Injury to the Developing Lung: experimental and clinic al aspects

Injury to the developing lung or disturbance of normal lung development may lead to a chronic lung disease, bronchopulmonary dysplasia (BPD), which may have long-term effects. BPD is characterized by an arrest of development of the lung and the pulmonary vascular system and occurs in around 20% of ventilated newborns. In the first part of this thesis, different factors that influence the development of BPD are studied, both in an experimental and a clinical setting. We found that components of the TGF-b/BMP signalling pathway play a central role in normal and abnormal late lung development. In addition, angiogenic factors, inflammatory cytokines and the nitric oxide system are shown to be of influence. Another factor in the aetiology of BPD is intra-uterine growth retardation. The second part of this thesis focuses on surfactant treatment in acute neonatal lung disorders. Surfactant therapy has become the standard therapy for respiratory distress syndrome in premature infants. There is a significant amount of evidence that near-term or term infants, as well as children, with acute respiratory failure have a profound functional surfactant deficiency. In an experimental setting, we compared synthetic versus natural surfactant and we demonstrated for the first time that both types of surfactant have a positive influence on lung function. However, synthetic surfactant had a significantly stronger effect on inflammatory cytokines. Thus, synthetic surfactant may cause less chronic lung disease and it may be an important part of treatment of these infants in the future

Does a narrative retelling task improve the assessment of language proficiency in school-aged children born very preterm?

Almost half of the children born very preterm (VP) experience language difficulties at school-age, specifically with more complex language tasks. Narrative retelling is such a task. Therefore, we explored the value of narrative retelling assessment in school-aged children born VP, compared to item-based language assessment. In 63 children born VP and 30 age-matched full-term (FT) controls Renfrew’s Bus Story Test and Clinical Evaluation of Language Fundamentals were assessed. The retelling of the Bus Story was transcribed and language complexity and content measures were analyzed with Computerised Language Analysis software. Narrative outcomes of the VP group were worse than that of the FT group. Group differences were significant for the language complexity measures, but not for the language content measures. However, the mean narrative composite score of the VP group was significantly better than their mean item-based language score, while in the FT group the narrative score was worse than the item-based score. Significant positive correlations between narrative and item-based language scores were found only in the VP group. In conclusion, in VP children narrative retelling appears to be less sensitive to detecting academic language problems than item-based language assessment. This might be related to the mediating role of attention in item-based tasks, that appears not to affect more spontaneous language tasks such as retelling. Therefore, in school-aged children born VP we recommend using narrative assessment, in addition to item-based assessments, because it is more related to spontaneous language and less sensitive to attention problems

Insufficient Sedation and Severe Side Effects after Fast Administration of Remifentanil during INSURE in Preterm Newborns

Background: Neonatal intubation is stressful and should be performed with premedication. In the case of an INSURE (intubation/surfactant/extubation) procedure a short duration of action of the premedication used is needed to facilitate fast extubation. Given its pharmacological profile, remifentanil seems a suitable candidate. Objectives: The aim here was to evaluate the effect and side effects of remifentanil as a premedication for preterm neonates undergoing INSURE. Methods: A prospective, single-center study in a level III neonatal intensive care unit was conducted. The quality of sedation was assessed in preterm infants receiving remifentanil prior to intubation for the INSURE procedure. Intravenous remifentanil was administered quickly and followed by a saline flush in approximately 30 s. The quality of sedation was defined by a combination of adequate sedation score, good intubation conditions and absence of side effects. Results: The study was terminated after the inclusion of 14 patients because of the high rate of side effects and the poor intubation conditions. Adequate sedation was achieved in only 2 patients (14%). Six patients (43%) needed additional propofol to obtain adequate sedation. Chest wall rigidity occurred in 6 patients (43%). Conclusions: The rapid administration of remifentanil provides insufficient sedation and is associated with a high risk of chest wall rigidity in preterm neonates

Cutaneous microcirculation in preterm neonates: comparison between sidestream dark field (SDF) and incident dark field (IDF) imaging

Incident dark field imaging (IDF) is a new generation handheld microscope for bedside visualization and quantification of microcirculatory alterations. IDF is the technical successor of sidestream dark field imaging (SDF), currently the most used device for microcirculatory measurements. In (pre)term neonates the reduced thickness of the skin allows non-invasive transcutaneous measurements. The goal of this study was to compare the existing device (SDF) and its technical successor (IDF) in preterm neonates. We hypothesized that IDF imaging produces higher quality images resulting in a higher vessel density. After written informed consent was given by the parents, skin microcirculation was consecutively measured on the inner upper arm with de SDF and IDF device. Images were exported and analyzed offline using existing software (AVA 3.0). Vessel density and perfusion were calculated using the total vessel density (TVD) proportion of perfused vessels (PPV) and perfused vessel density. The microcirculation images quality score was used to evaluate the quality of the video images. In a heterogeneous group of twenty preterm neonates (median GA 27.6 weeks, range 24–33.4) IDF imaging visualized 19.9 % more vessels resulting in a significantly higher vessel density (TVD 16.9 vs. 14.1/mm, p value < 0.001). The perfusion of vessels could be determined more accurately in the IDF images, resulting in a significant lower PPV (88.7 vs. 93.9 %, p value 0.002). The IDF video images scored optimal in a higher percentage compared to the SDF video images. IDF imaging of the cutaneous microcirculation in preterm neonates resulted in a higher vessel density and lower perfusion compared to the existing SDF device

Evaluation of an Intubation Readiness Score to Assess Neonatal Sedation before Intubation

Background: Premedication for neonatal intubation facilitates the procedure and reduces stress and physiological disturbances. However, no validated scoring system to assess the effect of premedication prior to intubation is available. Objective: To evaluate the usefulness of an Intubation Readiness Score (IRS) to assess the effect of premedication prior to intubation in newborn infants. Methods: Two-center prospective study in neonates who needed endotracheal intubation. Intubation was performed using a standardized procedure with propofol 1-2 mg/kg as premedication. The level of sedation was assessed with the IRS by evaluating the motor response to a firm stimulus (1 = spontaneous movement; 2 = movement on slight touch; 3 = movement on firm stimulus; 4 = no movement). Intubation was proceeded if an adequate effect, defined as an IRS of 3 or 4, was reached. IRS was compared to the quality of intubation measured with the Viby-Mogensen intubation score. Results: A total of 115 patients, with a median gestational age of 27.7 weeks (interquartile range 5.3) and a median birth weight of 1,005 g (interquartile range 940), were included. An adequate IRS was achieved in 105 patients, 89 (85%) of whom also had a good Viby-Mogensen intubation score and 16 (15%) had an inadequate Viby-Mogensen intubation score. The positive predictive value of the IRS was 85%. Conclusions: Preintubation sedation assessment using the IRS can adequately predict optimal conditions during intubation in the majority of neonates. We suggest using the IRS in routine clinical care. Further research combining the IRS with other parameters could further improve the predictability of adequate sedation during intubation

Risk factors for necrotizing enterocolitis in neonates: A systematic review of prognostic studies

Background: Necrotizing enterocolitis (NEC) is a severe multifactorial disease in preterm neonates associated with high morbidity and mortality. Better insight into prognostic values of the many reported factors associated with NEC is needed to enable identification of neonates at risk for NEC. The aim was to systematically review the literature to identify independent risk factors for NEC from the literature. Methods: Medline, Cochrane, Embase, Pubmed and Google Scholar were searched systematically for cohort studies reporting prognostic factors for NEC in neonates using multivariable analysis. Studies were scored with the Quality In Prognosis Studies tool (QUIPS). Results: From 5154 initial hits, 14 prognostic studies were included, with various designs. Study quality was rated high in th

Acute Pain Assessment in Prematurely Born Infants Below 29 Weeks A Long Way to Go

Objectives: Neonates born extremely prematurely are at high risk of acute and prolonged pain. Effective treatment requires reliable pain assessment, which is currently missing. Our study explored whether existing pain assessment tools and physiological indicators measure pain and comfort accurately in this population. Materials and Methods: We prospectively collected data in 16 neonates born at less than 29 weeks’ gestational age during 3 conditions: skin-to-skin care, rest, and heelstick procedure for capillary blood sampling in the incubator. The neonates were video recorded in these situations, and recordings were coded using 5 observational pain assessment tools and numeric rating scales for pain and distress. We simultaneously collected heart rate, respiratory rate, arterial oxygen saturation, regional cerebral oxygenation, and the number of skin conductance peaks. All measures across the 3 conditions were compared using general linear modeling. Results: The median gestational age was 27.1 weeks (range: 24.1 to 28.7). Forty measurement periods across the 3 conditions were analyzed. Heart rate was significantly higher during heelstick procedures compared with during rest, with a mean difference of 10.7 beats/min (95% confidence interval [CI]: 2.7-18.6). Oxygen saturation was significantly higher during skin-to-skin care compared with during heelstick procedures with a mean difference of 5.5% (95% CI: 0.2-10.8). The Premature Infant Pain Profile-revised (PIPP-R) score was significantly higher during heelstick procedures compared with skin-to-skin care with a mean difference of 3.2 points (95% CI: 1.6-5.0). Discussion: Pain measurement in clinical practice in prematurely born infants below 29 weeks remains challenging. The included behavioral and physiological indicators did not adequately distinguish between a painful situation, rest, and skin-to-skin care in premature neonates

Ceramides: A potential therapeutic target in pulmonary emphysema

Background: The aim of this manuscript was to characterize airway ceramide profiles in a rodent model of elastase-induced emphysema and to examine the effect of pharmacological intervention directed towards ceramide metabolism.Methods: Adult mice were anesthetized and treated with an intratracheal instillation of elastase. Lung function was measured, broncho-alveolar lavage fluid collected and histological and morphometrical analysis of lung tissue performed within 3 weeks after elastase injection, with and without sphingomyelinase inhibitors or serine palmitoyltransferase inhibitor. Ceramides in broncho-alveolar lavage (BAL) fluid were quantified by tandem mass spectrometry.Results: BAL fluid showed a transient increase in total protein and IgM, and activated macrophages and neutrophils. Ceramides were transiently upregulated at day 2 after elastase treatment. Histology showed persistent patchy alveolar destruction at day 2 after elastase installation. Acid and neutral sphingomyelinase inhibitors had no effect on BAL ceramide levels, lung function or histology. Addition of a serine palmitoyltransferase inhibitor ameliorated lung function changes and reduced ceramides in BAL.Conclusions: Ceramides were increased during the acute inflammatory phase of elastase-induced lung injury. Since addition of a serine palmitoyltransferase inhibitor diminished the rise in ceramides and ameliorated lung function, ceramides likely contributed to the early phase of alveolar destruction and are a potential therapeutic target in the elastase model of lung emphysema

Risk Factors for Chronic Lung Disease and Mortality in Newborns with Congenital Diaphragmatic Hernia

Background: Congenital diaphragmatic hernia (CDH) is associated with a mortality rate of 10-35% in live-born infants. Moreover, CDH survivors have a substantial risk of developing long-term pulmonary sequelae, such as bronchopulmonary dysplasia (BPD). Objectives: This study aims to evaluate risk factors associated with BPD and mortality in neonates with CDH, with particular focus on the initial ventilation mode. Methods: Eligible for inclusion were live-born infants with CDH born from 2001 through 2006 at the centers participating in the CDH Study Group. BPD (defined as oxygen dependency at day 30) and/or mortality by day 30 served as the primary endpoint. Results: A total of 2,078 neonates were included in the analysis. At day 30, 56% of the patients had either died or met the criteria for BPD. In infants who survived until day 30, the prevalence of BPD was 41%. The overall mortality rate was 31%. High-frequency oscillatory ventilation as initial ventilation mode, a right-sided defect, a prenatal diagnosis, a lower Apgar score at 5 min, a cardiac anomaly, a chromosomal anomaly and a lower gestational age were all associated with BPD and/or mortality by day 30. Conclusions: Despite improvements in neonatal care, the rates of BPD and early mortality in newborns with CDH are still considerable. Several important risk factors for a worse outcome are reported in this nonrandomized prospe