Hospital. A sample of 147 was prospectively recruited and assessed at two ages: at term with the ATNAT and at 24months CA with Bayley Scales of Infant Development-II. RESULTS No major impairment such as cerebral palsy and no neurosensory impairment were observed. Developmental delay defined by an index<70 on the mental or psychomotor scale was reported respectively in 6.2% and 5.4% of the cohort. Significant differences in mental, psychomotor and behavioral performances were found according to neurological status. Neurological status was the only variable to enter the predictive model for psychomotor and behavioral indexes. Gender and neurological status remained in the predictive model for mental performance. CONCLUSION This study supports the inclusion of the ATNAT among the eligibility criteria for systematic neurodevelopmental surveillance as it allows early identification of infants at higher risk of low developmental performances at 24months CA.

Association between Fetal Cerebral Ventriculomegaly and Platelet Alloimmunisation

Introduction: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare condition that may lead to intracerebral haemorrhage (ICH) in the fetus or neonate. Platelet alloimmunisation causing FNAIT has been described in association with fetal cerebral ventriculomegaly (VM), presumably due to subclinical ICH. The objective of this study was to assess the association between fetal VM and platelet alloimmunisation. Methods: This is a case series of pregnancies with fetal VM screened for platelet alloantibodies from 2003 to 2012. Cases of multiple pregnancies, structural anomalies, aneuploidies, or congenital infection were excluded. Results: Of 45 pregnancies with fetal VM that were screened for platelet alloantibodies, 5 (11%) were positive. There was only one antenatal ICH, with confirmed fetal severe thrombocytopenia before termination of pregnancy. The other cases were treated with intravenous immunoglobulins without prior fetal blood sampling. No other case of neonatal thrombocytopenia was confirmed. Conclusions: The prevalence of platelet alloimmunisation was high in this series of fetal VM. Prospective large studies are needed to confirm the role of platelet alloimmunisation in fetal VM.

Learning Neonatal Intubation Using the Videolaryngoscope: A Randomized Trial on Mannequins.

Introduction The use of the videolaryngoscope (VL) facilitates intubation in adults and children, but experience in neonates is scarce. The objective of this study was to compare the VL with the classic laryngoscope (CL) in acquiring the skill of neonatal endotracheal intubation (ETI) and evaluate transferability of skill from VL to CL. We hypothesize that, on a neonatal mannequin, the VL will be superior to the CL with regard to success rate and that the skill will be transferred from VL to CL. Methods A randomized controlled trial was held at Sainte-Justine Hospital’s simulation center. Third- and fourth-year medical students were randomized into group A, which used VL for the first phase and CL for the second phase, and group B, which used CL for both phases. Each subject performed 9 ETI on 3 simulated neonatal airways in each phase. Results Thirty-four students performed 612 intubations. Success in group A was higher than in group B in the first phase of the study (96.5% vs. 84.6%, P < 0.001). During phase 2, group A’s success did not change significantly (91.7% vs. 96.5%, P = 0.07). Time to successful intubation was longer using the VL (27.6 vs. 15.6 seconds, P < 0.001), but there was no difference in phase 2 (12.5 vs. 10.2 seconds, P = 0.24). There were no esophageal intubations using the VL. Conclusions Success rate of ETI on mannequins was improved, and esophageal intubations decreased while learning ETI using the VL compared with the CL. Once ETI is learned on mannequins using the VL, this skill is transferrable to the CL.

Cardio-respiratory Events and Inflammatory Response After Primary Immunization in Preterm Infants < 32 Weeks Gestational Age: A Randomized Controlled Study

Background: Inflammation may depress respiration in neonates. This study aimed to establish a link between postimmunization inflammation and cardio-respiratory events (CREs). Methods: Randomized double-blind controlled study of infants born < 32 weeks gestation receiving the 2 months vaccine, which comprised diphtheria and tetanus toxoids and acellular pertussis adsorbed combined with inactivated poliomyelitis vaccines and Haemophilus b conjugate and the pneumococcal conjugate 10-valent vaccines. Infants were randomized to ibuprofen treatment or a placebo group (n = 28/group). C-reactive protein (CRP) and prostaglandins E2 (PgE2) levels were assessed before and after immunization. CREs were recorded for 72 hours. Heart rate variability was assessed by polysomnography. Results: In the placebo group, immunization was associated with significantly increased CRP levels and an increase in CRE (8.6 ± 11.1 before versus 14.0 ± 12.8 after), which did not reach statistical significance (P = 0.08), and no change in PgE2. The increase in CRP was correlated with changes in CRE (r = 0.4: P < 0.05). In the ibuprofen group, immunization significantly increased CRP levels but was not associated with change in CRE (6.7 ± 7.7 before versus 6.8 ± 9.7 after) and PgE2 levels. Comparing the groups, variation in CRE (&Dgr;CRE before versus after immunization) was significantly lower in the ibuprofen group (0.1 ± 7.9 versus 5.4 ± 10.0 &Dgr;CRE; P < 0.05). Conclusion: The first immunization of infants born < 32 weeks was associated with an increase in CRP. Ibuprofen treatment significantly attenuated the variation (&Dgr;) in CRE following first immunization in these infants but the current study could not demonstrate an impact on CRP and PgE2 levels. The impact of anti-inflammatory treatment on antigenicity must be evaluated before their clinical use aiming at reducing CRE after immunization in preterm infants.

The Impact of Neonatal Simulations on Trainees’ Stress and Performance: A Parallel-Group Randomized Trial*

Objectives: Assess impact of neonatal simulation and simulated death on trainees’ stress and performance. Design: A parallel-group randomized trial (November 2011 to April 2012). Setting: Sainte-Justine University Hospital, Montreal, Canada. Subjects: Sixty-two pediatric trainees eligible, 59 consented, and 42 completed the study. Interventions: Trainees performed two simulations where a term neonate was born pulseless. They were randomized to start with either survival (manikin responded to appropriate resuscitation) or death scenario (manikin remained pulseless despite resuscitation). Measurements and Main Results: Performance was assessed using the Neonatal Resuscitation Program megacode score sheet by two reviewers. Subjective stress was assessed with a questionnaire. Three salivary cortisol (objective stress) values were compared: at baseline (T0: during lecture), presimulation (T1), and postsimulation (T2: after first scenario). Performance scores were similar in both groups in the first (83% vs 82%; p = 0.85) and second scenarios (82% vs 79 %; p = 0.87). Salivary cortisol levels at T0 (0.10 vs 0.10; p = 0.54), T1 (0.15 vs 0.11; p = 0.35), and T2 (0.23 vs 0.17; p = 0.23) did not differ between groups. Perceived stress level was six out of 10 in survival group versus seven out of 10 in death group (p = 0.19). Salivary cortisol increased significantly from T0 to T1 (p < 0.01). T2 cortisol levels were significantly higher than T1 (p< 0.001), yet this increase was not scenario dependent (p = 0.41) nor associated with performance on either scenario. Subscores for bag mask ventilation were lower than subscores for advanced resuscitation skills. Conclusions: Neonatal simulations cause significant anticipatory and participatory stress. Despite this, trainees’ performance score in simulation was over 80%. Simulated death did not impact performance, magnitude of rise in salivary cortisol level, and perceived stress level. Trainees performed better at advanced resuscitation skills (which are rarely needed) compared with basic skills routinely performed in practice.

Stability of neurocranial signs in the first two years of life in infants at risk.

BACKGROUND Acknowledgement of low-severity/high-prevalence disabilities in infants born preterm singles out the need to identify early markers of brain impairments which could predict these late emergent disabilities. The neurological status as assessed by the Amiel-Tison Neurological Assessments (ATNA) has been proposed as one such potential marker. However, the stability of the ATNA has never been formally assessed. AIM This study aimed to assess the stability of the ATNA. STUDY DESIGN A total of 89 infants born preterm with a gestational age ranging from 29 0/7 to 37 0/7 weeks inclusively and a birth weight below 2500 g were followed during their first two years of life (term age, 4, 8, 12 and 24 months corrected age) in a clinical context. RESULTS Of these, 62 children (69.7%) were classified in the same category on the five assessments while 14 (15.7%) had only one divergent result and 13 (14.6%) had two divergent results over the follow-up. The neurological status throughout the assessments remains stable according to Cochrans Q. CONCLUSION As the neurological status identified by the ATNA remained stable throughout repeated measurements in a regular clinical context and has been shown to correlate with later developmental performances, it should be included as a criterion to target children at risk and used during follow-up.