Onset Of Intraventricular Hemorrhage Research Articles

A review on development of placental transfusion in term and preterm infants.

In recent years, it has been verified that placental transfusion can replenish blood volume of neonates, improve organ perfusion in the early postnatal stage, and facilitate the transition from fetal circulation to adult circulation. Meanwhile, placental transfusion can reduce the need for blood transfusion and the onset of intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, and other complications. Furthermore, it can improve the iron store and the long-term prognosis of central nervous system, and reduce infant mortality. Different methods have been used, including delayed cord clamping, intact umbilical cord milking, and cut umbilical cord milking. The World Health Organization (WHO) and other academic organizations recommend the routine use of delayed cord clamping at birth for the most vigorous term and preterm neonates. However, details of placental transfusion should be clarified, and the short/long-term impacts of this technology on some infants with special conditions still require further study.

Preterm Intraventricular Hemorrhage-Induced Inflammatory Response in Human Choroid Plexus Epithelial Cells.

Following an intraventricular hemorrhage (IVH), red blood cell lysis and hemoglobin (Hb) oxidation with the release of heme can cause sterile neuroinflammation. In this study, we measured Hb derivates and cellular adhesion molecules ICAM-1 and VCAM-1 with cell-free miRNAs in cerebrospinal fluid (CSF) samples obtained from Grade-III and Grade-IV preterm IVH infants (IVH-III and IVH-IV, respectively) at multiple time points between days 0–60 after the onset of IVH. Furthermore, human choroid plexus epithelial cells (HCPEpiCs) were incubated with IVH and non-IVH CSF (10 v/v %) for 24 h in vitro to investigate the IVH-induced inflammatory response that was investigated via: (i) HMOX1, IL8, VCAM1, and ICAM1 mRNAs as well as miR-155, miR-223, and miR-181b levels by RT-qPCR; (ii) nuclear translocation of the NF-κB p65 subunit by fluorescence microscopy; and (iii) reactive oxygen species (ROS) measurement. We found a time-dependent alteration of heme, IL-8, and adhesion molecules which revealed a prolonged elevation in IVH-IV vs. IVH-III with higher miR-155 and miR-181b expression at days 41–60. Exposure of HCPEpiCs to IVH CSF samples induced HMOX1, IL8, and ICAM1 mRNA levels along with increased ROS production via the NF-κB pathway activation but without cell death, as confirmed by the cell viability assay. Additionally, the enhanced intracellular miR-155 level was accompanied by lower miR-223 and miR-181b expression in HCPEpiCs after CSF treatment. Overall, choroid plexus epithelial cells exhibit an abnormal cell phenotype after interaction with pro-inflammatory CSF of IVH origin which may contribute to the development of later clinical complications in preterm IVH.

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.

The Role of Hemoglobin Oxidation Products in Triggering Inflammatory Response Upon Intraventricular Hemorrhage in Premature Infants.

Intraventricular hemorrhage (IVH) is a frequent complication of prematurity that is associated with high neonatal mortality and morbidity. IVH is accompanied by red blood cell (RBC) lysis, hemoglobin (Hb) oxidation, and sterile inflammation. Here we investigated whether extracellular Hb, metHb, ferrylHb, and heme contribute to the inflammatory response after IVH. We collected cerebrospinal fluid (CSF) (n = 20) from premature infants with grade III IVH at different time points after the onset of IVH. Levels of Hb, metHb, total heme, and free heme were the highest in CSF samples obtained between days 0 and 20 after the onset of IVH and were mostly non-detectable in CSF collected between days 41 and 60 of post-IVH. Besides Hb monomers, we detected cross-linked Hb dimers and tetramers in post-IVH CSF samples obtained in days 0–20 and 21–40, but only Hb tetramers were present in CSF samples obtained after 41–60 days. Vascular cell adhesion molecule-1 (VCAM-1) and interleukin-8 (IL-8) levels were higher in CSF samples obtained between days 0 and 20 than in CSF collected between days 41 and 60 of post-IVH. Concentrations of VCAM-1, intercellular adhesion molecule-1 (ICAM-1), and IL-8 strongly correlated with total heme levels in CSF. Applying the identified heme sources on human brain microvascular endothelial cells revealed that Hb oxidation products and free heme contribute to the inflammatory response. We concluded that RBC lysis, Hb oxidation, and heme release are important components of the inflammatory response in IVH. Pharmacological interventions targeting cell-free Hb, Hb oxidation products, and free heme could have potential to limit the neuroinflammatory response following IVH.

Venous Thromboembolism After Intraventricular Hemorrhage: Results From the CLEAR III Trial.

Venous thromboembolism (VTE) after intracerebral hemorrhage is well studied, but data on patients with spontaneous intraventricular hemorrhage (IVH) are limited. To study the factors associated with VTE, association between VTE and clinical outcomes in IVH, and safety of VTE chemoprophylaxis in IVH treated with intraventricular catheters and thrombolysis. Retrospective cohort study of patients enrolled in the CLEAR III trial, a multicenter, randomized trial comparing external ventricular drainage, with administration of intraventricular alteplase vs placebo, for obstructive IVH. Predictor variable was incident VTE in the first 30 d. Outcome measures were factors associated with VTE, and death/severe disability (modified Rankin Score 4-6) at 6 mo. Of the 500 patients with IVH, VTE occurred in 59 patients (11.8%) within the first 30 d. VTE chemoprophylaxis was initiated in 412 (82.4%) patients, but before VTE diagnosis in only 401 (80.2%) at median of 4 d (interquartile range, 1-8) from IVH onset, and was not associated with intracranial bleeding or catheter tract hemorrhage. In the multivariate logistic regression analysis, infection within 30 d (odds ratio, 1.80; confidence interval, 1.03-3.17) was significantly associated with higher odds of VTE occurrence. Starting VTE chemoprophylaxis after 72 h was additionally associated with VTE occurrence after the first week. Infection and delay in timely initiation of VTE chemoprophylaxis were associated with VTE occurrence. VTE chemoprophylaxis in IVH appears safe and should not be delayed beyond standard care policies for ICH including when intraventricular catheter placement and thrombolytic therapy are performed.

Hyaluronidase and Hyaluronan Oligosaccharides Promote Neurological Recovery after Intraventricular Hemorrhage.

Intraventricular hemorrhage (IVH) in premature infants results in inflammation, arrested oligodendrocyte progenitor cell (OPC) maturation, and reduced myelination of the white matter. Hyaluronan (HA) inhibits OPC maturation and complexes with the heavy chain (HC) of glycoprotein inter-α-inhibitor to form pathological HA (HC-HA complex), which exacerbates inflammation. Therefore, we hypothesized that IVH would result in accumulation of HA, and that either degradation of HA by hyaluronidase treatment or elimination of HCs from pathological HA by HA oligosaccharide administration would restore OPC maturation, myelination, and neurological function in survivors with IVH. To test these hypotheses, we used the preterm rabbit model of glycerol-induced IVH and analyzed autopsy samples from premature infants. We found that total HA levels were comparable in both preterm rabbit pups and human infants with and without IVH, but HA receptors--CD44, TLR2, TLR4--were elevated in the forebrain of both humans and rabbits with IVH. Hyaluronidase treatment of rabbits with IVH reduced CD44 and TLR4 expression, proinflammatory cytokine levels, and microglia infiltration. It also promoted OPC maturation, myelination, and neurological recovery. HC-HA and tumor necrosis factor-stimulated gene-6 were elevated in newborns with IVH; and depletion of HC-HA levels by HA oligosaccharide treatment reduced inflammation and enhanced myelination and neurological recovery in rabbits with IVH. Hence, hyaluronidase or HA oligosaccharide treatment represses inflammation, promotes OPC maturation, and restores myelination and neurological function in rabbits with IVH. These therapeutic strategies might improve the neurological outcome of premature infants with IVH. Significance statement: Approximately 12,000 premature infants develop IVH every year in the United States, and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The onset of IVH induces inflammation of the periventricular white matter, which results in arrested maturation of OPCs and myelination failure. HA is a major component of the extracellular matrix of the brain, which regulates inflammation through CD44 and TLR2/4 receptors. Here, we show two mechanism-based strategies that effectively enhanced myelination and neurological recovery in preterm rabbit model of IVH. First, degrading HA by hyaluronidase treatment reduced CD44 and TLR4 expression, proinflammatory cytokines, and microglial infiltration, as well as promoted oligodendrocyte maturation and myelination. Second, intraventricular injection of HA oligosaccharide reduced inflammation and enhanced myelination, conceivably by depleting HC-HA levels.

Delayed neural degeneration following gamma knife radiosurgery in a patient with an arteriovenous malformation: A diffusion tensor imaging study

Gamma knife surgery (GKS) is a proven modality for the treatment of arteriovenous malformations (AVMs), but neural degeneration is a serious complication of GKS. In this study, we report on a patient who displayed delayed neural degeneration following GKR, using diffusion tensor imaging (DTI). A 43-year-old male patient was diagnosed with an intraventricular hemorrhage (IVH) due to rupture of an AVM in the right middle cerebellar peduncle, and exhibited cognitive impairment, quadriparesis, and ataxia after IVH onset. He underwent GKS 5 weeks after onset. Brain MRIs performed at 6 weeks, 7 months, and 21 months post-onset revealed encephalomalactic lesions in the right pons, middle cerebellar peduncle, and medulla oblongata. DTI at 6 weeks post-onset suggested neural injuries of the right corticospinal tract (CST), right middle cerebellar peduncle (MCP), and right inferior cerebellar peduncle (ICP). DTI at 7 months suggested that the right CST and right ICP had recovered to some extent, which concurred with improved clinical manifestations. However, at 21 months, four neural tracts (right CST, right MCP, and both ICPs) appeared to have degenerated, which was in-line with aggravation of corresponding clinical manifestations. Experiences of this patient suggest DTI is a useful technique for the detection of neural degeneration after GKS.

Periventricular White Matter Injury by Primary Intraventricular Hemorrhage: A Diffusion Tensor Imaging Study

Objectives: Intraventricular hemorrhage (IVH) in adult stroke patients is known to be an independent risk factor for poor functional outcome. Using diffusion tensor imaging (DTI), we attempted to investigate the effect of IVH on the white matter. Methods: We recruited 10 consecutive patients with IVH and 18 age- and sex-matched control subjects. Using a 1.5-T Philips Gyroscan Intera system, DTI data was acquired at an average of 84 days (range: 38–149) after IVH onset. We measured fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values at the fornix, corpus callosum (CC), corona radiata (CR), and posterior limb of the internal capsule (PL). In addition, integrity and fiber number were measured for the fornix. Results: DTI revealed disruption of the fornix in all patients. FA values showed a decrease in the fornix, CC, and CR; in contrast, the ADC value showed an increase in the CC, without changes in the fornix or CR. Fiber number of the fornix also decreased. However, no change was observed in the PL. Conclusions: We found periventricular white matter (fornix, CC, and CR) injury following IVH. We think that this result would be helpful in the establishment of management strategies for patients with IVH.

Early-onset intraventricular hemorrhage in preterm neonates: Incidence of neurodevelopmental handicap

The neurodevelopmental outcome of very low birth weight infants experiencing early-onset intraventricular hemorrhage (IVH) occurring within the first 6 postnatal hours was compared with that of their peers without early-onset IVH at 3 years corrected age. The 440 surviving preterm infants (birth weight 600 to 1,250 g) who had been enrolled in a multicenter, prospectively randomized, controlled trial evaluating the efficacy of postnatal indomethacin to prevent IVH were evaluated with the Stanford-Binet Intelligence Scale and neurological examinations at 3 years corrected age. All study infants had echoencephalography between 5 and 11 hours of life, and testing is reported for all children residing in English monolingual households at 3 years corrected age (i.e., from the obstetric due date). Fifty five of the 73 (75%) infants with IVH within the first 5 to 11 hours survived to 3 years of age, compared with 385 of the 432 (89%) children without early-onset hemorrhage who were alive at 3 years corrected age (P<.001). Eleven of the 29 (38%) English monolingual children with early-onset IVH had Stanford-Binet intelligence quotient scores of less than 70, compared with 47 of the 249 (19%) children without early IVH (P = .03). Similarly, 7 of 28 (25%) early IVH children were found to have cerebral palsy, compared with 20 of 241 (8%) children without early IVH (P = .01). These data suggest that infants who experience the early onset of IVH are at high risk for both cognitive and motor handicaps at 3 years corrected age.