Monica Fumagalli

Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus

OBJECTIVE To compare the effects on cerebral perfusion and oxygenation of intravenous ibuprofen and indomethacin as treatment for patent ductus arteriosus in preterm infants. STUDY DESIGN Sixteen infants receiving mechanical ventilation (< 31 weeks gestation) with patent ductus arteriosus received either 0.2 mg/kg indomethacin (n = 8) or 10 mg/kg ibuprofen (n = 8) infused over 1 minute. Near-infrared spectroscopy was used to measure changes in cerebral blood volume and in oxidized cytochrome oxidase concentration. Cerebral blood flow velocity in the pericallosal artery was measured using Doppler ultrasonography. RESULTS Indomethacin caused a significant reduction of CBV (maximal changes in cerebral blood volume: -320 +/- 171 microL/100 gm) and, in four of eight patients, a fall in oxidized cytochrome oxidase concentration (maximal change in oxidized cytochrome oxidase concentration in the eight patients: -0.68 +/- 0.98 mumol/L, NS). Cerebral blood flow velocity fell significantly. Ibuprofen caused no significant reduction of cerebral blood volume, oxidized cytochrome oxidase concentration, or cerebral blood flow velocity, whereas a significant increase of cerebral blood volume (+207 +/- 200 microL/100 gm) was observed after 60 minutes. Ductus closure was seen in six of eight infants after the first dose of indomethacin and in five of eight infants after the first dose of ibuprofen. The therapeutic cycle involved administration of a second and third dose, provided no side effects occurred. Treatment was effective in all infants. CONCLUSION Compared with indomethacin, treatment with ibuprofen does not significantly reduce cerebral perfusion and oxygen availability; the observed increase in cerebral blood volume requires further investigation.

Cerebral near infrared spectroscopy oximetry in extremely preterm infants : Phase II randomised clinical trial

Objective To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry. Design Phase II randomised, single blinded, parallel clinical trial. Setting Eight tertiary neonatal intensive care units in eight European countries. Participants 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support. Interventions Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control). Main outcome measures The primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography. Randomisation Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (<26 weeks or ≥26 weeks). Blinding Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation. Results The 86 infants randomised to the NIRS group had a median burden of hypoxia and hyperoxia of 36.1%hours (interquartile range 9.2-79.5%hours) compared with 81.3 (38.5-181.3) %hours in the control group, a reduction of 58% (95% confidence interval 35% to 73%, P<0.001). In the experimental group the median burden of hypoxia was 16.6 (interquartile range 5.4-68.1) %hours, compared with 53.6 (17.4-171.3) %hours in the control group (P=0.0012). The median burden of hyperoxia was similar between the groups: 1.2 (interquartile range 0.3-9.6) %hours in the experimental group compared with 1.1 (0.1-23.4) %hours in the control group (P=0.98). We found no statistically significant differences between the two groups at term corrected age. No severe adverse reactions were associated with the device. Conclusions Cerebral oxygenation was stabilised in extremely preterm infants using a dedicated treatment guideline in combination with cerebral NIRS monitoring. Trial registration ClinicalTrial.gov NCT01590316.

Pediatric Outcome after Maternal Cancer Diagnosed during Pregnancy.

BACKGROUND Data on the long-term outcome of children who are exposed to maternal cancer with or without treatment during pregnancy are lacking. METHODS In this multicenter case-control study, we compared children whose mothers received a diagnosis of cancer during the pregnancy with matched children of women without a cancer diagnosis. We used a health questionnaire and medical files to collect data regarding neonatal and general health. All children were prospectively assessed (by means of a neurologic examination and the Bayley Scales of Infant Development) at 18 months, 36 months, or both. A cardiac assessment was performed at 36 months. RESULTS A total of 129 children (median age, 22 months; range, 12 to 42) were included in the group whose mother had cancer (prenatal-exposure group) with a matching number in the control group. During pregnancy, 96 children (74.4%) were exposed to chemotherapy (alone or in combination with other treatments), 11 (8.5%) to radiotherapy (alone or in combination), 13 (10.1%) to surgery alone, 2 (1.6%) to other drug treatments, and 14 (10.9%) to no treatment. Birth weight was below the 10th percentile in 28 of 127 children (22.0%) in the prenatal-exposure group and in 19 of 125 children (15.2%) in the control group (P=0.16). There was no significant between-group difference in cognitive development on the basis of the Bayley score (P=0.08) or in subgroup analyses. The gestational age at birth was correlated with the cognitive outcome in the two study groups. Cardiologic evaluation among 47 children at 36 months of age showed normal cardiac findings. CONCLUSIONS Prenatal exposure to maternal cancer with or without treatment did not impair the cognitive, cardiac, or general development of children in early childhood. Prematurity was correlated with a worse cognitive outcome, but this effect was independent of cancer treatment. (Funded by Research Foundation-Flanders and others; ClinicalTrials.gov number, NCT00330447.).

The pathophysiology of retinopathy of prematurity : an update of previous and recent knowledge

Retinopathy of prematurity (ROP) is a disease that can cause blindness in very low birthweight infants. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Despite current therapies, ROP continues to be a highly debilitating disease. Our advancing knowledge of the pathogenesis of ROP has encouraged investigations into new antivasculogenic therapies. The purpose of this article is to review the findings on the pathophysiological mechanisms that contribute to the transition between the first and second phases of ROP and to investigate new potential therapies. Oxygen has been well characterized for the key role that it plays in retinal neoangiogenesis. Low or high levels of pO2 regulate the normal or abnormal production of hypoxia‐inducible factor 1 and vascular endothelial growth factors (VEGF), which are the predominant regulators of retinal angiogenesis. Although low oxygen saturation appears to reduce the risk of severe ROP when carefully controlled within the first few weeks of life, the optimal level of saturation still remains uncertain. IGF‐1 and Epo are fundamentally required during both phases of ROP, as alterations in their protein levels can modulate disease progression. Therefore, rhIGF‐1 and rhEpo were tested for their abilities to prevent the loss of vasculature during the first phase of ROP, whereas anti‐VEGF drugs were tested during the second phase. At present, previous hypotheses concerning ROP should be amended with new pathogenetic theories. Studies on the role of genetic components, nitric oxide, adenosine, apelin and β‐adrenergic receptor have revealed new possibilities for the treatment of ROP. The genetic hypothesis that single‐nucleotide polymorphisms within the β‐ARs play an active role in the pathogenesis of ROP suggests the concept of disease prevention using β‐blockers. In conclusion, all factors that can mediate the progression from the avascular to the proliferative phase might have significant implications for the further understanding and treatment of ROP.

Magnetic resonance imaging assessment of brain maturation in preterm neonates with punctate white matter lesions

IntroductionEarly white matter (WM) injury affects brain maturation in preterm infants as revealed by diffusion tensor imaging and volumetric magnetic resonance (MR) imaging at term postmenstrual age (PMA). The aim of the study was to assess quantitatively brain maturation in preterm infants with and without milder forms of WM damage (punctate WM lesions, PWML) using conventional MRI.MethodsBrain development was quantitatively assessed using a previously validated scoring system (total maturation score, TMS) which utilizes four parameters (progressive myelination and cortical infolding, progressive involution of glial cell migration bands and germinal matrix tissue). PWML were defined as foci of increased signal on T1-weighted images and decreased signal on T2-weighted images with no evidence of cystic degeneration. A group of 22 preterm infants with PWML at term PMA (PWML group) were compared with 22 matched controls with a normal MR appearance.ResultsThe two groups were comparable concerning gestational age, birth weight and PMA. TMS was significantly lower in the PWML group than in the control group (mean TMS 12.44 ± 2.31 vs 14.00 ± 1.44; P = 0.011). Myelination (mean 2.76 ± 0.42 PWML group vs 3.32 ± 0.55 control group, P = 0.003) and cortical folding (3.64 ± 0.79 vs 4.09 ± 0.43, P = 0.027) appeared to be significantly delayed in babies with PWML.ConclusionConventional MRI appears able to quantify morphological changes in brain maturation of preterm babies with PWML; delayed myelination and reduced cortical infolding seem to be the most significant aspects.

The SafeBoosC Phase II Randomised Clinical Trial: A Treatment Guideline for Targeted Near-Infrared-Derived Cerebral Tissue Oxygenation versus Standard Treatment in Extremely Preterm Infants

Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rStO2 and a treatment guideline to correct deviations in rStO2 outside a predefined target range. Aims: To describe the rationale for and content of this treatment guideline. Methods: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. Results and Conclusions: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting.

Neonatal cerebral sinovenous thrombosis

Cerebral sinovenous thrombosis (CSVT) is an uncommon condition among paediatric patients involving major sinuses, with a preponderant occurrence in neonates. The clinical presentation is unspecific, either early, within 48h from birth, or later. An early presentation may be accompanied by several comorbidities (respiratory distress, poor tone, fetal distress, asphyxia), whereas a later presentation is more often associated with conventional neurological signs such as seizures, lethargy, apnoea and poor feeding. These differences in clinical presentation render the neuroradiological diagnosis difficult, in particular before the introduction of magnetic resonance imaging. The interest in CSVT is based on the complex pathogenesis, often resulting from a combination of inherited and acquired thrombophilic patterns. In addition, the course of CSVT can be influenced by medical treatment, currently based on the consensus of experts more than on randomised trials.

Closed versus Open Endotracheal Suctioning in Preterm Infants: Effects on Cerebral Oxygenation and Blood Volume

The aim of our study was to compare, using near-infrared spectroscopy (NIRS), the effects on cerebral intracellular oxygenation and cerebral blood volume (CBV) of closed endotracheal suctioning (CS), which permits continuous ventilation of the patient, with open endotracheal suctioning (OS), which requires disconnection from the ventilator. Eleven preterm infants were studied. Each patient underwent one CS, followed, after 60 min, by one OS, or vice versa, three times during the same day. Modifications in CBV and oxidized cytochrome oxidase (CytO2) were continuously detected by NIRS; arterial oxygen saturation (SaO2) heart rate (HR), transcutaneous carbon dioxide tension and mean arterial blood pressure were simultaneously recorded. Significant reductions in HR and SaO2 were observed following OS; the magnitude and duration of these negative effects of suctioning were significantly reduced with CS. In addition, the decrease in CBV was more pronounced than following CS. No changes in CytO2 concentration were seen.

Respiratory mechanics during NCPAP and HHHFNC at equal distending pressures

Objective To compare the effect of heated, humidified, high-flow nasal cannula (HHHFNC) and nasal continuous positive airways pressure (NCPAP) on lung function and mechanics in preterm infants with respiratory distress syndrome (RDS) at the same level of retropharyngeal pressure (Prp). Design Randomised crossover trial. Setting Neonatal intensive care unit, Ospedale Maggiore Policlinico, Milan, Italy. Patients 20 preterm infants (gestational age: 31±1 wks) with mild-moderate RDS requiring non-invasive respiratory support within 96 h after birth. Interventions Infants were exposed to a randomised sequence of NCPAP and HHHFNC at different settings (2, 4 and 6 cmH2O for NCPAP and 2, 4, 6 L/min for HHHFNC) to enable comparison at the same level of Prp. Main outcome measures Tidal volume by respiratory inductance plethysmography, pleural pressure estimated by oesophageal pressure, and gas exchange were evaluated at each setting and used to compute breathing pattern parameters, lung mechanics and work of breathing (WOB). Results A poor linear regression between flow and Prp was found during HHHFNC (Prp=0.3+0.7*flow; r2=0.37). Only in 15 out of 20 infants it was possible to compare HHHFNC and NCPAP at a Prp of 2 and 4 cmH2O. No statistically significant differences were found in breathing pattern, gas exchange, lung mechanics and total WOB. Resistive WOB in the upper airways was slightly but significantly higher during HHHFNC (0.65 (0.49;1.09) vs 1.57 (0.85;2.09) cmH2O median (IQR)). Conclusions Despite differing mechanisms for generating positive airway pressure, when compared at the same Prp, NCPAP and HHHFNC provide similar effects on all the outcomes explored.

Germinal Matrix Hemorrhage: Intraventricular Hemorrhage in Very-Low-Birth-Weight Infants: The Independent Role of Inherited Thrombophilia

Background and Purpose— The etiology of germinal matrix hemorrhage–intraventricular hemorrhage (GMH-IVH) is multifactorial and the role of genetic polymorphisms is unclear. The aim of this prospective study was to evaluate prothrombotic genetic mutations as independent risk factors for the development of all grades of GMH-IVH in very-low-birth-weight infants. Methods— The presence of both factor V Leiden and prothrombin gain-of-function gene mutations were prospectively assessed in 106 very-low-birth-weight infants. Infants with GMH-IVH were compared to those without GMH-IVH according to genetic and clinical characteristics. Results— Twenty-two out of 106 infants had GMH-IVH develop (20.7%). Infants with GMH-IVH had significantly lower gestational ages and birth weights. In the multivariate Poisson regression model, the prevalence of GMH-IVH appeared to be inversely related to gestational age, with a risk ratio of 0.83 (95% CI, 0.72–0.97; P=0.02) per week. Risk ratio of GMH-IVH for carriers of either prothrombotic mutation was 2.65 (95% CI, 1.23–5.72; P=0.01), similar to the risk ratio associated with need for resuscitation at birth (2.30; 95% CI, 1.02–5.18; P=0.04). Conclusions— Very-low-birth-weight infants who are carriers for either prothrombotic mutations are at increased risk for development of GMH-IVH. Genetic factors act as independent risk factors of the same magnitude as other known risk factors.