Riesgo de hemorragia cerebral en el traumatismo craneal leve y tratamiento antitrombótico / Risk of cerebral hemorrhage in mild traumatic brain injury and antithrombotic treatment

Objetivo El tiempo de observación en el traumatismo craneoencefálico leve (TCEL) es controvertido. Nuestro objetivo se basó en evaluar el riesgo de complicaciones neurológicas en el TCEL con y sin tratamiento antitrombótico. Método Evaluamos retrospectivamente los pacientes con TCEL atendidos en urgencias durante 3 años. Consideramos TCEL aquellos con Glasgow ≥13 al ingreso. Se realizó una TC craneal en todos los casos con >1 factor de riesgo al ingreso y a las 24h en aquellos con deterioro neurológico o TC craneal inicial patológica. Se revisó retrospectivamente las complicaciones en los siguientes 3 meses. Resultados Evaluamos 907 pacientes con una edad media de 73±19 años. El 91% presentaron factores de riesgo, con un 60% en tratamiento antitrombótico. Detectamos un 11% de hemorragia cerebral inicial, 0,4% a las 24h y ningún caso a los 3 meses. El tratamiento antitrombótico no se asoció con incremento de riesgo de hemorragia cerebral (9,9 con vs. 11,9% sin tratamiento; p=0,3). El 39% de las hemorragias presentaron síntomas neurológicos (18% amnesia postraumática, 12% cefalea, 8% vómitos, 1% convulsiones), siendo en un 78,4% síntomas leves. De las 4 hemorragias detectadas a las 24h, 3 fueron asintomáticas y un caso emporó la cefalea inicial. Ningún paciente asintomático sin lesión en la TC craneal inicial presentó clínica a las 24h. Conclusiones Nuestro estudio sugiere que los pacientes con TCEL asintomáticos, sin lesión en la TC craneal inicial no precisarían periodo de observación ni TC craneal de control, independientemente del tratamiento antitrombótico o nivel de INR (AU)

Introduction The observation time in mild traumatic brain injury (mTBI) is controversial. Our aim was to assess the risk of neurological complications in mTBI with and without antithrombotic treatment. Method We retrospectively evaluated patients with mTBI seen in the emergency room for 3 years. We considered MTBI those with Glasgow ≥13 at admission. A cranial CT was performed in all cases with >1 risk factor at admission and at 24h in those with neurological impairment or initial pathological cranial CT. Complications in the following 3 months were retrospectively reviewed. Results We evaluated 907 patients with a mean age of 73±19 years. Ninety-one percent presented risk factors, with 60% on antithrombotic treatment. We detected 11% of initial brain hemorrhage, 0.4% at 24h, and no cases at 3 months. Antithrombotic treatment was not associated with an increased risk of brain hemorrhage (9.9% with vs. 11.9% without treatment, P=.3). 39% of the hemorrhages presented neurological symptoms (18% post-traumatic amnesia, 12% headache, 8% vomiting, 1% seizures), with 78.4% having mild symptoms. Of the 4 hemorrhages detected at 24h, 3 were asymptomatic and one case that worsened the initial headache. No asymptomatic patient without lesion on initial clinical cranial CT presented at 24h. Conclusions Our study suggests that patients with asymptomatic mTBI, without a lesion on the initial cranial CT, would not require the observation period or CT control regardless of antithrombotic treatment or INR level (AU)

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.

Reducing Severe Intraventricular Hemorrhage in Preterm Infants With Improved Care Bundle Adherence.

BACKGROUND AND OBJECTIVES: Intraventricular hemorrhage prevention bundles (IVHPBs) can decrease the incidence of intraventricular hemorrhage (IVH) in premature infants. Our center had a high rate of severe (grade III/IV) IVH (9.8%), and poor adherence (24%) to an IVHPB in neonates born ≤1250 g or ≤30 gestational weeks. Improvement initiatives were planned to decrease the incidence of severe IVH by 30% over 2 years. METHODS: A multidisciplinary team undertook interventions including in-service training, prompt initiation of IVHPB, revision of guidelines, and process standardization. Baseline data were collected from May 2016 to June 2018, with interventions occurring from July 2018 to May 2020. Adherence to the IVHPB was the primary process measure, and incidence of severe IVH the primary outcome measure. Control charts were used to analyze the effect of interventions on outcome. Balancing measures included use of breast milk at discharge, use of mechanical ventilation after initial resuscitation, and bronchopulmonary dysplasia. RESULTS: A total of 240 infants were assessed preintervention, and 185 during interventions. Adherence to the IVHPB improved from 24% to 88%. During this period, the incidence of severe IVH decreased from 9.8% to 2.4%, a 76% reduction from baseline. A higher adherence score was associated with reduced odds of IVH (odds ratio 0.30; 95% confidence interval 0.10-0.90, P = .03). CONCLUSIONS: Interventions focused on enhancing adherence to an IVHPB were associated with a reduced rate of severe IVH in high-risk neonates, highlighting the importance of assessing adherence to clinical guidelines.

Pharmacological pain and sedation interventions for the prevention of intraventricular hemorrhage in preterm infants on assisted ventilation - an overview of systematic reviews.

BACKGROUND: Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) may contribute to neonatal morbidity and mortality and result in long-term neurodevelopmental sequelae. Appropriate pain and sedation management in ventilated preterm infants may decrease the risk of GMH-IVH; however, it might be associated with harms. OBJECTIVES: To summarize the evidence from systematic reviews regarding the effects and safety of pharmacological interventions related to pain and sedation management in order to prevent GMH-IVH in ventilated preterm infants. METHODS: We searched the Cochrane Library August 2022 for reviews on pharmacological interventions for pain and sedation management to prevent GMH-IVH in ventilated preterm infants (< 37 weeks' gestation). We included Cochrane Reviews assessing the following interventions administered within the first week of life: benzodiazepines, paracetamol, opioids, ibuprofen, anesthetics, barbiturates, and antiadrenergics. Primary outcomes were any GMH-IVH (aGMH-IVH), severe IVH (sIVH), all-cause neonatal death (ACND), and major neurodevelopmental disability (MND). We assessed the methodological quality of included reviews using the AMSTAR-2 tool. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included seven Cochrane Reviews and one Cochrane Review protocol. The reviews on clonidine and paracetamol did not include randomized controlled trials (RCTs) matching our inclusion criteria. We included 40 RCTs (3791 infants) from reviews on paracetamol for patent ductus arteriosus (3), midazolam (3), phenobarbital (9), opioids (20), and ibuprofen (5). The quality of the included reviews was high. The certainty of the evidence was moderate to very low, because of serious imprecision and study limitations. Germinal matrix hemorrhage-intraventricular hemorrhage (any grade) Compared to placebo or no intervention, the evidence is very uncertain about the effects of paracetamol on aGMH-IVH (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.38 to 2.07; 2 RCTs, 82 infants; very low-certainty evidence); midazolam may result in little to no difference in the incidence of aGMH-IVH (RR 1.68, 95% CI 0.87 to 3.24; 3 RCTs, 122 infants; low-certainty evidence); the evidence is very uncertain about the effect of phenobarbital on aGMH-IVH (RR 0.99, 95% CI 0.83 to 1.19; 9 RCTs, 732 infants; very low-certainty evidence); opioids may result in little to no difference in aGMH-IVH (RR 0.85, 95% CI 0.65 to 1.12; 7 RCTs, 469 infants; low-certainty evidence); ibuprofen likely results in little to no difference in aGMH-IVH (RR 0.99, 95% CI 0.81 to 1.21; 4 RCTs, 759 infants; moderate-certainty evidence). Compared to ibuprofen, the evidence is very uncertain about the effects of paracetamol on aGMH-IVH (RR 1.17, 95% CI 0.31 to 4.34; 1 RCT, 30 infants; very low-certainty evidence). Compared to midazolam, morphine may result in a reduction in aGMH-IVH (RR 0.28, 95% CI 0.09 to 0.87; 1 RCT, 46 infants; low-certainty evidence). Compared to diamorphine, the evidence is very uncertain about the effect of morphine on aGMH-IVH (RR 0.65, 95% CI 0.40 to 1.07; 1 RCT, 88 infants; very low-certainty evidence). Severe intraventricular hemorrhage (grade 3 to 4) Compared to placebo or no intervention, the evidence is very uncertain about the effect of paracetamol on sIVH (RR 1.80, 95% CI 0.43 to 7.49; 2 RCTs, 82 infants; very low-certainty evidence) and of phenobarbital (grade 3 to 4) (RR 0.91, 95% CI 0.66 to 1.25; 9 RCTs, 732 infants; very low-certainty evidence); opioids may result in little to no difference in sIVH (grade 3 to 4) (RR 0.98, 95% CI 0.71 to 1.34; 6 RCTs, 1299 infants; low-certainty evidence); ibuprofen may result in little to no difference in sIVH (grade 3 to 4) (RR 0.82, 95% CI 0.54 to 1.26; 4 RCTs, 747 infants; low-certainty evidence). No studies on midazolam reported this outcome. Compared to ibuprofen, the evidence is very uncertain about the effects of paracetamol on sIVH (RR 2.65, 95% CI 0.12 to 60.21; 1 RCT, 30 infants; very low-certainty evidence). Compared to midazolam, the evidence is very uncertain about the effect of morphine on sIVH (grade 3 to 4) (RR 0.08, 95% CI 0.00 to 1.43; 1 RCT, 46 infants; very low-certainty evidence). Compared to fentanyl, the evidence is very uncertain about the effect of morphine on sIVH (grade 3 to 4) (RR 0.59, 95% CI 0.18 to 1.95; 1 RCT, 163 infants; very low-certainty evidence). All-cause neonatal death Compared to placebo or no intervention, the evidence is very uncertain about the effect of phenobarbital on ACND (RR 0.94, 95% CI 0.51 to 1.72; 3 RCTs, 203 infants; very low-certainty evidence); opioids likely result in little to no difference in ACND (RR 1.12, 95% CI 0.80 to 1.55; 5 RCTs, 1189 infants; moderate-certainty evidence); the evidence is very uncertain about the effect of ibuprofen on ACND (RR 1.00, 95% CI 0.38 to 2.64; 2 RCTs, 112 infants; very low-certainty evidence). Compared to midazolam, the evidence is very uncertain about the effect of morphine on ACND (RR 0.31, 95% CI 0.01 to 7.16; 1 RCT, 46 infants; very low-certainty evidence). Compared to diamorphine, the evidence is very uncertain about the effect of morphine on ACND (RR 1.17, 95% CI 0.43 to 3.19; 1 RCT, 88 infants; very low-certainty evidence). Major neurodevelopmental disability Compared to placebo, the evidence is very uncertain about the effect of opioids on MND at 18 to 24 months (RR 2.00, 95% CI 0.39 to 10.29; 1 RCT, 78 infants; very low-certainty evidence) and at five to six years (RR 1.6, 95% CI 0.56 to 4.56; 1 RCT, 95 infants; very low-certainty evidence). No studies on other drugs reported this outcome. AUTHORS' CONCLUSIONS: None of the reported studies had an impact on aGMH-IVH, sIVH, ACND, or MND. The certainty of the evidence ranged from moderate to very low. Large RCTs of rigorous methodology are needed to achieve an optimal information size to assess the effects of pharmacological interventions for pain and sedation management for the prevention of GMH-IVH and mortality in preterm infants. Studies might compare interventions against either placebo or other drugs. Reporting of the outcome data should include the assessment of GMH-IVH and long-term neurodevelopment.

Low-Dose Aspirin and the Risk of Stroke and Intracerebral Bleeding in Healthy Older People: Secondary Analysis of a Randomized Clinical Trial.

Importance: Low-dose aspirin has been widely used for primary and secondary prevention of stroke. The balance between potential reduction of ischemic stroke events and increased intracranial bleeding has not been established in older individuals. Objective: To establish the risks of ischemic stroke and intracranial bleeding among healthy older people receiving daily low-dose aspirin. Design, Setting, and Participants: This secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, double-blind, placebo-controlled trial of daily low-dose aspirin was conducted among community-dwelling people living in Australia or the US. Participants were older adults free of symptomatic cardiovascular disease. Recruitment took place between 2010 and 2014, and participants were followed up for a median (IQR) of 4.7 (3.6-5.7) years. This analysis was completed from August 2021 to March 2023. Interventions: Daily 100-mg enteric-coated aspirin or matching placebo. Main Outcomes and Measures: Stroke and stroke etiology were predetermined secondary outcomes and are presented with a focus on prevention of initial stroke or intracranial bleeding event. Outcomes were assessed by review of medical records. Results: Among 19 114 older adults (10 782 females [56.4%]; median [IQR] age, 74 [71.6-77.7] years), 9525 individuals received aspirin and 9589 individuals received placebo. Aspirin did not produce a statistically significant reduction in the incidence of ischemic stroke (hazard ratio [HR], 0.89; 95% CI, 0.71-1.11). However, a statistically significant increase in intracranial bleeding was observed among individuals assigned to aspirin (108 individuals [1.1%]) compared with those receiving placebo (79 individuals [0.8%]; HR, 1.38; 95% CI, 1.03-1.84). This occurred by an increase in a combination of subdural, extradural, and subarachnoid bleeding with aspirin compared with placebo (59 individuals [0.6%] vs 41 individuals [0.4%]; HR, 1.45; 95% CI, 0.98-2.16). Hemorrhagic stroke was recorded in 49 individuals (0.5%) assigned to aspirin compared with 37 individuals (0.4%) in the placebo group (HR, 1.33; 95% CI, 0.87-2.04). Conclusions and Relevance: This study found a significant increase in intracranial bleeding with daily low-dose aspirin but no significant reduction of ischemic stroke. These findings may have particular relevance to older individuals prone to developing intracranial bleeding after head trauma. Trial Registration: ISRCTN.org Identifier: ISRCTN83772183.

Indomethacin Prophylaxis Is Associated with Reduced Risk of Intraventricular Hemorrhage in Extremely Preterm Infants Born in the Context of Amniotic Infection Syndrome.

BACKGROUND: Amniotic infection syndrome (AIS) with perinatal inflammation may increase the susceptibility to intraventricular hemorrhage (IVH) in preterm infants. Given its anti-inflammatory and ductus arteriosus constricting capacities, we hypothesized that prophylactic administration of indomethacin reduces the incidence, severity, and consequences of IVH in the context of perinatal inflammation. METHODS: We evaluated data of infants born between 2009 and 2020 of 22 + 0-25+6 weeks of gestation from 68 German Neonatal Network centers. The effect of indomethacin prophylaxis on outcomes was analyzed in univariate analyses and multivariate regression models including a subgroup of infants with available data on 5-year follow-up. RESULTS: 4760 infants were included with a median gestational age of 24.6 SSW [interquartile range (IQR) 24.1w-25.2w] and a birth weight of 640 g [IQR 550-750 g]. 1767/4760 (37.1%) preterm infants were born in the context of AIS and 527/4760 (11.1%) received indomethacin prophylaxis. AIS infants receiving prophylactic indomethacin had lower rates of IVH (32.7% vs. 36.9%, p = 0.04), IVH III/IV (9.7% vs. 16.0%, p = 0.02) and the combined outcome of severe IVH or death (15.9% vs. 23.2%, p = 0.01) as compared to infants without prophylaxis. Multivariate logistic regression analyses confirmed our observations. In a subgroup analysis of 730 preterm infants at 5 years of age, we did not find any correlation between prophylactic indomethacin and intelligence quotient <70 or cerebral palsy. CONCLUSIONS: Our observational data demonstrate that prophylactic indomethacin is associated with a reduced risk of IVH in the highly vulnerable subgroup of preterm infants <26 weeks of gestation born from AIS.

Postnatal phenobarbital for the prevention of intraventricular haemorrhage in preterm infants.

BACKGROUND: Intraventricular haemorrhage (IVH) is a major complication of preterm birth. Large haemorrhages are associated with a high risk of disability and hydrocephalus. Instability of blood pressure and cerebral blood in the newborn flow are postulated as causative factors. Another mechanism may involve reperfusion damage from oxygen free radicals. It has been suggested that phenobarbital stabilises blood pressure and may protect against free radicals. This is an update of a review first published in 2001 and updated in 2007 and 2013. OBJECTIVES: To assess the benefits and harms of the postnatal administration of phenobarbital in preterm infants at risk of developing IVH compared to control (i.e. no intervention or placebo). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL and clinical trial registries in January 2022. A new, more sensitive search strategy was developed, and searches were conducted without date limits.  SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs in which phenobarbital was given within the first 24 hours of life to preterm infants identified as being at risk of IVH because of gestational age below 34 weeks, birth weight below 1500 g or respiratory failure. Phenobarbital was compared to no intervention or placebo. We excluded infants with serious congenital malformations. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were all grades of IVH and severe IVH (i.e. grade III and IV); secondary outcomes were ventricular dilation or hydrocephalus, hypotension, pneumothorax, hypercapnia, acidosis, mechanical ventilation, neurodevelopmental impairment and death. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 10 RCTs (792 infants). The evidence suggests that phenobarbital results in little to no difference in the incidence of IVH of any grade compared with control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.84 to 1.19; risk difference (RD) 0.00, 95% CI -0.06 to 0.07; I² for RD = 65%; 10 RCTs, 792 participants; low certainty evidence) and in severe IVH (RR 0.88, 95% CI 0.64 to 1.21; 10 RCTs, 792 participants; low certainty evidence). The evidence is very uncertain about the effect of phenobarbital on posthaemorrhagic ventricular dilation or hydrocephalus (RR 0.62, 95% CI 0.31 to 1.26; 4 RCTs, 271 participants; very low certainty evidence), mild neurodevelopmental impairment (RR 0.57, 95% CI 0.15 to 2.17; 1RCT, 101 participants; very low certainty evidence), and severe neurodevelopmental impairment (RR 1.12, 95% CI 0.44 to 2.82; 2 RCTs, 153 participants; very low certainty evidence). Phenobarbital may result in little to no difference in death before discharge (RR 0.88, 95% CI 0.64 to 1.21; 9 RCTs, 740 participants; low certainty evidence) and mortality during study period (RR 0.98, 95% CI 0.72 to 1.33; 10 RCTs, 792 participants; low certainty evidence) compared with control. We identified no ongoing trials. AUTHORS' CONCLUSIONS: The evidence suggests that phenobarbital results in little to no difference in the incidence of IVH (any grade or severe) compared with control (i.e. no intervention or placebo). The evidence is very uncertain about the effects of phenobarbital on ventricular dilation or hydrocephalus and on neurodevelopmental impairment. The evidence suggests that phenobarbital results in little to no difference in death before discharge and all deaths during the study period compared with control. Since 1993, no randomised studies have been published on phenobarbital for the prevention of IVH in preterm infants, and no trials are ongoing. The effects of postnatal phenobarbital might be assessed in infants with both neonatal seizures and IVH, in both randomised and observational studies. The assessment of benefits and harms should include long-term outcomes.

[Intracerebral Hemorrhage]. / Intrazerebrale Blutungen.

Intracerebral hemorrhage (ICB) causes approximately 12% of all strokes in Germany and 9-27% of all strokes worldwide 1 2. Epidemiological studies show a decrease in younger individuals mainly due to better antihypertensive management, but there is also an increase in incidence in older individuals due to cerebral amyloid angiopathy and increasing use of anticoagulants 3.

Secondary prevention after intracerebral haemorrhage.

BACKGROUND: Intracerebral haemorrhage (ICH) has high mortality in the acute phase and poor functional outcome in the majority of survivors. ICH recurrence is a major determinant of long-term prognosis and is the most feared complication of antithrombotic treatment. On the other hand, ICH patients are at high risk of future ischaemic vascular events. METHODS: This narrative review provides a critical analysis of the current knowledge on the topic. We performed a Pubmed search with the following terms 'intracerebral haemorrhage', 'stroke', 'outcome', 'secondary prevention', 'anticoagulation' and 'atrial fibrillation', including only English written studies with no time restrictions. RESULTS: Blood pressure management is the cornerstone of secondary ICH prevention, regardless of ICH location or underlying cerebral small vessel disease. Resumption of antiplatelet and anticoagulation therapy is often challenging, with limited evidence from randomized trials. Clinical and imaging predictors can inform the stratification of ICH recurrence risk and might identify patients at very high probability of future haemorrhagic events. This narrative review provides a summary of the main diagnostic tools and therapeutic strategies available for secondary prevention in ICH survivors. CONCLUSION: Appropriate recognition and treatment of modifiable risk factors for ICH recurrence might improve outcomes in ICH survivors. Ongoing randomized trials might provide novel insights and improve long-term management.

Stem cell-based interventions for the prevention and treatment of intraventricular haemorrhage and encephalopathy of prematurity in preterm infants.

BACKGROUND: Germinal matrix-intraventricular haemorrhage (GMH-IVH) and encephalopathy of prematurity (EoP) remain substantial issues in neonatal intensive care units worldwide. Current therapies to prevent or treat these conditions are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies. This is an update of the 2019 review, which did not include EoP. OBJECTIVES: To evaluate the benefits and harms of stem cell-based interventions for prevention or treatment of GM-IVH and EoP in preterm infants. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was April 2022. SELECTION CRITERIA: We attempted to include randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing 1. stem cell-based interventions versus control; 2. mesenchymal stromal cells (MSCs) of type or source versus MSCs of other type or source; 3. stem cell-based interventions other than MSCs of type or source versus stem cell-based interventions other than MSCs of other type or source; or 4. MSCs versus stem cell-based interventions other than MSCs. For prevention studies, we included extremely preterm infants (less than 28 weeks' gestation), 24 hours of age or less, without ultrasound diagnosis of GM-IVH or EoP; for treatment studies, we included preterm infants (less than 37 weeks' gestation), of any postnatal age, with ultrasound diagnosis of GM-IVH or with EoP. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. all-cause neonatal mortality, 2. major neurodevelopmental disability, 3. GM-IVH, 4. EoP, and 5. extension of pre-existing non-severe GM-IVH or EoP. We planned to use GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We identified no studies that met our inclusion criteria. Three studies are currently registered and ongoing. Phase 1 trials are described in the 'Excluded studies' section. AUTHORS' CONCLUSIONS: No evidence is currently available to evaluate the benefits and harms of stem cell-based interventions for treatment or prevention of GM-IVH or EoP in preterm infants. We identified three ongoing studies, with a sample size range from 20 to 200. In two studies, autologous cord blood mononuclear cells will be administered to extremely preterm infants via the intravenous route; in one, intracerebroventricular injection of MSCs will be administered to preterm infants up to 34 weeks' gestational age.

The effectiveness of interventions to prevent intraventricular haemorrhage in premature infants: A systematic review and network meta-analysis.

BACKGROUND: Intraventricular haemorrhage (IVH) is a common problem in preterm infants, being a major cause of morbidity and mortality. Despite many randomised controlled trials comparing interventions to prevent IVH, the best prevention remains unclear. This study aims to review all the interventions which intended to reduce the incidence of IVH and compare them in a network meta-analysis. METHODS: A search on MEDLINE, EMBASE, Emcare, and CENTRAL was performed. Randomised controlled trials which evaluated neonatal interventions with a primary aim to reduce incidence of IVH in preterm infants were eligible. A surface under a cumulative ranking curve (SUCRA) was produced to indicate the intervention's likelihood of being the most effective for preventing IVH. RESULTS: 40 studies were eligible, enrolling over 6760 infants. Twelve intervention groups were found, including delayed cord clamping, erythropoietin, ethamsylate, fresh frozen plasma, heparin, ibuprofen, indomethacin, magnesium, nursing interventions, sedation, tranexamic acid, and vitamin E. Vitamin E and indomethacin had the highest probability of being the best interventions to prevent IVH in premature infants, but interpretation of these results is difficult due to study limitations. CONCLUSION: Despite the impact of IVH, we were unable to identify a clearly beneficial treatment to reduce its incidence. Interpretation of the network meta-analysis was limited due to differences within studied populations, wide range of therapies trialled, and underlying advances in neonatal care between units, and over time. Although vitamin E and indomethacin appear to be promising candidates, contemporaneous trials of these, or novel agents, enrolling the most at-risk infants is needed urgently.

Intracerebral haemorrhage expansion: definitions, predictors, and prevention.

Haematoma expansion affects a fifth of patients within 24 h of the onset of acute intracerebral haemorrhage and is associated with death and disability, which makes it an appealing therapeutic target. The time in which active intervention can be done is short as expansion occurs mostly within the first 3 h after onset. Baseline haemorrhage volume, antithrombotic treatment, and CT angiography spot signs are each associated with increased risk of haematoma expansion. Non-contrast CT features are promising predictors of haematoma expansion, but their potential contribution to current models is under investigation. Blood pressure lowering and haemostatic treatment minimise haematoma expansion but have not led to improved functional outcomes in randomised clinical trials. Ultra-early enrolment and selection of participants on the basis of non-contrast CT imaging markers could focus future clinical trials to show clinical benefit in people at high risk of expansion or investigate heterogeneity of treatment effects in clinical trials with broad inclusion criteria.

Reducing intraventricular hemorrhage following the implementation of a prevention bundle for neonatal hypothermia.

INTRODUCTION: In very low birth weight (VLBW) infants, hypothermia immediately following birth is common even in countries rich in medical resources. The purpose of this study is to design a standard prevention bundle that decreases the rate of hypothermia among infants after birth and to investigate efficacy of the bundle and short-term outcomes for VLBW infants. METHODS: This quality improvement project was conducted from February 2017 to July 2018 on all VLBW preterm infants admitted at a single referral level III neonatal intensive care unit. The infants were classified into the pre-intervention (February to September 2017) and post-intervention (October 2017 to July 2018) groups according to the time periods when they were recruited. During the pre-intervention period, we analyzed the primary causes of hypothermia, developed solutions corresponding to each cause, integrated all solutions into a prevention bundle, and applied the bundle during the post-intervention period. Afterwards, the incidence of neonatal hypothermia and short-term outcomes, such as intraventricular hemorrhage (IVH), acidosis, and shock requiring inotropic agents, in each group were compared. RESULTS: A total of 95 VLBW infants were enrolled in the study, including 37 pre-intervention, and 58 post-intervention cases. The incidence of hypothermia in preterm infants decreased significantly upon the implementation of our prevention bundle, both in the delivery room (from 45.9% to 8.6%) and on admission (59.5% to 15.5%). In addition, the short-term outcomes of VLBW infants improved significantly, especially with the decreased incidence of IVH (from 21.6% to 5.2%, P = 0.015). CONCLUSIONS: Our standardized prevention bundle for preventing hypothermia in VLBW infants is effective and decreased the IVH rate in VLBW infants. We strongly believe that this prevention bundle is a simple, low-cost, replicable, and effective tool that hospitals can adopt to improve VLBW infant outcomes.

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.

Targeting Oxidative Stress and Inflammatory Response for Blood-Brain Barrier Protection in Intracerebral Hemorrhage.

Significance: Blood-brain barrier (BBB) disruption is a major pathological change after intracerebral hemorrhage (ICH) and is both the cause and result of oxidative stress and of the immune response post-ICH. These processes contribute to ICH-induced brain injury. Recent Advances: After the breakdown of cerebral vessels, blood components, including erythrocytes and their metabolites, thrombin, and fibrinogen, can access the cerebral parenchyma through the compromised BBB, triggering oxidative stress and inflammatory cascades. These aggravate BBB disruption and contribute to further infiltration of blood components, resulting in a vicious cycle that exacerbates brain edema and neurological injury after ICH. Experimental and clinical studies have highlighted the role of BBB disruption in ICH-induced brain injury. Critical Issues: In this review, we focus on the strategies to protect the BBB in ICH. Specifically, we summarize the evidence and the underlying mechanisms, including the ICH-induced process of oxidative stress and inflammatory response, and we highlight the potential therapeutic targets to protect BBB integrity after ICH. Future Directions: Future studies should probe the mechanism of ferroptosis as well as oxidative stress-inflammation coupling in BBB disruption after ICH and investigate the effects of antioxidants and immunomodulatory agents in more ICH clinical trials. Antioxid. Redox Signal. 37, 115-134.

Blood Pressure in Acute Stroke and Secondary Stroke Prevention.

PURPOSE OF REVIEW: Hypertension is common in patients presenting with stroke and is independently associated with unfavorable outcomes. This article reviews current guidelines for early management of blood pressure (BP) and highlights the findings of recent investigative works. RECENT FINDINGS: Intensive blood pressure reduction after receiving alteplase has not been shown to improve outcomes. Patients with large vessel occlusions may benefit from lower blood pressure targets post-intervention. Retrospective analyses of large intracerebral hemorrhage trials suggest that specific subgroups of patients may disproportionately benefit from or be harmed by intensive BP reduction. Robust data for management of blood pressure in subarachnoid hemorrhage patients is lacking and expert consensus continues to guide decision-making. Despite the impact of hypertension on outcomes, most prospective trials assessing efficacy of blood pressure reduction have yielded neutral or inconclusive results. Further trials are necessary to determine which patient populations are most likely to benefit from blood pressure control.

Reduction of Severe Intraventricular Hemorrhage in Preterm Infants: A Quality Improvement Project.

OBJECTIVES: The aim of this quality improvement project was to reduce the rate of severe intraventricular hemorrhage (sIVH) by 50% within 3 years for extremely preterm infants born at a children's teaching hospital. METHODS: A multidisciplinary team developed key drivers for the development of intraventricular hemorrhage in preterm infants. Targeted interventions included the development of potentially better practice guidelines, promoting early noninvasive ventilation, consistent use of rescue antenatal betamethasone, and risk-based indomethacin prophylaxis. The outcome measure was the rate of sIVH. Process measures included the rate of intubation within 24 hours and receipt of rescue betamethasone and risk-based indomethacin prophylaxis. Common markers of morbidity were balancing measures. Data were collected from a quarterly chart review and analyzed with statistical process control charts. The preintervention period was from January 2012 to March 2016, implementation period was from April 2016 to December 2018, and sustainment period was through June 2020. RESULTS: During the study period, there were 268 inborn neonates born at <28 weeks' gestation or <1000 g (127 preintervention and 141 postintervention). The rate of sIVH decreased from 14% to 1.2%, with sustained improvement over 2 and a half years. Mortality also decreased by 50% during the same time period. This was associated with adherence to process measures and no change in balancing measures. CONCLUSIONS: A multipronged quality improvement approach to intraventricular hemorrhage prevention, including evidence-based practice guidelines, consistent receipt of rescue betamethasone and indomethacin prophylaxis, and decreasing early intubation was associated with a sustained reduction in sIVH in extremely preterm infants.

Magnitude of Blood Pressure Change After Endovascular Therapy and Outcomes: Insight From the BP-TARGET Trial.

BACKGROUND AND PURPOSE: To assess the association between systolic blood pressure change (ΔSBP) at different time intervals after successful reperfusion with radiographic and clinical outcomes. METHODS: This is a post hoc analysis of the BP-TARGET multicenter trial (Blood Pressure Target in Acute Stroke to Reduce Hemorrhage After Endovascular Therapy). ΔSBP was defined as end of procedure SBP minus mean SBP at different time intervals (15-60 minutes, 1-6 hours, and 6-24 hours postprocedure). The primary outcome was the poor functional outcome (90-day modified Rankin Scale score 3-6). RESULTS: We included a total of 267 patients (130 in the intensive treatment group). Compared with patients with favorable outcome, patients with poor outcome had lower ΔSBP (less SBP reduction) at all times intervals. After adjusting for potential confounders including baseline SBP, both ΔSBP15-60M and ΔSBP6-24H were associated with lower odds of poor outcome (adjusted odds ratio per 5 mm Hg SBP reduction, 0.89 [95% CI, 0.81-0.99], and adjusted odds ratio 0.82 [95% CI, 0.73-0.92], respectively). Concerning safety outcomes, patients with intraparenchymal hemorrhage had lower ΔSBP at all time intervals. ΔSBP15-60M was associated with lower odds of any intraparenchymal hemorrhage (adjusted odds ratio per 5 mm Hg SBP reduction 0.91 [95% CI, 0.83-0.99]). Conversely, ΔSBP was not associated with mortality or neurological deterioration at any time interval. CONCLUSIONS: After successful reperfusion, ΔSBP had a linear relationship with poor outcome and the risk of poor outcome was higher with less reduction from the baseline SBP. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03160677.

Five-Day Bed Rest Reduces Postoperative Intracerebral Hemorrhage After Direct Bypass for Moyamoya Disease.

OBJECTIVE: Postoperative intracerebral hemorrhage (ICH) after direct bypass surgery for Moyamoya disease could contribute to neurologic deterioration. The aim of this study was to evaluate the effectiveness of 5-day bed rest in reducing the occurrence of postoperative ICH. METHODS: This study included 122 consecutive hemispheres in 87 Japanese adult MMD patients, composed of 80 control hemispheres from historical data and 42 hemispheres after 5-day bed rest. They all underwent direct bypass surgery. The incidence of postoperative ICH and neurologic deterioration assessed via the modified Rankin Scale were investigated and statistically analyzed. RESULTS: Postoperative ICH was observed in 9 out of the 80 (11.3%) control patients, but not in the 42 patients with 5-day bed rest. The incidence of postoperative ICH and neurologic deterioration via the modified Rankin Scale were significantly different between the 2 groups (P = 0.0268 and 0.0078, respectively). Univariate logistic analysis revealed that 5-day bed rest significantly reduced the incidence of postoperative ICH (P = 0.0048). CONCLUSIONS: Five-day bed rest after direct bypass surgery dramatically can reduce the incidence of postoperative ICH and neurologic deterioration after direct bypass surgery.

Clinical outcomes of pharmacological thromboprophylaxis among patients with intracerebral hemorrhage: Systematic review and meta-analysis.

OBJECTIVE: Efficacy and safety of pharmacologic thromboprophylaxis after an episode of intracerebral hemorrhage remains unclear. This meta-analysis aimed at comparing the clinical outcomes of intracerebral hemorrhage patients with or without pharmacologic thromboprophylaxis. METHODS: We performed a comprehensive literature review of PubMed to identified relevant studies. The primary and secondary endpoints included venous thromboembolism, deep venous thrombosis, pulmonary emboli, rebleeding, hematoma enlargement (defined as increase in hematoma volume of ≥33%), major disability (defined as modified Rankin score of 3-5), and death. Pooled outcomes were estimated by fitting random effects model with restricted maximum likelihood method. A total of 8 original studies including 3893 patients were analyzed. RESULT: Compared to the control group, pharmacologic thromboprophylaxis was associated with a lower risk of pulmonary embolism (odds ratio [OR]: 0.34, 95% CI: 0.15-0.80, P = 0.01). There was no significant difference in the risk of DVT (OR: 0.75; [95% CI: 0.37-1.53], P = 0.44) and VTE (OR: 0.65; [95% CI: 0.34-1.25], P = 0.20). Finally, anticoagulation was not associated with an increase rate of major disability (OR:1.36; [95% CI: 0.57 - 3.23], P = 0.48), rebleeding (OR: 0.35; [95% CI: 0.10-1.19], P = 0.09), hematoma enlargement (OR:1.34; [95% CI: 0.58-3.12], P = 0.49), or death (OR:0.90; [95% CI: 0.68-1.19], P = 0.46). CONCLUSION: Among patients with intracerebral hemorrhage, pharmacologic thromboprophylaxis was associated with a significant reduction in pulmonary embolism, without an increase in rebleeding or hematoma enlargement. The results of this meta-analysis need to be further validated in large scale clinical trials.