Pathogenesis Of Intraventricular Hemorrhage Research Articles

Evaluation of recombinant human IGF-1/IGFBP-3 on intraventricular hemorrhage prevention and survival in the preterm rabbit pup model

Insulin-like growth factor-1 (IGF-1) is essential for normal brain development and regulates processes of vascular maturation. The pathogenesis of intraventricular hemorrhage (IVH) relates to the fragility of the immature capillaries in the germinal matrix, and its inability to resist fluctuations in cerebral blood flow. In this work, using different experimental setups, we aimed to (i) establish an optimal time-point for glycerol-induction of IVH in relation to time-point of recombinant human (rh) IGF-1/rhIGFBP-3 administration, and (ii) to evaluate the effects of a physiologic replacement dose of rhIGF-1/rhIGFBP-3 on prevention of IVH and survival in the preterm rabbit pup. The presence of IVH was evaluated using high-frequency ultrasound and post-mortem examinations. In the first part of the study, the highest incidence of IVH (> 60%), occurred when glycerol was administered at the earliest timepoint, e.g., 6 h after birth. At later time-points (18 and 24 h) the incidence decreased substantially. In the second part of the study, the incidence of IVH and mortality rate following rhIGF-1/rhIGFBP-3 administration was not statistically different compared to vehicle treated animals. To evaluate the importance of maintaining intrauterine serum levels of IGF-1 following preterm birth, as reported in human interventional studies, additional studies are needed to further characterize and establish the potential of rhIGF-1/rhIGFBP-3 in reducing the prevalence of IVH and improving survival in the preterm rabbit pup.

Azithromycin reduces hemoglobin-induced innate neuroimmune activation

Neonatal intraventricular hemorrhage (IVH) releases blood products into the lateral ventricles and brain parenchyma. There are currently no medical treatments for IVH and surgery is used to treat a delayed effect of IVH, post-hemorrhagic hydrocephalus. However, surgery is not a cure for intrinsic brain injury from IVH, and is performed in a subacute time frame. Like many neurological diseases and injuries, innate immune activation is implicated in the pathogenesis of IVH. Innate immune activation is a pharmaceutically targetable mechanism to reduce brain injury and post-hemorrhagic hydrocephalus after IVH. Here, we tested the macrolide antibiotic azithromycin, which has immunomodulatory properties, to reduce innate immune activation in an in vitro model of microglial activation using the blood product hemoglobin (Hgb). We then utilized azithromycin in our in vivo model of IVH, using intraventricular blood injection into the lateral ventricle of post-natal day 5 rat pups. In both models, azithromycin modulated innate immune activation by several outcome measures including mitochondrial bioenergetic analysis, cytokine expression and flow cytometric analysis. This suggests that azithromycin, which is safe for neonates, could hold promise for modulating innate immune activation after IVH.

Pathogenesis and Prevention of Intraventricular Hemorrhage in Preterm Infants.

Intraventricular hemorrhage (IVH) is a serious concern for preterm infants and can predispose such infants to brain injury and poor neurodevelopmental outcomes. IVH is particularly common in preterm infants. Although advances in obstetric management and neonatal care have led to a lower mortality rate for preterm infants with IVH, the IVH-related morbidity rate in this population remains high. Therefore, the present review investigated the pathophysiology of IVH and the evidence related to interventions for prevention. The analysis of the pathophysiology of IVH was conducted with a focus on the factors associated with cerebral hemodynamics, vulnerabilities in the structure of cerebral vessels, and host or genetic predisposing factors. The findings presented in the literature indicate that fluctuations in cerebral blood flow, the presence of hemodynamic significant patent ductus arteriosus, arterial carbon dioxide tension, and impaired cerebral venous drainage; a vulnerable or fragile capillary network; and a genetic variant associated with a mechanism underlying IVH development may lead to preterm infants developing IVH. Therefore, strategies focused on antenatal management, such as routine corticosteroid administration and magnesium sulfate use; perinatal management, such as maternal transfer to a specialized center; and postnatal management, including pharmacological agent administration and circulatory management involving prevention of extreme blood pressure, hemodynamic significant patent ductus arteriosus management, and optimization of cardiac function, can lower the likelihood of IVH development in preterm infants. Incorporating neuroprotective care bundles into routine care for such infants may also reduce the likelihood of IVH development. The findings regarding the pathogenesis of IVH further indicate that cerebrovascular status and systemic hemodynamic changes must be analyzed and monitored in preterm infants and that individualized management strategies must be developed with consideration of the risk factors for and physiological status of each preterm infant.

Hemangioma-related gene polymorphisms in the pathogenesis of intraventricular hemorrhage in preterm infants

PurposeThe aim of this study was to evaluate the possible relationship between four single nucleotide polymorphisms of hemangioma-linked genes encoding for anthrax toxin receptor 1 (ANTXR1 G976A), R kinase insert domain receptor (KDR T1444C), adrenoceptor beta 2 (ADRB C79CG), and insulin-like growth factor 1 receptor (IGF-1R G3174A) and the occurrence of IVH in a population of preterm infants.MethodsThe study includes a population of 105 infants born from 24 + 0 to 32 + 0 weeks of gestation and hospitalized at the Department of Neonatology (III level hospital) of Poznan University of Medical Science. Intraventricular hemorrhage was diagnosed with the use of cranial ultrasound. The classification of intraventricular bleeding was based on the Papile IVH classification.ResultsThe incidence of IVH was higher in infants with lower birth weight, lower APGAR scores, and low birth weight. The study revealed that IVH was approximately two times less likely to occur in infants with the allele G of IGF-1R 3174G > A.ConclusionIdentifying susceptible premature infants through genetic analysis could be a potential way to alleviate severe IVH and its subsequent consequences. Further research examining a wider range of relevant gene polymorphisms could help highlight any genetic patterns in this deleterious bleeding complication.

Pathogenesis and prevention of intraventricular hemorrhage

Despite improvements in the mortality rates of preterm infants, rates of germinal matrix intraventricular hemorrhage (IVH) have remained static with an overall incidence of 25% in infants less than 32 weeks. The importance of the lesion relates primarily to the underlying injury to the developing brain and the associated long-term neurodevelopmental consequences. This clinical-orientated review focuses on the pathogenesis of IVH and discusses the evidence behind proposed prevention strategies.

Cerebral Oxygenation and Autoregulation in Very Preterm Infants Developing IVH During the Transitional Period: A Pilot Study.

Background: The transitional period, defined as the first 72 h after preterm birth, is often characterized by a significant hemodynamic instability, which represents an important risk factor for such neurological complications of prematurity as intraventricular hemorrhage (IVH). The impairment of cerebral autoregulation plays a key role in the pathogenesis of IVH, whose incidence is highest during the transitional period. This pilot study aimed to evaluate whether patterns of cerebral autoregulation and oxygenation differ in relation to IVH development in very preterm infants during the transitional period.Methods: Infants <32 weeks' gestation were enrolled within 12 h from birth. A simultaneous monitoring of cerebral oxygenation (CrSO2) by near-infrared spectroscopy and of heart rate and peripheral oxygen saturation by pulse oximetry was performed over the first 72 h. Cerebral fractional oxygen extraction (cFTOE) and tissue oxygenation-heart rate reactivity index (TOHRx), which represents a marker of cerebrovascular reactivity, were calculated. Daily cranial and cardiac ultrasound scans were performed, in order to assess the hemodynamic status and to detect a possible IVH onset. CrSO2 and cFTOE, clustered on 6-hour epochs, were compared between infants who developed IVH during the study period and those who did not. A between-group comparison of TOHRx before and after IVH detection was also performed.Results: Twenty preterm infants with a median gestational age of 27 weeks (interquartile range, IQR: 25-30 weeks) and median birth weight of 895 g (IQR: 822-1208 g) were enrolled. Of these, 8 developed IVH. The median age at IVH detection was 40 h (IQR: 30-48 h). Pre-IVH TOHRx was significantly higher compared to matched control periods (p <0.001). CrSO2 was significantly lower from 12 to 30 h and from 42 h onwards in cases compared to controls; however, a temporary CrSO2 rise preceded IVH detection. Similarly, cFTOE was significantly higher in IVH infants from 12 to 30 h and from 48 to 72 h, with a transient decrease between the two periods.Conclusions: In preterm infants during the transitional period, the development of IVH is preceded by transient changes in cerebral oxygenation and oxygen extraction which, in turn, may underlie an early impairment of cerebral autoregulation. Larger studies are needed to confirm these preliminary findings.

Role of Fibronectin-1 polymorphism genes with the pathogenesis of intraventricular hemorrhage in preterm infants

Background/introductionIntraventricular hemorrhage (IVH) is a dangerous complication facing a significant proportion of preterm infants. It is multifactorial in nature, and an observed fibronectin deficiency in the germinal matrix basal lamina is among the most prominent factors that influence such rupture. Better understanding of the FN1 gene polymorphisms and their role in IVH may further clarify the presence of a genetic susceptibility of certain babies to this complication. The aim of this study was to assess if 5 single nucleotide polymorphisms of the fibronectin gene may be linked to an increased incidence of IVH.Material and methodsThe study included 108 infants born between 24 and 32 weeks of gestation. IVH was diagnosed using cranial ultrasound performed on the 1st,3rd, and 7th day after birth and classified according to Papile et al. IVH classification. The 5 FN1 gene polymorphisms assessed in the study were the following: rs3796123; rs1968510; rs10202709; rs6725958; and rs35343655.ResultsIVH developed in 51 (47.2%) out of the 108 preterm infants. This includes, 18 (35.3%) with stage I IVH, 19 (37.3%) with stage II, 11 (21.6%) with stage III, and 3 (5.9%) with stage IV IVH. Incidence of IVH was higher in infants with lower APGAR scores, low gestational age, and low birthweight. Analysis showed that IVH stage II to IV was approximately seven times more likely to occur in infants with the genotype TT FN1 rs10202709 (OR 7237 (1046–79.59; p = 0,044)). No other significant association was found with the rest of the polymorphisms.ConclusionThe results of our study indicate a sevenfold increased genetic susceptibility to IVH in preterm infants with the TT FN1 rs10202709 gene polymorphism. The fibronectin gene polymorphism may therefore be of crucial importance as a genetic risk factor for IVH in preterm infants. Further studies are warranted.

The role of FV 1691G>A, FII 20210G>A mutations and MTHFR 677C>T; 1298A>C and 103G>T FXIII gene polymorphisms in pathogenesis of intraventricular hemorrhage in infants born before 32 weeks of gestation

BackgroundCongenital thrombophilia is associated with an increased intraventricular hemorrhage (IVH) risk among newborns, but it may also play a protective role. The role of genetic polymorphisms involved in the coagulation pathway of IVH pathogenesis is probably a consequence of an increased risk of thrombosis in the fine blood vessels in the germinal matrix region.Material and methodsThe aim of this study was to evaluate the possible relationship between Factor V (FV) 1691G>A, Factor II (FII) 20210G>A mutations and methylenetetrahydrofolate reductase (MTHFR) 677C>T; 1298A>C and Factor XIII (FXIII) 103G>T gene polymorphisms and the occurrence of IVH in 100 infants born from 24 + 0 to 32 + 0 weeks of gestation, born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroid therapy, and without congenital abnormalities.ResultsIVH developed 45 (45%) infants, including 15 (33.33%) diagnosed with IVH stage I, 20 (42.22%) with stage II, 8 (17.77%) with stage III, and 3 (6.66%) with stage IV. Analysis showed a prevalence 4.5 times higher of IVH stages II to IV in infants with the genotype CC (OR 4511 (1147–17.75);p = 0.026) of MTHFR 1298A>C gene polymorphism. Our investigation did not confirm any significant prevalence of IVH development in other studied mutations/polymorphisms.ConclusionsThis study confirmed that the MTHFR 1298A>C polymorphism is associated with the risk of IVH. IVH is a significant problem for preterm infants. In addition to little progress in preventing IVH in preterm babies, substantial research that is focused on understanding the etiology, mechanism, and risk factors for IVH is imperative. In the era of personalized medicine, identification of genetic risk factors creates opportunities to generate preventative strategies.

Role of endothelial nitric oxide synthase and endothelin-1 polymorphism genes with the pathogenesis of intraventricular hemorrhage in preterm infants

In the pathogenesis of neonatal intraventricular hemorrhage (IVH) in preterm infants, an important role is played by changes in venous and arterial cerebral flows. It has been shown that the ability of autoregulation of cerebral flows in response to variations in arterial blood pressure in preterm infants is impaired. This impaired autoregulation causes an increased risk of germinal matrix rupture and IVH occurrence. We examined three polymorphisms of genes, related to regulation of blood flow, for an association with IVH in 100 preterm infants born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroids therapy, and without congenital abnormalities. These polymorphisms include: eNOS (894G > T and −786T > C) and EDN1 (5665G > T ) gene. We found that infants with genotype GT eNOS 894G > T have 3.4-fold higher risk developing of IVH born before 28 + 6 weeks of gestation. Our investigation did not confirm any significant prevalence for IVH development according to eNOS −786T > C genes polymorphism. Our novel investigations in EDN1 5665G > T polymorphism did not show any link between alleles or genotypes and IVH. Future investigations of polymorphisms in blood-flow associated genes may provide valuable insight into the pathogenetic mechanisms underlying the development of IVH.

Elevated Interleukin-6 Concentration and Alterations of the Coagulation System Are Associated with the Development of Intraventricular Hemorrhage in Extremely Preterm Infants

Background: Pathogenesis of intraventricular hemorrhage (IVH) in premature infants is multifactorial. Little is known about the influence of pro-inflammatory cytokine activation on the coagulation system in extremely preterm infants and its impact on the development of IVH. Objective: To determine the interaction between serum interleukin-6 (IL-6) and the coagulation system in preterm infants predisposed to the development of IVH. Methods: Vitamin K-dependent coagulation factors were examined retrospectively in 132 extremely preterm infants prior to vitamin K administration at the first day of life. Patients were grouped according to the occurrence of IVH and serum concentration of IL-6 >/<100 pg/ml. Results: Occurrence of IVH was associated with clinical diagnosis of chorioamnionitis, low gestational age, high CRIB score, air leak, catecholamine treatment, low initial hematocrit and increased serum concentration of IL-6. Infants developing IVH showed a diminished coagulation profile. Multivariable logistic regression analysis revealed decreased activity of coagulation factor VII, development of pneumothorax and low hematocrit as independent risk factors for the development of IVH. An increased IL-6 serum concentration was associated with a significantly decreased activity of coagulation factor VII and increased levels of fibrinogen. Conclusions: The association of elevated IL-6 levels with alterations of the coagulation profile and development of IVH found in our study supports the assumption of a close pathophysiological relation between inflammation and IVH.

Does Admission Hypothermia Predispose to Intraventricular Hemorrhage in Very-Low-Birth-Weight Infants?

Background: The etiology of intraventricular hemorrhage (IVH) in very-low-birth-weight (VLBW) infants is multifactorial and is associated with low gestational age (GA) and severity of neonatal respiratory disease. The role of admission hypothermia (AHT) in the pathogenesis of IVH in VLBW infants has not yet been elucidated. We searched risk factors for IVH in VLBW infants while focusing on AHT. Patients and Methods: VLBW infants ≤33 weeks’ gestation from three participating medical centers were included. From patients’ medical charts we collected variables known to be associated with IVH, focusing on AHT. AHT was defined as rectal temperature ≤35.5°C at admission to the NICU. Head ultrasound was performed at 2–5 and 6–10 days of age and before discharge. Results: 271 VLBW infants were studied. Univariate analysis showed that AHT at ≤35.5°C was not significantly associated with IVH (all grades; p = 0.16), but associated with IVH grade 3–4 (p = 0.034), while AHT at ≤35°C was significantly associated with IVH (p = 0.036) and with IVH grade 3–4 (p = 0.003). Multivariate logistic regression analysis showed that AHT (at ≤35.5 and at ≤35°C) were not associated with IVH. Only four variables were independently significantly associated with IVH: GA, use of nitric oxide, hypocarbia and base deficit >10. Four variables were strongly associated with severe IVH (grades 3–4): GA, hypotension, base deficit >10 and hyponatremia. Conclusions: In VLBW infants, AHT at ≤35.5 and at ≤35.0°C were not significantly associated with IVH. GA, use of nitric oxide, hypocarbia and base deficit >10 were strongly associated with IVH.

Neonatal IVH – mechanisms and management

Intra-ventricular hemorrhage (IVH) occurs predominantly in very low birth weight premature infants. Survivors of severe IVH frequently experience long-term consequences including major neurological deficits. Advances in neonatal and obstetric care in the last decades, have led to a steady decline in mortality and in the incidence of IVH. However, significant improvements in the survival rates small premature infants have led to an increase in the population of newborns prone to IVH. The pathogenesis of IVH is multifactorial. Prematurity of the germinal matrix, fluctuations in cerebral blood flow, hypoxic ischemic cerebral injury and developmental hemostatic abnormalities of newborns are important risk factors. The following manuscript will address the epidemiology and pathogenesis of IVH and review studies regarding potential pro-coagulant therapy.

A Retrospective Evaluation of Children Who Have Suffered a Grade III or IV Intraventricular Hemorrhage and Their Parents for Platelet Dysfunction.

AbstractAbstract 1440This study is intended to evaluate children that have survived a grade III or IV intraventricular head bleed and their parents for a potential autosomal dominant inherited platelet dysfunction due to platelet dense granule deficiency (δ-SPD). Intraventricular hemorrhage (IVH) poses a significant risk in premature neonates less than 32 weeks gestation. Infants suffering from high grade (III-IV) periventricular or intraventicular bleeding have mortality rates approaching 50%. In addition, survivors of high grade IVH may suffer severe brain damage or a multitude of other long term neurological sequelae. Thus, we believe that investigation into the pathogenesis of neonatal IVH is not only crucial for the survival of these infants, but also for their quality of life in the future.Current data suggest that the pathogenesis of IVH in the premature infant is related to a loss of ability to regulate cerebral blood flow. Changes in local blood pressure, which would otherwise be autoregulated, remain unrestrained and result in capillary bleeding. Previous prospective studies from our lab have shown that full term neonates have a transient platelet dysfunction at the time of birth (Blood, 100(11), 691a, 2002), which appears to be related to a platelet dense granule storage pool deficiency (δ-SPD). We have also found that 1 day old, full term neonates have mature platelets similar to adults. Our prospective data suggests that at day 3–5 after birth, premature infants of gestational age 26–33 weeks (n=29) have a δ-SPD similar to that observed in full-term umbilical cord blood platelets suggesting a delay in platelet maturation. Only one preemie included in the study had suffered an IVH (grade I); all preemies who suffered Grade III/IV IVH during our study died before we could obtain blood (Blood 108(11):1113, 2006). Parents evaluated had normal platelet storage pools.Our current and on-going retrospective study of children that have survived a grade III/IV IVH and their parents supports our hypothesis that platelet dysfunction may play a significant role in the etiology of IVH. Survivors were identified from a database and parents sent a letter requesting their participation in the study. For those agreeing to participate, informed consent was obtained for this Institutional Review Board approved project. A vial of peripheral blood was obtained from both the IVH surviving child and their parent(s) to determine the platelet dense granule storage pool using the electron microscopy whole mount technique. Parents completed a vetted bleeding questionnaire for assessment of bleeding history/tendencies. Our preliminary data from 6 families reveals that all children surviving a grade III/IV IVH have a δ-SPD with an average of 2.64 ± 0.14 dense granules per platelet (DG/PL) whereas normal = 4–6 DG/PL. Their mothers also have a tendency for δ-SPD (5/6 δ-SPD and 1 within normal limits) with an overall average of 2.93 ± 0.35 DG/PL. Data collected from the questionnaires substantiate the laboratory results with a history of menorrhagia (determined by an established numerical pictorial method) the most significant correlation in 4/6 mothers. The fathers (4/5) tend to have normal numbers of DG/PL (4.06 ± 0.61; 1 had δ-SPD at 1.72 DG/PL). Interestingly, for the one mother with a normal number of DG/PL, the father had δ-SPD. Thus, all children evaluated to date in this study have δ-SPD and a parent who also has δ-SPD. The implication of these preliminary data suggest that potential identification of platelet dysfunction in women at risk for premature delivery could allow for prophylactic intervention for the premature neonate to reduce the morbidity and mortality related to IVH. As this study is currently ongoing, it is anticipated that additional data will be available for presentation. Disclosures:No relevant conflicts of interest to declare.

Does Platelet Dysfunction Mediate the Development of Intraventricular Hemorrhage in the Premature Neonate?.

The purpose of this investigation is to evaluate the potential of platelet dysfunction as a risk factor for the development of intraventricular hemorrhage (IVH) in the premature neonate. Intraventricular hemorrhage is relatively common, especially in infants weighing less than 1500 grs or less than 35 weeks of gestation. Neonates less than 32 weeks gestation are at significant risk for periventricular/intraventicular bleeding with mortality rates approaching 50% for those having a high grade (III-IV) IVH. The pathogenesis of IVH in the premature infant is thought to be related to loss of an ability to regulate cerebral blood flow (cerebral autoregulation) in the subependymal germinal matrix. This leads to abrupt changes in local blood pressure regulation and results in capillary bleeding. It is also apparent that birth weight and gestational age are not the only risk factors for IVH; relationships with lung development and ventilation, or lack thereof, also exist as risk factors.In a previous study of platelets obtained from umbilical cord blood, we have found that the neonate has a transient platelet dysfunction at the time of birth which appears to be related to a platelet (PL) dense granule (DG) storage pool deficiency (δ-SPD). We have found that platelets obtained from umbilical cord blood have an average of 0.79 ± 0.08 DG/PL (n=62), which is significantly decreased compared to the adult population (4–6 DG/PL) (Blood , 100(11):691a, 2002). Although the concentration of ADP and ATP were found to be decreased compared to normal adult platelets, the ATP/ADP ratio in neonatal platelets is 1.95 (n=61), consistent with established adult normal range ratio values (1.4–1.95). We have data establishing that a one-day-old full-term neonate has adenine nucleotide values consistent with adult levels. We postulate that a failure of platelet maturation related to gestational age of the preterm neonate, or an inherent δ-SPD, may extend the platelet dysfunction at birth and should therefore be considered a potential risk factor for development of IVH in the premature neonate.We have collected peripheral blood with informed consent from premature neonates, 26–33 weeks gestational age and their parents to assess the PL DG content and the adenine nucleotide content of each subject. Preliminary data (mean ± 2 SE) from the peripheral blood of premature infants (n=19) obtained 3–5 d after birth include: gestational age 30.18 ± 1.28 weeks and wt 1378.2 ± 27.8 gr. The DG number (1.00 ± 0.29/PL) is significantly decreased compared to normal adults, while the ATP (3.19 ± 0.36 M/1011 PL), ADP (2.63 ± 0.54 M/1011 PL) and ATP/ADP ratio (1.46 ± 0.13) are normal. The decreased DG number in premature PLs is essentially identical to the DG number in umbilical cord blood PLs. The parents studied to date have had a normal DG number and adenine nucleotide content. Our preliminary data suggests that at day 3–5 after birth, premature infants of gestational age 26–33 weeks have a δ-SPD similar to that observed in full-term umbilical cord blood PLs. Additional subjects are needed, especially premature neonates who have suffered a grade III or IV IVH to fully assess our hypothesis. A retrospective study of high-grade IVH survivors and their parents is currently being implemented to investigate an inherited δ-SPD mediator/risk factor for IVH in the premature neonate.

Different Doses of Dopamine Have Heterogeneous Effects on Cerebral Hemodynamics and Dopamine Receptors in Young Rabbits as Measured with Near Infrared Spectroscopy

Background: Fluctuations in cerebral blood volume and cerebral oxygenation may be important in the pathogenesis of intraventricular hemorrhage and hypoxic-ischemic brain injury in the neonate. The cerebral hemodynamic response to dopamine infusion in premature infants is not well established. The newborn rabbit, a rather immature species at birth, is a suitable model for monitoring the physiological changes of the cerebral circulation. Methods: The effect of dopamine upon cerebral hemodynamics and basal ganglia dopaminergic receptors were studied using four different dopamine doses. Results: No significant changes in near infrared spectroscopy (NIRS) parameters were observed in the animals that received 0.5 (n = 5) and 1 µg/kg/min (n = 4) of dopamine intravenously. In contrast, in those animals that received dopamine at 5 µg/kg/min (n = 7) and 50 µg/kg/min (n = 7), there was a significant decrease in oxygenated hemoglobin. Moreover, this was accompanied by a significant increase in deoxygenated hemoglobin soon after drug infusion. Cerebral blood volume was increased in the group that received 5 µg/kg/min, but significantly decreased in the group that received 50 µg/kg/min. In both groups NIRS parameters returned to baseline values soon after stopping dopamine infusion. Conclusion: Despite evidence of a physiological response, we found no difference in the distribution of dopamine receptors between experimental and control animals. We therefore speculate that dopamine has an effect on the cerebrovasculature that could be mediated by factors other than changes in the basal ganglia dopamine receptors.

Morphine, Hypotension, and Intraventricular Hemorrhage in the Ventilated Premature Infant

The article in this issue of Pediatrics entitled “Morphine, Hypotension, and Adverse Outcomes Among Preterm Neonates: Who’s to Blame?” is a reanalysis of a data set recently published.1,2 Before attributing blame and passing judgment, it is important to briefly review the data. Thus, the genesis of the study was based on pilot observations that suggest that morphine infusions decrease the frequency of early neurologic injury in ventilated infants.3 The authors extended these initial observations and conducted a multicenter, blinded, randomized trial to test the hypothesis that preemptive morphine, compared with a placebo group, would significantly reduce the frequency of early neurologic injury in ventilated preterm neonates. The primary outcome was neonatal death, severe intraventricular hemorrhage (IVH) (grade III/IV), or periventricular leukomalacia (PVL) defined as cystic echolucency adjacent to the lateral ventricles on cranial sonography obtained at 4 to 7 days and at 28 to 35 days of postnatal life. Ventilated infants were stratified by gestational age (GA) at birth as follows: 23 to 26, 27 to 29, and 30 to 32 weeks. The principal findings were that both groups had similar rates of composite outcome, severe IVH, and PVL. Because open-labeled morphine was an option for both groups, when the data were reanalyzed the morphine as well as the placebo group of infants, who received open-labeled morphine, had significantly worse rates of severe IVH or composite outcome, respectively.2 Regarding adverse effects, infants in the group receiving morphine had an increased incidence of hypotension (defined as the need for vasopressor support or intravenous fluid boluses ≥20 mL/kg), particularly during the … Address correspondence to Jeffrey M. Perlman, MB, ChB, Department of Pediatrics, Weill Cornell Medical Center, New York, NY 10021. E-mail: jmp2007{at}med.cornell.edu

Relationship between extracellular matrix both in choroid plexus and the wall of lateral ventricles and intraventricular hemorrhage in preterm neonates

Pathogenesis of intraventricular hemorrhage (IVH) may relate to immature vessels. However extracellular matrix—such as Type IV collagen, laminin, and fibronectin has a direct bearing on the development of the endothelium and the immature microvessel. Twenty specimens taken from lateral ventricular walls and choroid plexus in 10 preterm neonates who died of intraventricular hemorrhage and another 10 preterm neonates who died of non-intraventricular hemorrhage, were marked with antibodies against Type IV collagen, laminin, and fibronectin. Average areas of positive staining around the microvessels in the IVH group showed less staining than that in the non-IVH group (P < 0.05), and the microvessel count of discontinuous positive staining in IVH group was more than that in non-IVH group, P < 0.05. We conclude that lacking Type IV collagen, laminin, and fibronectin may result not only in an incomplete basement membrane in choroid plexus and subependymal immature microvessels but also may be a factor contributing to IVH in preterm neonates. Clin. Anat. 13:422–428, 2000. © 2000 Wiley-Liss, Inc.

Relationship between extracellular matrix both in choroid plexus and the wall of lateral ventricles and intraventricular hemorrhage in preterm neonates.

Pathogenesis of intraventricular hemorrhage (IVH) may relate to immature vessels. However extracellular matrix--such as Type IV collagen, laminin, and fibronectin has a direct bearing on the development of the endothelium and the immature microvessel. Twenty specimens taken from lateral ventricular walls and choroid plexus in 10 preterm neonates who died of intraventricular hemorrhage and another 10 preterm neonates who died of non-intraventricular hemorrhage, were marked with antibodies against Type IV collagen, laminin, and fibronectin. Average areas of positive staining around the microvessels in the IVH group showed less staining than that in the non-IVH group (P < 0.05), and the microvessel count of discontinuous positive staining in IVH group was more than that in non-IVH group, P < 0.05. We conclude that lacking Type IV collagen, laminin, and fibronectin may result not only in an incomplete basement membrane in choroid plexus and subependymal immature microvessels but also may be a factor contributing to IVH in preterm neonates.

Radial glial interaction with cerebral germinal matrix capillaries in the fetal baboon

The occurrence of intraventricular hemorrhage (IVH) is a frequent problem in premature infants delivered between 24 (60%) and 32 weeks (80%) of gestation, a time during which the germinal matrix (GM) is prominent over the head of the caudate nucleus. Most IVH arises from the GM and it has been proposed that an important factor in the pathogenesis of IVH is a weakness of GM capillary walls due to deficient support by surrounding immature glial cells. The purpose of this study was to examine the glial-capillary interaction in the GM of fetal baboons sacrificed at 100 days (54%) gestation, a stage of GM development comparable to that during which human neonatal IVH occurs. Brains from a later gestational stage (162 days, 88%), after GM involution, were also examined. At 100 days of gestational age, the GM was prominent over the head of the caudate and contained vimentin positive, but not glial fibrillary acidic protein positive, radial glial cells which formed endfeet on capillaries in the region. Ultrastructurally, all the GM capillaries examined from this gestational time had complete, continuous endothelia marked by few pinocytotic vescicles and prominent tight junctions. The endothelial cells rested upon uninterrupted basement membranes which were contacted by clearly identifiable glial endfeet. These data show that GM capillaries have morphologies typical of CNS capillaries and suggest that the capillary immaturity within the GM is not a major contributing factor to IVH.

Etiology and Pathogenesis of Intraventricular Hemorrhage in Newborns

The article by Miall-Allen et al is an important contribution to the status of BP control and intracranial hemorrhage in the newborn. Until 10 years ago, there were limited methods of assessment. Hemorrhagic brain lesions were diagnosed mainly by clinical criteria and postmortem examination. In the late 1970s, CT scans provided much more in vivo information. However, CT scanning is inherently difficult in the newborn. Early machines produced a significant amount of radiation and the infants had to be transported to a radiology unit. These difficulties meant that a limited number of scans were done and children were rarely sequentially exposed.