Intraventricular haemorrhage in premature infants: the role of immature neuronal salt and water transport.

Intraventricular hemorrhage (IVH) is a common complication of premature birth. Survivors are often left with cerebral palsy, intellectual disability, and/or hydrocephalus. Animal models suggest that brain tissue shrinkage with subsequent vascular stretch and tear is an important step in the pathophysiology, but the cause of this shrinkage is unknown. Clinical risk factors for IVH are biomarkers of hypoxic-ischemic stress, which causes mature neurons to swell. However, immature neuronal volume might shift in the opposite direction under these conditions. This is because immature neurons express the chloride salt and water transporter NKCC1, which subserves regulatory volume increases in nonneural cells, whereas mature neurons express KCC2, which subserves regulatory volume decreases. When hypoxic ischemic conditions reduce active ion transport and increase the cytoplasmic membrane permeability, the effects of these transporters will be diminished. As a consequence, while mature neurons swell (cytotoxic edema) immature neurons might shrink. After hypoxic-ischemic stress, in vivo and in vitro multi-photon imaging of perinatal transgenic mice demonstrated shrinkage of viable immature neurons, bulk tissue shrinkage, and blood vessel displacement. Neuronal shrinkage was correlated with age-dependent membrane salt and water transporter expression using immunohistochemistry. Shrinkage of immature neurons was prevented by prior genetic or pharmacological inhibition of NKCC1 transport. These findings open new avenues of investigation for the detection of acute brain injury by neuroimaging, as well as prevention of neuronal shrinkage and the ensuing IVH, in premature infants.

Neurodevelopmental outcome in preterm infants with intraventricular hemorrhages: the potential of quantitative brainstem MRI.

OBJECTIVES: This retrospective study aimed to identify quantitative magnetic resonance imaging markers in the brainstem of preterm neonates with intraventricular hemorrhages. It delves into the intricate associations between quantitative brainstem magnetic resonance imaging metrics and neurodevelopmental outcomes in preterm infants with intraventricular hemorrhage, aiming to elucidate potential relationships and their clinical implications. MATERIALS AND METHODS: Neuroimaging was performed on preterm neonates with intraventricular hemorrhage using a multi-dynamic multi-echo sequence to determine T1 relaxation time, T2 relaxation time, and proton density in specific brainstem regions. Neonatal outcome scores were collected using the Bayley Scales of Infant and Toddler Development. Statistical analysis aimed to explore potential correlations between magnetic resonance imaging metrics and neurodevelopmental outcomes. RESULTS: Sixty preterm neonates (mean gestational age at birth 26.26 ± 2.69 wk; n = 24 [40%] females) were included. The T2 relaxation time of the midbrain exhibited significant positive correlations with cognitive (r = 0.538, P < 0.0001, Pearson's correlation), motor (r = 0.530, P < 0.0001), and language (r = 0.449, P = 0.0008) composite scores at 1 yr of age. CONCLUSION: Quantitative magnetic resonance imaging can provide valuable insights into neurodevelopmental outcomes after intraventricular hemorrhage, potentially aiding in identifying at-risk neonates. Multi-dynamic multi-echo sequence sequences hold promise as an adjunct to conventional sequences, enhancing the sensitivity of neonatal magnetic resonance neuroimaging and supporting clinical decision-making for these vulnerable patients.

Cesarean delivery is associated with lower neonatal mortality among breech pregnancies: a systematic review and meta-analysis of preterm deliveries ≤32 weeks of gestation.

OBJECTIVE: To investigate the association between actual and planned modes of delivery, neonatal mortality, and short-term outcomes among preterm pregnancies ≤32 weeks of gestation. DATA SOURCES: A systematic literature search was conducted in 3 main databases (PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to November 16, 2022. The protocol was registered in advance in the International Prospective Register of Systematic Reviews (CRD42022377870). STUDY ELIGIBILITY CRITERIA: Eligible studies examined pregnancies ≤32nd gestational week. All infants received active care, and the outcomes were reported separately by different modes of delivery. Singleton and twin pregnancies at vertex and breech presentations were included. Studies that included pregnancies complicated with preeclampsia and abruptio placentae were excluded. Primary outcomes were neonatal mortality and intraventricular hemorrhage. STUDY APPRAISAL AND SYNTHESIS METHODS: Articles were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random effects model-based odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes. Risk Of Bias In Non-randomized Studies - of Interventions-I was used to assess the risk of bias. RESULTS: A total of 19 observational studies were included involving a total of 16,042 preterm infants in this systematic review and meta-analysis. Actual cesarean delivery improves survival (odds ratio, 0.62; 95% confidence interval, 0.42-0.9) and decreases the incidence of intraventricular hemorrhage (odds ratio, 0.70; confidence interval, 0.57-0.85) compared to vaginal delivery. Planned cesarean delivery does not improve the survival of very and extremely preterm infants compared to vaginal delivery (odds ratio, 0.87; 95% confidence interval, 0.53-1.44). Subset analysis found significantly lower odds of death for singleton breech preterm deliveries born by both planned (odds ratio, 0.56; 95% confidence interval, 0.32-0.98) and actual (odds ratio, 0.34; 95% confidence interval, 0.13-0.88) cesarean delivery. CONCLUSION: Cesarean delivery should be the mode of delivery for preterm ≤32 weeks of gestation breech births due to the higher mortality in preterm infants born via vaginal delivery.

Expectant management of preeclampsia with severe features diagnosed at less than 24 weeks.

BACKGROUND: The recent American College of Obstetricians and Gynecologists Practice Bulletin offers no guidance on the management of preeclampsia with severe features at <24 weeks of gestation. Historically, immediate delivery was recommended because of poor perinatal outcomes and high maternal morbidity. Recently, advances in neonatal resuscitation have led to increased survival at periviable gestational ages. OBJECTIVE: This study aimed to report perinatal and maternal outcomes after expectant management of preeclampsia with severe features at <24 weeks of gestation. STUDY DESIGN: This was a retrospective case series of preeclampsia with severe features at <24 weeks of gestation at a level 4 center between 2017 and 2023. Individuals requiring delivery within 24 hours of diagnosis were excluded. Perinatal and maternal outcomes were analyzed. Categorical variables from our database were compared with previously published data using chi-square tests. RESULTS: A total of 41 individuals were diagnosed with preeclampsia with severe features at <24 weeks of gestation. After the exclusion of delivery within 24 hours, 30 individuals (73%) were evaluated. The median gestational age at diagnosis was 22 weeks (interquartile range, 22-23). Moreover, 16% of individuals had assisted reproductive technology, 27% of individuals had chronic hypertension, 13% of individuals had pregestational diabetes mellitus, 30% of individuals had previous preeclampsia, and 73% of individuals had a body mass index of >30 kg/m2. The median latency periods at 22 and 23 weeks of gestation were 7 days (interquartile range, 4-23) and 8 days (interquartile range, 4-13). In preeclampsia with severe features, neonatal survival rates were 44% (95% confidence interval, 3%-85%) at 22 weeks of gestation and 29% (95% confidence interval, 1%-56%) at 23 weeks of gestation. There were 2 cases of acute kidney injury (7%) and 2 cases of pericardial or pleural effusions (7%). Overall perinatal survival at <24 weeks of gestation was 30% in our current study vs 7% in previous reports (P=.02). CONCLUSION: For cases of expectant management of preeclampsia with severe features at <24 weeks of gestation, our findings showed an increased perinatal survival rate with decreased maternal morbidity compared with previously published data. This information may be used when counseling on expectant management of preeclampsia with severe features at <24 weeks of gestation.

Extracorporeal Membrane Oxygenation Before 34 Wks' Gestation: A Single-Center Experience.

INTRODUCTION: Traditionally, gestational age <34 wk and weight <2 kg are considered relative contraindications to extracorporeal membrane oxygenation (ECMO). There is a paucity of information that explains the outcomes in this unique population of premature neonates. The purpose of this study is to examine outcomes of patients who undergo ECMO at <34 wk at a single institution. METHODS: A single-center retrospective review was performed for neonates managed with ECMO in the neonatal intensive care unit from January 2012 to April 2022. Characteristics and outcome data were collected. The primary outcome studied was survival at discharge. Secondary outcomes were intraventricular hemorrhage, ischemic brain injury, and thrombosis. Data were analyzed with descriptive statistics. RESULTS: Following exclusion, 107 patients were included with eight having initiating ECMO at <34 wk. Three (38%) patients, who received ECMO at <34 wk, incurred intraventricular hemorrhages compared to 14 (14%) in the ≥34-wk cohort. Two (25%), who underwent ECMO at <34 wk, exhibited signs of brain ischemia on imaging compared to 9 (9%) in those ≥34 wk, and 3 (38%) patients <34 wk experienced thrombosis compared to 31 (31%) in the ≥34-wk cohort. Five (63%) of those in the <34-wk cohort survived to discharge, similar to 61 (61%) in the ≥34 wk cohort. CONCLUSIONS: Our data suggest that EGA <34 wk may not be a contraindication for ECMO, with appropriate counseling of potential risks.

Premature newborns with intraventricular hemorrhage do not have vasospasm pattern by cranial Doppler ultrasound: A pilot study.

Preterm neonates are at risk for neurodevelopmental impairment, especially those with intraventricular hemorrhage (IVH). Cerebral vasospasm (VSP) is a common complication after subarachnoid hemorrhage (SAH) in adult population, but it is unknown if preterm neonates with IVH may develop it. We prospectively enrolled premature newborns < 32 weeks with IVH and without IVH. All patients received serial transcranial sonography through the temporal window of the middle cerebral artery, anterior cerebral artery, posterior cerebral artery, and the internal carotid artery with transcranial Doppler sonography days 2, 4, and 10 of life. Cerebral blood velocities (CBFVs) were measured including median velocity flow (MV), peak systolic velocity (PSV), and maximum end-diastolic velocity (EDV). Resistance index and pulsatility index were calculated. VSP was defined as an increase of 50% in the baseline velocity per day and/or a Lindegaard ratio higher than 3. Fifty subjects were enrolled. None of the patients with IVH showed elevation of MV or a Lindegaard ratio > 3. There were no differences between IVH and without IVH groups regarding resistance index and pulsatility index.    Conclusion: Preterm infants with IVH do not present a pattern of VSP analyzed by Doppler transcranial ultrasound in this pilot study. What is Known: • In adult population with subarachnoid hemorrhage the most treatable cause of cerebral ischemia is due cerebral vasospasm but is unknown if premature newborn may have vasospasm due the extravasation of blood in the context of intraventricular hemorrhage What is New: •In this pilot study we did not find in premature newborn with intraventricular hemorrhage signs of vasoespam measured by transcranial color doppler ultrasound.

Impact of Early Hemodynamic Screening on Extremely Preterm Outcomes in a High-Performance Center.

Rationale: Increasing survival of extremely preterm infants with a stable rate of severe intraventricular hemorrhage represents a growing health risk for neonates. Objectives: To evaluate the role of early hemodynamic screening (HS) on the risk of death or severe intraventricular hemorrhage. Methods: All eligible patients 22-26+6 weeks' gestation born and/or admitted <24 hours postnatal age were included. As compared with standard neonatal care for control subjects (January 2010-December 2017), patients admitted in the second epoch (October 2018-April 2022) were exposed to HS using targeted neonatal echocardiography at 12-18 hours. Measurements and Main Results: A primary composite outcome of death or severe intraventricular hemorrhage was decided a priori using a 10% reduction in baseline rate to calculate sample size. A total of 423 control subjects and 191 screening patients were recruited with a mean gestation and birth weight of 24.7 ± 1.5 weeks and 699 ± 191 g, respectively. Infants born at 22-23 weeks represented 41% (n = 78) of the HS epoch versus 32% (n = 137) of the control subjects (P = 0.004). An increase in perinatal optimization (e.g., antepartum steroids) but with a decline in maternal health (e.g., increased obesity) was seen in the HS versus control epoch. A reduction in the primary outcome and each of severe intraventricular hemorrhage, death, death in the first postnatal week, necrotizing enterocolitis, and severe bronchopulmonary dysplasia was seen in the screening era. After adjustment for perinatal confounders and time, screening was independently associated with survival free of severe intraventricular hemorrhage (OR 2.09, 95% CI [1.19, 3.66]). Conclusions: Early HS and physiology-guided care may be an avenue to further improve neonatal outcomes; further evaluation is warranted.

The performance of the practices associated with the occurrence of severe intraventricular hemorrhage in the very premature infants: data analysis from the Chinese neonatal network.

BACKGROUND: The occurrence of severe intraventricular hemorrhage (sIVH) was high in the very preterm infants (VPIs) in China. The management strategies significantly contributed to the occurrence of sIVH in VPIs. However, the status of the perinatal strategies associated with sIVH for VPIs was rarely described across the multiple neonatal intensive care units (NICUs) in China. We aim to investigate the characteristics of the perinatal strategies associated with sIVH for VPIs across the multiple NICUs in China. METHODS: This was a retrospective analysis of data from a prospective cohort of Chinese Neonatal Network (CHNN) dataset, enrolling infants born at 24+0-31+6 from 2019 to 2021. Eleven perinatal practices performed within the first 3 days of life were investigated including antenatal corticosteroids use, antenatal magnesium sulphate therapy, intubation at birth, placental transfusion, need for advanced resuscitation, initial inhaled gas of 100% FiO2 in delivery room, initial invasive respiratory support, surfactant and caffeine administration, early enteral feeding, and inotropes use. The performances of these practices across the multiple NICUs were investigated using the standard deviations of differences between expected probabilities and observations. The occurrence of sIVH were compared among the NICUs. RESULTS: A total of 24,226 infants from 55 NICUs with a mean (SD) gestational age of 29.5 (1.76) and mean (SD) birthweight of 1.31(0.32) were included. sIVH was detected in 5.1% of VPIs. The rate of the antenatal corticosteroids, MgSO4 therapy, and caffeine was 80.0%, 56.4%, and 31.5%, respectively. We observed significant relationships between sIVH and intubation at birth (AOR 1.52, 95% CI 1.13 to 1.75) and initial invasive respiratory support (AOR 2.47, 95% CI 2.15 to 2.83). The lower occurrence of sIVH (4.8%) was observed corresponding with the highest utility of standard antenatal care, the lowest utility of invasive practices, and early enteral feeding administration. CONCLUSIONS: The current evidence-based practices were not performed in each VPI as expected among the studied Chinese NICUs. The higher utility of the invasive practices could be related to the occurrence of sIVH.

Regional variations in morbidity and mortality among neonates with intraventricular hemorrhage: a national database analysis.

BACKGROUND: Intraventricular hemorrhage (IVH) often affects newborns of low gestational age and low birth weight, requires critical care for neonates, and is linked to long-term neurodevelopmental outcomes. Assessing regional differences in the U.S. in care for neonatal IVH and subsequent outcomes can shed light on ways to mitigate socioeconomic disparities. METHODS: Using the 2016-2019 National Inpatient Sample (NIS), patients with a primary diagnosis of IVH were identified using ICD-10-CM codes. A retrospective cohort study was conducted with patients stratified by hospital region. Demographics, comorbidities, presentation, intraoperative variables, and inpatient outcomes were assessed. Multivariate logistic regression analyses were used to identify the impact of insurance status on extended LOS (defined as > 75th percentile of LOS), exorbitant cost (defined as > 75th percentile of cost), and mortality. RESULTS: Included in this study were 1630 newborns with IVH. A larger portion of patients in the South and Midwest were Black, compared to the Northeast and West (Northeast: 12.2% vs Midwest: 30.2% vs South: 22.8% vs West: 5.8%, p < 0.001), while a greater percentage of patients in the West and South were Hispanic (Northeast: 7.3% vs Midwest: 9.5% vs South: 22.8% vs West: 36.2%, p < 0.001). LOS was similar among all regions. Factors associated with prolonged LOS included hydrocephalus and CSF diversions. Median total cost of admission was highest in the West, while the South was associated with decreased odds of exorbitant cost. LOS was associated with exorbitant cost, and large bed-volume hospital, VLBW, and permanent CSF shunt were associated with mortality. CONCLUSIONS: Demographic variables, but not presenting or intraoperative variables, differed among regions, pointing to possible geographic health disparities. The West had the highest total cost of admission, while the South was associated with reduced odds of exorbitant admission costs.

Ratios of head circumference to ventricular size vary over time and predict eventual need for CSF diversion in intraventricular hemorrhage of prematurity.

PURPOSE: Intraventricular hemorrhage (IVH) of prematurity can lead to hydrocephalus, sometimes necessitating permanent cerebrospinal fluid (CSF) diversion. We sought to characterize the relationship between head circumference (HC) and ventricular size in IVH over time to evaluate the clinical utility of serial HC measurements as a metric in determining the need for CSF diversion. METHODS: We included preterm infants with IVH born between January 2000 and May 2020. Three measures of ventricular size were obtained: ventricular index (VI), Evan's ratio (ER), and frontal occipital head ratio (FOHR). The Pearson correlations (r) between the initial (at birth) paired measurements of HC and ventricular size were reported. Multivariable longitudinal regression models were fit to examine the HC:ventricle size ratio, adjusting for the age of the infant, IVH grade (I/II vs. III/IV), need for CSF diversion, and sex. RESULTS: A total of 639 patients with an average gestational age of 27.5 weeks were included. IVH grade I/II and grade III/IV patients had a positive correlation between initial HC and VI (r = 0.47, p < 0.001 and r = 0.48, p < 0.001, respectively). In our longitudinal models, patients with a low-grade IVH (I/II) had an HC:VI ratio 0.52 higher than those with a high-grade IVH (p-value < 0.001). Patients with low-grade IVH had an HC:ER ratio 12.94 higher than those with high-grade IVH (p-value < 0.001). Patients with low-grade IVH had a HC:FOHR ratio 12.91 higher than those with high-grade IVH (p-value < 0.001). Infants who did not require CSF diversion had an HC:VI ratio 0.47 higher than those who eventually did (p < 0.001). Infants without CSF diversion had an HC:ER ratio 16.53 higher than those who received CSF diversion (p < 0.001). Infants without CSF diversion had an HC:FOHR ratio 15.45 higher than those who received CSF diversion (95% CI (11.34, 19.56), p < 0.001). CONCLUSIONS: There is a significant difference in the ratio of HC:VI, HC:ER, and HC:FOHR size between patients with high-grade IVH and low-grade IVH. Likewise, there is a significant difference in HC:VI, HC:ER, and HC:FOHR between those who did and did not have CSF diversion. The routine assessments of both head circumference and ventricle size by ultrasound are important clinical tools in infants with IVH of prematurity.

Experience in endoscope choice for neuroendoscopic lavage for intraventricular hemorrhage of prematurity: a systematic review.

OBJECTIVE: Intraventricular hemorrhage (IVH) of prematurity occurs in 20-38% of infants born < 28 weeks gestational age and 15% of infants born in 28-32 weeks gestational age. Treatment has evolved from conservative management and CSF diversion of temporizing and shunting procedures to include strategies aimed at primarily clearing intraventricular blood products. Neuroendoscopic lavage (NEL) aims to decrease the intraventricular blood burden under the same anesthetic as temporizing CSF diversion measures in cases of hydrocephalus from IVH of prematurity. Given the variety of neuroendoscopes, we sought to review the literature and practical considerations to help guide neuroendoscope selection when planning NEL. METHODS: We conducted a systematic review of the literature on neuroendoscopic lavage in IVH of prematurity to examine data on the choice of neuroendoscope and outcomes regarding shunt rate. We then collected manufacturer data on neuroendoscopic devices, including inflow and outflow mechanisms, working channel specifications, and tools compatible with the working channel. We paired this information with the advantages and disadvantages reported in the literature and observations from the experiences of pediatric neurosurgeons from several institutions to provide a pragmatic evaluation of international clinical experience with each neuroendoscope in NEL. RESULTS: Eight studies were identified; four neuroendoscopes have been used for NEL as reported in the literature. These include the Karl Storz Flexible Neuroendoscope, LOTTA® system, GAAB system, and Aesculap MINOP® system. The LOTTA® and MINOP® systems were similar in setup and instrument options. Positive neuroendoscope features for NEL include increased degrees of visualization, better visualization with the evolution of light and camera sources, the ability to sterilize with autoclave processes, balanced inflow and outflow mechanisms via separate channels, and a working channel. Neuroendoscope disadvantages for NEL may include special sterilization requirements, large outer diameter, and limitations in working channels. CONCLUSIONS: A neuroendoscope integrating continuous irrigation, characterized by measured inflow and outflow via separate channels and multiple associated instruments, appears to be the most commonly used technology in the literature. As neuroendoscopes evolve, maximizing clear visualization, adequate inflow, measured outflow, and large enough working channels for paired instrumentation while minimizing the footprint of the outer diameter will be most advantageous when applied for NEL in premature infants.

Risk factors associated with intraventricular hemorrhage in very-low-birth-weight premature infants.

PURPOSE: To analyze the association between risk factors and severe intraventricular hemorrhage (grade II-IV) in PNB under 1500 g. METHODS: Multicenter, retrospective, analytical, case-control study in PNB under 34 weeks and under 1500 g admitted to the NICU. CASE: PNB with severe intraventricular hemorrhage (grade II-IV). Logistic regression analysis was used to adjust for IVH-associated variables and odds ratios (OR). RESULTS: A total of 90 PNB files were analyzed, 45 cases and 45 controls. The highest risk factors for severe IVH were lower gestational age (OR 1.3, p < 0.001), perinatal asphyxia (OR 12, p < 0.001), Apgar < 6 at minute 1 and 5 (OR 6.3, p < 0.001). CONCLUSION: Lower gestational age, birth asphyxia, Apgar score lower of 6, and respiratory-type factors are associated with increased risk for severe IVH.

Reduced racial disparities among newborns with intraventricular hemorrhage.

INTRODUCTION: Intraventricular hemorrhage (IVH) can ensue permanent neurologic dysfunction, morbidity, and mortality. While previous reports have identified disparities based on patient gender or weight, no prior study has assessed how race may influence in neonatal or infantile IVH patients. The aim of this study was to investigate the impact of race on adverse event (AE) rates, length of stay (LOS), and total cost of admission among newborns with IVH. METHODS: Using the 2016-2019 National Inpatient Sample database, newborns diagnosed with IVH were identified using ICD-10-CM codes. Patients were stratified based on race. Patient characteristics and inpatient outcomes were assessed. Multivariate logistic regression analyses were used to identify the impact of race on extended LOS and exorbitant cost. RESULTS: Of 1435 patients, 650 were White (45.3%), 270 African American (AA) (18.8%), 300 Hispanic (20.9%), and 215 Other (15.0%). A higher percentage of AA and Other patients than Hispanic and White patients were < 28 days old (p = 0.008). Each of the cohorts had largely similar presenting comorbidities and symptoms, although AA patients did have significantly higher rates of NEC (p < 0.001). There were no observed differences in rates of AEs, rates of mortality, mean LOS, or mean total cost of admission. Similarly, on multivariate analysis, no race was identified as a significant independent predictor of extended LOS or exorbitant cost. CONCLUSIONS: Our study found that in newborns with IVH, race is not associated with proxies of poor healthcare outcomes like prolonged LOS or excessive cost. Further studies are needed to validate these findings.

Practical techniques for safely removing long-term implanted ventricular catheters to minimize bleeding.

INTRODUCTION: Removing ventricular catheters, particularly those implanted for extended periods, poses significant challenges for neurosurgeons due to potential complications such as bleeding from adhesions to the ependyma or choroid plexus. OBJECTIVE: This study aimed to review various techniques for safely removing ventricular catheters, emphasizing methods that minimize the risk of hemorrhagic complications. METHODS: A comprehensive narrative review focused on techniques developed and documented in the literature for safely detaching ventricular catheters adhered to brain structures. RESULTS: Various techniques have been identified that enhance the safety of catheter removal. Notably, the use of monopolar diathermy to coagulate and release adhesions has proven effective. Innovations such as insulated suction devices and the strategic use of flexible endoscopes have also contributed to safer removal procedures, minimizing the risk of damaging surrounding cerebral tissue and preventing catastrophic hemorrhage. CONCLUSION: The removal of ventricular catheters, especially those with long-term implantation, requires precise and cautious techniques to avoid severe complications. The study underscores the importance of adopting advanced surgical techniques and the continuous evolution of safer practices in neurosurgery. These methods not only ensure patient safety but also facilitate the handling of potentially complex and life-threatening situations during catheter removal.

Continuous irrigation with thrombolytics for intraventricular hemorrhage: case-control study.

Intraventricular hemorrhage (IVH) is a complication of a spontaneous intracerebral hemorrhage. Standard treatment is with external ventricular drain (EVD). Intraventricular thrombolysis may improve mortality but does not improve functional outcomes. We present our initial experience with a novel irrigating EVD (IRRAflow) that automates continuous irrigation with thrombolysis.Single-center case-control study including patients with IVH treated with EVD compared to IRRAflow. We compared standard demographics, treatment, and outcome parameters between groups. We developed a brain phantom injected with a human clot and assessed clot clearance using EVD/IRRAflow approaches with CT imaging.Twenty-one patients were treated with standard EVD and 9 patients with IRRAflow. Demographics were similar between groups. Thirty-three percent of patients with EVD also had at least one dose of t-PA and 89% of patients with IRRAflow received irrigation with t-PA (p = 0.01). Mean drain days were 8.8 for EVD versus 4.1 for IRRAflow (p = 0.02). Days-to-clearance of ventricular outflow was 5.8 for EVD versus 2.5 for IRRAflow (p = 0.02). Overall clearance was not different. Thirty-seven percent of EVD patients achieved good outcome (mRS ≥ 3) at 90 days versus 86% of IRRAflow patients (p = 0.03). Assessing only t-PA, reduction in mean days-to-clearance (p = 0.0004) and ICU days (p = 0.04) was observed. In the benchtop model, the clot treated with IRRAflow and t-PA showed a significant reduction of volume compared to control.Irrigation with IRRAflow and t-PA is feasible and safe for patients with IVH. Improving clot clearance with IRRAflow may result in improved clinical outcomes and should be incorporated into randomized trials.

Cerebellar injury in preterm infants less than 28 weeks gestational age.

BACKGROUND: Cerebellar injury is one of the perinatal complications in preterm infants. Recent studies have highlighted the effect of perinatal complications on neurological morbidity. We investigated the perinatal risk factors and morbidity for cerebellar injury in extremely premature infants. METHODS: This retrospective cohort study included 285 infants born between April 2009 and December 2020 at gestational age <28 weeks at our institution. The infants were divided into two groups based on magnetic resonance imaging findings: those with and without cerebellar injury. We performed a statistical analysis of the perinatal background and short-term morbidity of the two groups. RESULTS: Significant differences (p < 0.05) were observed between the groups with respect to the perinatal background, especially gestational weeks, birthweight, and hemoglobin values at birth. In the short-term morbidity, significant differences (p < 0.05) were observed in the incidence of respiratory distress syndrome, chronic lung disease, hydrocephalus, severe intraventricular hemorrhage (IVH), and cerebellar hemorrhage. Extensive cerebellar lesions, such as cerebellar agenesis or global cerebellar hypoplasia, accounted for 11 of the 22 cases of cerebellar injury; seven of the 11 cases had severe IVH in addition to cerebellar hemorrhage. CONCLUSIONS: Gestational age was significantly lower in the cerebellar injury group. The combination of severe IVH and cerebellar hemorrhage may promote cerebellar injury.

Aquaporin 4 Mediates the Effect of Iron Overload on Hydrocephalus After Intraventricular Hemorrhage.

BACKGROUND: Iron overload plays an important role in hydrocephalus development following intraventricular hemorrhage (IVH). Aquaporin 4 (AQP4) participates in the balance of cerebrospinal fluid secretion and absorption. The current study investigated the role of AQP4 in the formation of hydrocephalus caused by iron overload after IVH. METHODS: There were three parts to this study. First, Sprague-Dawley rats received an intraventricular injection of 100 µl autologous blood or saline control. Second, rats had IVH and were treated with deferoxamine (DFX), an iron chelator, or vehicle. Third, rats had IVH and were treated with 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a specific AQP4 inhibitor, or vehicle. Rats underwent T2-weighted and T2* gradient-echo magnetic resonance imaging to assess lateral ventricular volume and intraventricular iron deposition at 7, 14, and 28 days after intraventricular injection and were then euthanized. Real-time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence analyses were conducted on the rat brains to evaluate the expression of AQP4 at different time points. Hematoxylin and eosin-stained brain sections were obtained to assess the ventricular wall damage on day 28. RESULTS: Intraventricular injection of autologous blood caused a significant ventricular dilatation, iron deposition, and ventricular wall damage. There was increased AQP4 mRNA and protein expression in the periventricular tissue in IVH rats through day 7 to day 28. The DFX treatment group had a lower lateral ventricular volume and less intraventricular iron deposition and ventricular wall damage than the vehicle-treated group after IVH. The expression of AQP4 protein in periventricular tissue was also inhibited by DFX on days 14 and 28 after IVH. The use of TGN-020 attenuated hydrocephalus development after IVH and inhibited the expression of AQP4 protein in the periventricular tissue between day 14 and day 28 without a significant effect on intraventricular iron deposition or ventricular wall damage. CONCLUSIONS: AQP4 located in the periventricular area mediated the effect of iron overload on hydrocephalus after IVH.

Association Between Neutrophil-Lymphocyte Ratio and 30-Day Infection and Thrombotic Outcomes After Intraventricular Hemorrhage: A CLEAR III Analysis.

BACKGROUND: Serum neutrophil-lymphocyte ratio (NLR) is a surrogate marker for the inflammatory response after intracerebral hemorrhage (ICH) and is associated with perihematomal edema and long-term functional outcomes. Whether NLR is associated with short-term ICH complications is poorly understood. We hypothesized that NLR is associated with 30-day infection and thrombotic events after ICH. METHODS: We performed a post hoc exploratory analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial. The study exposure was the serum NLR obtained at baseline and on days 3 and 5. The coprimary outcomes, ascertained at 30 days, were any infection and a thrombotic event, defined as composite of cerebral infarction, myocardial infarction, or venous thromboembolism; both infection and thrombotic event were determined through adjudicated adverse event reporting. Binary logistic regression was used to study the relationship between NLR and outcomes, after adjustment for demographics, ICH severity and location, and treatment randomization. RESULTS: Among the 500 patients enrolled in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III trial, we included 303 (60.6%) without missing data on differential white blood cell counts at baseline. There were no differences in demographics, comorbidities, or ICH severity between patients with and without data on NLR. In adjusted logistic regression models, NLR ascertained at baseline (odds ratio [OR] 1.03; 95% confidence interval [CI] 1.01-1.07, p = 0.03) and NLR ascertained at day 3 were associated with infection (OR 1.15; 95% CI 1.05-1.20, p = 0.001) but not with thrombotic events. Conversely, NLR at day 5 was associated with thrombotic events (OR 1.07, 95% CI 1.01-1.13, p = 0.03) but not with infection (OR 1.13; 95% CI 0.76-1.70, p = 0.56). NLR at baseline was not associated with either outcome. CONCLUSIONS: Serum NLR ascertained at baseline and on day 3 after randomization was associated with 30-day infection, whereas NLR obtained on day 5 was associated with thrombotic events after ICH, suggesting that NLR could be a potential early biomarker for ICH-related complications.

Pharmacologic Venous Thromboembolism Prophylaxis in Patients with Nontraumatic Subarachnoid Hemorrhage Requiring an External Ventricular Drain.

BACKGROUND: Optimal pharmacologic thromboprophylaxis dosing is not well described in patients with subarachnoid hemorrhage (SAH) with an external ventricular drain (EVD). Our patients with SAH with an EVD who receive prophylactic enoxaparin are routinely monitored using timed anti-Xa levels. Our primary study goal was to determine the frequency of venous thromboembolism (VTE) and secondary intracranial hemorrhage (ICH) for this population of patients who received pharmacologic prophylaxis with enoxaparin or unfractionated heparin (UFH). METHODS: A retrospective chart review was performed for all patients with SAH admitted to the neurocritical care unit at Emory University Hospital between 2012 and 2017. All patients with SAH who required an EVD were included. RESULTS: Of 1,351 patients screened, 868 required an EVD. Of these 868 patients, 627 received enoxaparin, 114 received UFH, and 127 did not receive pharmacologic prophylaxis. VTE occurred in 7.5% of patients in the enoxaparin group, 4.4% in the UFH group (p = 0.32), and 3.2% in the no VTE prophylaxis group (p = 0.08). Secondary ICH occurred in 3.83% of patients in the enoxaparin group, 3.51% in the UFH group (p = 1), and 3.94% in the no VTE prophylaxis group (p = 0.53). As steady-state anti-Xa levels increased from 0.1 units/mL to > 0.3 units/mL, there was a trend toward a lower incidence of VTE. However, no correlation was noted between rising anti-Xa levels and an increased incidence of secondary ICH. When compared, neither enoxaparin nor UFH use was associated with a significantly reduced incidence of VTE or an increased incidence of ICH. CONCLUSIONS: In this retrospective study of patients with nontraumatic SAH with an EVD who received enoxaparin or UFH VTE prophylaxis or no VTE prophylaxis, there was no statistically significant difference in the incidence of VTE or secondary ICH. For patients receiving prophylactic enoxaparin, achieving higher steady-state target anti-Xa levels may be associated with a lower incidence of VTE without increasing the risk of secondary ICH.

Current Status and Associated Factors of Post-Hemorrhagic Hydrocephalus in Infants of 22 to 28 Weeks Gestation With Severe Intraventricular Hemorrhage in Korea: A Nationwide Cohort Study.

BACKGROUND: Post-hemorrhagic hydrocephalus (PHH), a common complication of severe intraventricular hemorrhage (IVH) in very low birth weight (BW) infants, is associated with significant morbidity and poor neurological outcomes. The objective of this study was to assess the current status of PHH and analyze the risk factors associated with the necessity of treatment for PHH in infants born between 22 and 28 weeks of gestation, specifically those with severe IVH (grade 3 or 4). METHODS: The analysis was conducted on 1,097 infants who were born between 22-28 gestational weeks and diagnosed with severe IVH, using data from the Korean Neonatal Network. We observed that the prevalence of PHH requiring treatment was 46.3% in infants with severe IVH. RESULTS: Higher rates of mortality, transfer during admission, cerebral palsy, and ventriculoperitoneal shunt after discharge were higher in infants with PHH than in those without PHH. PHH in severe IVH was associated with a higher rate of pulmonary hemorrhage, seizures, and IVH grade 4 in the entire cohort. In addition, it was associated with a lower rate of small for gestational age and chorioamnionitis. In the subgroup analysis, high BW, outborn status, pulmonary hemorrhage, seizure, sepsis, and IVH grade 4 were associated with a higher incidence of PHH between 22 and 25 gestational weeks (GW). In infants born between 26 and 28 GW, a higher incidence of PHH was associated with seizures and IVH grade 4. CONCLUSION: It is necessary to maintain meticulous monitoring and neurological intervention for infants with PHH not only during admission but also after discharge. In addition, identifying the clinical factors that increase the likelihood of developing PHH from severe IVH is crucial.