Purpose: To characterize the environment in both ground and aerial ambulances in an effort to identify and quantify the risk factors associated with intraventricular hemorrhage (IVH) in preterm infants, with the goal of developing a device to mitigate this problem. Methods: A small, stand-alone battery operated device was developed to characterize the environment inside neonatal transports. This device included an array of sensors to measure acceleration forces, sound levels, temperature, pressure, and light intensities. Two of the data acquisition devices were used to collect data inside and outside the transport incubator simultaneously for a period of thirty minutes during a test flight in a transport helicopter. Real-time digital signal processing was performed for the sound signals to reduce data. Furthermore batch digital signal processing was performed on an external computer to calculate the vibration spectrograms, occurrence of impulsive forces, and variations in ambient temperature, pressure and luminance. The results were compared between the two devices to determine whether the current transport incubator design is reducing or increasing the suspected risk factors. Results: The vibration levels registered in the transport incubator during flight were five times greater than in the crew cabin in the vertical direction. High vibration levels were registered in the horizontal direction in the transport incubator, which were not registered in the crew cabin. In contrast, vibration in lateral direction was nearly half of that registered in the crew cabin. Sound levels were on average 70 dBA in the transport incubator. Luminance levels reached values up to 6920 Lux. No major changes in temperature and pressure were registered. Conclusions: IVH is a serious consequence of transporting preterm infants from one health care facility to another and occurs in roughly one out of three infants. To address this problem, a transport monitoring device can help characterize the environment in these transports in an effort to design a new state of the art transport incubator to mitigate this problem. / Master of Science

Technological advances in neonatal care have dramatically improved the survival and disability rates among low birthweight infants (LBW). One common factor associated with later problems among these babies is intraventricular hemorrhage (IVH). A meta-analysis was conducted among LBW infants with and without IVH to determine developmental outcome. More than 450 studies were located. Only 125 studies met inclusion criteria. Mean effect sizes were computed by comparing the LBW group to either a fullterm children, LBW children scored worse in all areas except gross motor skills. Cognitive assessment was done commonly up to 6 years of age. LBW infants scored about 1/2 standard deviation below their comparison group. A positive linear trend was found for severity of IVH: those children without an IVH scored comparably to fullterm children, while those with severe bleeds were about one standard deviation behind. Assessment of academic skills was done with the 8- to 11-year olds. There was no information given on presence/severity of IVH. Very few assessments were done. On general academic measures, the LBW children scored about 1/2 standard deviation behind the comparison group. Over 80% of the language assessments were done at 15- to 38-months of age. LBW children tended to score 1/2 to 3/4 of a standard deviation below the comparison group. The severity of hemorrhage did not mediate these results. Fine motor assessments were performed on children 9 months to 11 years old. LBW children were about 2/3 of a standard deviation behind the comparison group. These skills were not affected by severity of IVH. Gross motor abilities were typically measured before the children were 24 months old. LBW children showed more deficits in this area than in any other: almost 90% of a standard deviation behind. Gross motor skills appear to be strongly impacted both by being low birthweight and by the severity of IVH. Results indicate that IVH is a mediating factor in outcome among LBW infants. More research needs to be conducted on these children when they are school age, so long-term effects of low birthweight can be determined.

Advances in medical technology have provided the mechanisms for sustaining life in premature and low-birthweight infants, resulting in the survival of more of these infants. Low-birthweight (LBW) and preterm infants are placed at risk by a number of medical complications, including intraventricular hemorrhage (IVH). The outcome of low-birthweight infants with intraventricular hemorrhage has been the subject of a great deal of research and continues to be a much-discussed topic in the medical and psychological communities. As more data become available, it appears that more questions arise concerning the later neuodevelopmental and neuropsychological outcome of these infants. For this reason, research concerning the later status of infants born with intraventricular hemorrhage is needed. The purpose of this study was to determine if there are differences in cognitive and motor functioning among infants with intraventricular hemorrhage (IVH), infants who were low birthweight (LBW), and normal-birthweight (NBW) infants. Forty-four subjects (10 with mild IVH, 9 with severe IVH, 12 LBW, and 13 NBW), who were born between January 1, 1984, and June 1, 1985, and were either patients in the neonatal intensive care unit at University of Utah Medical Center (the IVH and LBW infants) or were residents of the well-baby nursery (the NBW infants) at University of Utah Medical Center, served as the sample population. The subjects were tested at 3 to 4.5 years of age using the Stanford-Binet Intelligence Scales (Fourth Edition) and the motor section of the McCarthy Scales of Children's Abilities. In addition, infant medical data were obtained from medical records, and demographic data were collected including mother's age at time of birth, family income, mother's and father's education level, and birth order of the infant. The MIVH, SIVH, and LBW groups had significantly lower gestational ages and birthweights and significantly more medical complications than did the NBW group. The MIVH and SIVH groups also had significantly lower birthweight and gestational ages than did the LBW group, but approximately equivalent numbers of medical complications. Significant group differences were found only between the MIVH and NBW groups on the McCarthy motor score, with the MIVH group appearing to outperform the NBW group following statistical manipulation with analysis of covariance. No other significant group differences were found. Further research with a larger sample is recommended in order to more fully understand the later outcome following LBW and IVH.

Purpose: This study sought to determine the previously undescribed cytologic and metabolic alterations that accompany endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC). Methods: Cerebrospinal fluid (CSF) samples were collected from infant patients with hydrocephalus at the time of index ETV/CPC and again at each reintervention for persistent hydrocephalus. Basic CSF parameters, including glucose, protein, and cell counts, were documented. A multivariable regression model, incorporating known predictors of ETV/CPC outcome, was constructed for each parameter to inform time-dependent normative values. Results: A total of 187 infants were treated via ETV/CPC for hydrocephalus; initial laboratory values were available for 164 patients. Etiology of hydrocephalus included myelomeningocele (53, 32%), intraventricular hemorrhage of prematurity (43, 26%), aqueductal stenosis (24, 15%), and others (44, 27%). CSF parameters did not differ significantly with age or etiology. Glucose levels initially drop below population average (36 to 32 mg/dL) post-operatively before slowly rising to normal levels (42 mg/dL) by 3 months. Dramatically elevated protein levels post-ETV/CPC (baseline of 59 mg/dL up to roughly 200 mg/dL at 1 month) also normalized over 3 months. No significant changes were appreciated in WBC. RBC counts were very elevated following ETV/CPC and quickly declined over the subsequent month. Conclusion: CSF glucose and protein deviate significantly from normal ranges following ETV/CPC before normalizing over 3 months. High RBC values immediately post-ETV/CPC decline rapidly. Age at time of procedure and etiology have little influence on common clinical CSF laboratory parameters. Of note, the retrospective study design necessitates ETV/CPC failure, which could introduce bias in the results.

No description available.

The regulation of surface tension (ST) by surfactants plays an important role in the human respiratory system but is largely unexplored in brain homeostasis. The aim of this study was to evaluate changes in ST in relation to surfactant proteins (SPs) in children with intraventricular hemorrhage (IVH). CSF samples from 93 patients were analyzed for ST with a force tensiometer and SP-A-D and -G with ELISA assays. Patients belonged to six groups: (i) IVH before primary intervention (PI), (ii) IVH 4–28 days after PI, (iii) IVH 44–357 days after PI, (iv) hydrocephalus, (v) sepsis and (vi) controls. We found indirect correlations and significant differences in ST and SPs (all p < 0.001; except for SP-C, p = 0.007). Post hoc analyses showed significantly decreased ST in IVH patients before PI compared with patients with hydrocephalus, sepsis or controls (p < 0.001), but it increased in IVH patients over time. All SPs were significantly elevated when comparing IVH patients before PI with controls (all p < 0.001; except for SP-C, p = 0.003). Children suffering from IVH displayed an increase in SPs and a decrease in ST as coping mechanisms to preserve CSF flow. The increase in ST over time could serve as prognostic marker for the healing process.

The regulation of surface tension (ST) by surfactants plays an important role in the human respiratory system but is largely unexplored in brain homeostasis. The aim of this study was to evaluate changes in ST in relation to surfactant proteins (SPs) in children with intraventricular hemorrhage (IVH). CSF samples from 93 patients were analyzed for ST with a force tensiometer and SP-A-D and -G with ELISA assays. Patients belonged to six groups: (i) IVH before primary intervention (PI), (ii) IVH 4–28 days after PI, (iii) IVH 44–357 days after PI, (iv) hydrocephalus, (v) sepsis and (vi) controls. We found indirect correlations and significant differences in ST and SPs (all p < 0.001; except for SP-C, p = 0.007). Post hoc analyses showed significantly decreased ST in IVH patients before PI compared with patients with hydrocephalus, sepsis or controls (p < 0.001), but it increased in IVH patients over time. All SPs were significantly elevated when comparing IVH patients before PI with controls (all p < 0.001; except for SP-C, p = 0.003). Children suffering from IVH displayed an increase in SPs and a decrease in ST as coping mechanisms to preserve CSF flow. The increase in ST over time could serve as prognostic marker for the healing process.:1. Einführung 3 1.1 Intraventrikuläre Hämorrhagie 3 1.1.1 Allgemeiner Überblick 3 1.1.2 Pathogenese 3 1.1.3 Risikofaktoren und Prävention 4 1.1.4 Klinik 5 1.1.5 Komplikationen 6 1.1.6 Behandlungsoptionen bei IVH und PHVD 7 1.1.6.1 Medikamente 7 1.1.6.2 Interventionen 7 1.2 Surfactant und Surfactant-Proteine 8 1.3 Zusammenfassung der IVH-Problematik und Fragestellungen der Dissertation 11 2. Publikationsmanuskript 13 3. Zusammenfassung der Arbeit 28 4. Literaturverzeichnis 32 5. Abkürzungsverzeichnis 39 6. Anlagen der Originalpublikation 41 7. Darstellung des eigenen Beitrags 48 8. Erklärung über die eigenständige Abfassung der Arbeit 49 9. Lebenslauf 50 10. Publikationen 51 11. Danksagung 52

Abstract The aim of the study was to evaluate the efficacy and safety of antenatal and postnatal corticosteroids in the prevention for mortality and acute and long-term morbidity in preterm infants. Altogether 109 eligible preterm infants participated in a randomized, multi-center, double-blinded controlled trial studying the efficacy of early dexamethasone (DX) treatment. The infants received either four doses of DX or placebo. DX treatment did not have a detectable influence on survival without bronchopulmonary dysplasia (BPD), severe intracranial hemorrhage, or periventricular leukomalacia. In a meta-analysis of 15 trials, we found that early prolonged DX treatment (> 96 h, n = 1594 infants) decreased the risk of BPD (RR 0.72 95% CI 0.61–0.87), whereas early short DX course did not (n = 1069 infants). However, prolonged DX increased the risk of gastrointestinal (GI) complications (RR 1.59 95% CI 1.02–2.46). Fifty-one very preterm infants participated in a randomized placebo-controlled trial studying early hydrocortisone (HC) started before 36 hours of age and continued for 10 days. The basal and stimulated serum cortisol levels were measured before the intervention. The study was interrupted because of GI perforations in the HC group. HC decreased the risk of patent ductus arteriosus. HC-treated infants with serum cortisol concentrations above the median had a high risk of GI perforation. HC increased survival without BPD among infants with low endogenous cortisol levels. Altogether 45 surviving infants were enrolled in the follow-up of the early HC trial at 2 years of age. None of the study patients had died after discharge. There was no difference in the recorded rehospitalization rate, growth characteristics, or neurological development between HC and placebo-treated children. Altogether 249 women pregnant at less than 34.0 gestational weeks participated in a randomized trial studying the efficacy of a single additional dose of betamethasone (BM). All of the 159 infants in the BM group and 167 in the placebo group were born before 36 weeks of gestation. Intact survival was comparable between the BM and placebo groups, whereas the need for surfactant therapy in RDS was increased in the BM group. According to a post hoc analysis of 206 infants delivered within 1–24 hours, the BM booster tended to increase the risk of RDS and to decrease intact survival.

No description available.

Human mesenchymal stem cell (MSC) therapy has shown neuroprotective effects and improvement on recovery from neonatal intraventricular hemorrhage (IVH). This study focused on histological evaluations of human amniotic fluid MSC therapy during early prenatal life in a preterm IVH rabbit model. IVH was diagnosed at 24 h of age with ultrasound and animals were randomized into subgroups with confirmed IVH and an IVH negative control group. Animals with confirmed IVH received vehicle only or MSCs at two different doses via intraperitoneal administration. The animals were sacrificed at 48 h post administration. The severity of IVH was histologically analyzed via staining of endogenous peroxidase activity in cryosections and the distribution of red blood cells and cell-free hemoglobin was scored. Primary antibodies targeting human epitopes were validated in IHC assays of frozen MSC pellet. An anti-human nuclear mitotic apparatus (hNuMA) antibody labeled the majority of cells in the MSC pellet and did not cross-react with rabbit NuMA when tested in the nontreated rabbit brain. Significant levels of red blood cells and cell-free hemoglobin were found in the IVH confirmed group, whereas the control group showed no hemorrhage. The MSC therapy groups showed similar scoring results as the IVH-vehicle group. Anti-hNuMA immunolabeling did not detect any cells in the brain of MSC treated rabbits. However, extracellular (nonnuclear) immunolabeling was detected, located in the midbrain of the animals that received MSCs, indicating the presence of MSC nuclear debris. The preterm rabbit model was proven successful for inducing IVH, whereas MSC treatment did not affect the degree of hemorrhage. To increase the possibility to detect the MSCs post administration, future studies should include prelabeling of the MSCs with a suitable cell tracker and analyses at time points closer to the administration of MSCs. / Human mesenkymal stamcellsterapi har visat neuroprotektiva effekter samt förbättring av återhämtning efter neonatal intraventrikulär blödning (IVH). Denna studie fokuserade på histologiska utvärderingar av stamcellsterapi med humana mesenkymala stamceller (MSC) från fostervatten under tidigt prenatalt liv i en prematur IVH-kaninmodell. IVH diagnostiserades med ultraljud vid 24 tim. ålder och djuren delades slumpmässigt in i undergrupper med konfirmerad IVH och en IVH-negativ kontrollgrupp. Djur med konfirmerad IVH mottog endast bärmedel eller MSC i två olika doser via intraperitoneal administration. Djuren avlivades 48 tim. post administration. Graden av IVH analyserades histologiskt genom färgning av peroxidasaktivitet i kryosnitt av hjärna och distributionen av erytrocyter samt fritt hemoglobin graderades. Primärantikroppar riktade mot humana epitop validerades i immunhistokemiska analyser av fryst MSC-pellet. En anti-human nukleär mitotisk apparat (hNuMA) antikropp märkte majoriteten av cellerna i MSC-pelleten och korsreagerade inte med kanin-NuMA under försök i obehandlad kaninhjärna. Signifikanta nivåer av erytrocyter och fritt hemoglobin påvisades i gruppen med konfirmerad IVH, medan kontrollgruppen inte visade någon blödning. Samtliga IVH-grupper; IVH-vehicle och de som mottog MSC- terapi, visade liknande blödningsgrad. Anti-hNuMA-immuninmärkning kunde inte detektera några celler i de MSC-behandlade kaninhjärnorna. Dock detekterades extracellulär (icke-nukleär) immuninmärkning lokaliserad i mitthjärnan hos de djur som mottog MSC, vilket indikerar närvaro av nukleär MSC-debris. Den prematura kaninmodellen bevisades vara framgångsrik för induktion av IVH, men MSC-terapi påverkade inte blödningsgraden. För att öka sannolikheten att detektera MSC efter administration, borde framtida studier inkludera förmärkning av MSC med en lämplig cellmarkör samt analyser vid tidpunkter närmare administrationen av MSC.