Updates on aneurysmal subarachnoid hemorrhage: is there anything really new? / Atualizações em hemorragia subaracnóidea aneurismática: há algo realmente novo?

Abstract Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe disease, with systemic involvement and complex diagnosis and treatment. Since the current guidelines were published by the AHA/ASA, Neurocritical Care Society and the European Stroke Organization in 2012-2013,there has been an evolution in the comprehension of SAH-associated brain injury and its multiple underlying mechanisms. As a result, several clinical and translational trials were developed or are underway. Objective: The aim of this article is to review some updates in the diagnosis and treatment of neurological complications of SAH. Methods: A review of PubMed (May, 2010 to February, 2022) was performed. Data was summarized. Results: Content of five meta-analyses, nine review articles and 23 new clinical trials, including pilots, were summarized. Conclusions:Advances in the comprehension of pathophysiology and improvements in critical care have been reflected in the reduction of mortality in SAH. However, despite the number of publications, the only treatments shown to be effective in adequate, well-controlled clinical trials are nimodipine and repair of the ruptured aneurysm. Thus, doubts about the optimal management of SAH still persist.

Resumo Antecedentes: Hemorragia subaracnóide aneurismática (HSAa) é uma doença grave, com envolvimento sistêmico, complexo diagnóstico e tratamento. Desde a publicação dos atuaisprotocolos de conduta pela AHA/ASA, NeurocriticalCare Society e EuropeanStrokeOrganization de 2012-2013, houve evolução na compreensão da lesão cerebral associada à HSA e seus múltiplos mecanismos subjacentes. Como resultado, muitos trabalhos clínicos e translacionais foram desenvolvidos ou estão em andamento. Objetivos: O objetivo deste artigo é revisar algumas das atualizações no diagnóstico e tratamento de complicações neurológicas de HSA. Métodos: Revisão de Pubmed (Maio de 201o a Fevereiro de 2022) foi realizada. Dados foram sintetizados. Resultados: O conteúdo de 5 metanálises, 9 artigos de revisão e 23 novos estudos clínicos, incluindo pilotos, foram sumarizados. Conclusões: Avanços na compreensão da fisiopatologia e melhorias no cuidado crítico têm se refletido na redução da mortalidade em HSA. Entretanto, apesar do volume de publicações, os únicos tratamentos que se mostraram efetivos com testes clínicos bem controlados são o uso de nimodipino e o tratamento dos aneurisma rotos. Assim, dúvidas acerca do manejo ideal em HSA ainda persistem.

Ultrasound Perfusion Imaging for the Detection of Cerebral Hypoperfusion After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Delayed cerebral ischemia increases mortality and morbidity after aneurysmal subarachnoid hemorrhage (aSAH). Various techniques are applied to detect cerebral vasospasm and hypoperfusion. Contrast-enhanced ultrasound perfusion imaging (UPI) is able to detect cerebral hypoperfusion in acute ischemic stroke. This prospective study aimed to evaluate the use of UPI to enable detection of cerebral hypoperfusion after aSAH. METHODS: We prospectively enrolled patients with aSAH and performed UPI examinations every second day after aneurysm closure. Perfusion of the basal ganglia was outlined to normalize the perfusion records of the anterior and posterior middle cerebral artery territory. We applied various models to characterize longitudinal perfusion alterations in patients with delayed ischemic neurologic deficit (DIND) across the cohort and predict DIND by using a multilayer classification model. RESULTS: Between August 2013 and December 2015, we included 30 patients into this prospective study. The left-right difference of time to peak (TTP) values showed a significant increase at day 10-12. Patients with DIND demonstrated a significant, 4.86 times increase of the left-right TTP ratio compared with a mean fold change in patients without DIND of 0.9 times (p = 0.032). CONCLUSIONS: UPI is feasible to enable detection of cerebral tissue hypoperfusion after aSAH, and the left-right difference of TTP values is the most indicative result of this finding.

Temporal Expression Pattern of Hemoxygenase-1 Expression and Its Association with Vasospasm and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Red blood cell-induced cerebral inflammation and toxicity has been shown to be attenuated by induction of the heme-catalyzing enzyme, hemoxygenase-1 (HO-1), in animal models of subarachnoid hemorrhage (SAH). Although inflammatory mechanisms leading to secondary neuronal injury in SAH are becoming increasingly well understood, markers of cerebral inflammation have so far not been implemented in clinical prediction models of SAH. METHODS: In this biomarker observational study, HO-1 messenger ribonucleic acid (mRNA) expression levels were determined in cerebrospinal fluid (CSF) and blood of 66 patients with aneurysmal SAH on days 1, 7, and 14 after the SAH event. HO-1 mRNA expression was determined via real time polymerase chain reaction (PCR), and relative expression changes were quantified in comparison with expression levels in nonhemorrhagic control CSF. Subarachnoid blood burden, as well as presence of vasospasm and delayed cerebral ischemia (DCI), were recorded. Short and long-term clinical outcomes were assessed using the Modified Rankin Scale at discharge and 1 year after the SAH event. RESULTS: CSF HO-1 expression levels showed a significant increase over the 14-day observation period (p < 0.001, F = 22.53) and correlated with intracranial hematoma burden (ρ = 0.349, p = 0.025). In multivariate analyses, CSF HO-1 expression levels did not reach significance as independent predictors of outcome. Vasospasm on computed tomographic angiography was associated with lower CSF HO-1 expression levels on day 7 after SAH (n = 53, p = 0.010), whereas patients with DCI showed higher CSF HO-1 expression levels on day 14 after SAH (n = 21, p = 0.009). CONCLUSIONS: HO-1 expression in CSF in patients with SAH follows a distinct temporal induction pattern and is dependent on intracranial hematoma burden. CSF HO-1 expression was unable to predict functional outcome. Associations of early low HO-1 expression with vasospasm and late elevated HO-1 expression with DCI may point to detrimental effects of late HO-1 induction, warranting the need for further investigation in a larger study population.

The predictive value of the CTA Vasospasm Score on delayed cerebral ischaemia and functional outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Delayed cerebral ischaemia (DCI) is a severe complication of aneurysmal subarachnoid hemorrhage that can significantly impact clinical outcome. Cerebral vasospasm is part of the pathophysiology of DCI and therefore a computed tomography angiography (CTA) Vasospasm Score was developed and an exploration was carried out of whether this score predicts DCI and subsequent poor outcome after aneurysmal subarachnoid hemorrhage. METHODS: The CTA Vasospasm Score sums the degree of angiographic cerebral vasospasm of 17 intradural arterial segments. The score ranges from 0 to 34 with a higher score reflecting more severe vasospasm. Outcome measures were cerebral infarction due to DCI (CI-DCI), radiological and clinical DCI, and unfavorable functional outcome defined as a modified Rankin Scale >2 at 6 months. Receiver operating characteristic analyses were used to assess predictive value and to determine optimal cut-off scores. Inter-rater reliability was evaluated by Cohen's kappa coefficient. RESULTS: This study included 59 patients. CI-DCI occurred in eight patients (14%), DCI in 14 patients (24%) and unfavorable outcome in 12 patients (20%). Median CTA Vasospasm Scores were higher in patients with (CI-)DCI and poor outcome. Receiver operating characteristic analysis revealed the highest area under the curve on day 5: CI-DCI 0.89 (95% confidence interval [CI] 0.79-0.99), DCI 0.68 (95% CI 0.50-0.87) and functional outcome 0.74 (95% CI 0.57-0.91). Cohen's kappa between the two raters was moderate to substantial (0.57-0.63). CONCLUSIONS: This study demonstrates that the CTA Vasospasm Score on day 5 can reliably identify patients with a high risk of developing (CI-)DCI and unfavorable outcome.

Reversible cerebral vasoconstriction syndrome characterized by postpartum headache: a case report / 中华围产医学杂志

We report the diagnosis and treatment of a case of reversible cerebral vasoconstriction syndrome characterized by postpartum thunderclap headache. The patient experienced a thunderclap headache on the second day after delivery, which gradually worsened. On postpartum day 4, she presented with sudden convulsion and hypertension on admission on May 19, 2020, and was initially diagnosed with postpartum eclampsia. We confirmed the diagnosis of reversible cerebral vasoconstriction syndrome based on the results of cranial magnetic resonance angiography (MRA) and other examinations and the consultation with neurologists. After antihypertensive and spasmolytic treatment, the patient's blood pressure returned to normal, and she was discharged on postpartum day 8. Reexamination with cranial MRA at 50 + days after delivery indicated that the cerebral vasospasm was relieved. No severe headaches or convulsions were observed during follow-up till June 2021.

Intravenous Milrinone for Cerebral Vasospasm in Subarachnoid Hemorrhage: The MILRISPASM Controlled Before-After Study.

BACKGROUND: Intravenous (IV) milrinone, in combination with induced hypertension, has been proposed as a treatment option for cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). However, data on its safety and efficacy are scarce. METHODS: This was a controlled observational study conducted in an academic hospital with prospectively and retrospectively collected data. Consecutive patients with cerebral vasospasm following aSAH and treated with both IV milrinone (0.5 µg/kg/min-1, as part of a strict protocol) and induced hypertension were compared with a historical control group receiving hypertension alone. Multivariable analyses aimed at minimizing potential biases. We assessed (1) 6-month functional disability (defined as a score between 2 and 6 on the modified Rankin Scale) and vasospasm-related brain infarction, (2) the rate of first-line or rescue endovascular angioplasty for vasospasm, and (3) immediate tolerance to IV milrinone. RESULTS: Ninety-four patients were included (41 and 53 in the IV milrinone and the control group, respectively). IV milrinone infusion was independently associated with a lower likelihood of 6-month functional disability (adjusted odds ratio [aOR] = 0.28, 95% confidence interval [CI] = 0.10-0.77]) and vasospasm-related brain infarction (aOR = 0.19, 95% CI 0.04-0.94). Endovascular angioplasty was less frequent in the IV milrinone group (6 [15%] vs. 28 [53%] patients, p = 0.0001, aOR = 0.12, 95% CI 0.04-0.38). IV milrinone (median duration of infusion, 5 [2-8] days) was prematurely discontinued owing to poor tolerance in 12 patients, mostly (n = 10) for "non/hardly-attained induced hypertension" (mean arterial blood pressure < 100 mmHg despite 1.5 µg/kg/min-1 of norepinephrine). However, this event was similarly observed in IV milrinone and control patients (n = 10 [24%] vs. n = 11 [21%], respectively, p = 0.68). IV milrinone was associated with a higher incidence of polyuria (IV milrinone patients had creatinine clearance of 191 [153-238] ml/min-1) and hyponatremia or hypokalemia, whereas arrhythmia, myocardial ischemia, and thrombocytopenia were infrequent. CONCLUSIONS: Despite its premature discontinuation in 29% of patients as a result of its poor tolerance, IV milrinone was associated with a lower rate of endovascular angioplasty and a positive impact on long-term neurological and radiological outcomes. These preliminary findings encourage the conduction of confirmatory randomized trials.

The Effect of Locally Administered Fibrinolytic Drugs Following Aneurysmal Subarachnoid Hemorrhage : A Meta-Analysis with Eight Randomized Controlled Studies.

OBJECTIVE: Rapid dissolution of blood clots reduces vasospasm and hydrocephalus after subarachnoid hemorrhage (SAH), and locally administered fibrinolytic drugs (LAFDs) could facilitate the dissolution. However, the efficacy of LAFDs remains controversial. The aim of this meta-analysis was to determine the efficacy of LAFDs for vasospasm and hydrocephalus and in clinical outcomes. METHODS: From PubMed, EMBASE, and Cochrane database, data were extracted by two authors. Meta-analysis was performed using a random effect model. Inclusion criteria were patients who had LAFDs with urokinase-type or recombinant tissue-plasminogen activator after SAH in comparison with medically untreated patients with fibrinolytic drugs. We only included randomized controlled trials (RCTs) in this analysis. The outcomes of interest were vasospasm, hydrocephalus, mortality, and 90-day unfavorable functional outcome. RESULTS: Data from eight RCTs with 550 patients were included. Pooled-analysis revealed that the LAFDs were significantly associated with lower rates of vasospasm (LAFDs group vs. control group, 26.5% vs. 39.2%; odds ratio [OR], 0.48; 95% confidence interval [CI], 0.32-0.73); hydrocephalus (LAFDs group vs. control group, 26.0% vs. 31.6%; OR, 0.54; 95% CI, 0.32-0.91); and mortality (LAFDs group vs. control group, 10.5% vs. 15.7%; OR, 0.58; 95% CI, 0.34-0.99). The proportion of 90-day unfavorable outcomes was lower in the LAFDs group (LAFDs group vs. control group, 32.7% vs. 43.5%; OR, 0.55; 95% CI, 0.37-0.80). CONCLUSION: This meta-analysis with eight RCTs indicated that LAFDs were significantly associated with lower rates of vasospasm and hydrocephalus after SAH. Thus, LAFDs could consequently reduce mortality and improve clinical outcome after SAH.

Acute platelet response to aneurysmal subarachnoid hemorrhage depends on severity and distribution of bleeding: an observational cohort study.

Microthrombosis after aneurysmal subarachnoid hemorrhage (aSAH) is considered to initiate neuroinflammation, vessel remodeling, and blood-brain barrier leakage. We aimed to verify the hypothesis that the intensity of thrombogenicity immediately after aSAH depends on the amount and distribution of extravasated blood. This observational cohort study included 37 consecutive aSAH patients admitted no longer than 24 h after ictus. Volumes of subarachnoid and intraventricular hemorrhages as well as the Subarachnoid Hemorrhage Early Brain Edema Scale (SEBES) score were calculated in each case. Platelet system status was described by platelet count (PLT), mean platelet volume (MPV), MPV to PLT ratio, and platelet-large cell ratio (P-LCR). Median hemorrhage volume amounted to 11.4 ml (interquartile range 2.8-26.8 ml). Patients with more severe hemorrhage had lower PLT and higher MPV to PLT ratio (ρ = - 0.49, p < .002; ρ = 0.50, p < .002, respectively). PLT decreased by 2.80 G/l per 1 ml of hemorrhage volume (95% CL 1.30-4.30, p < .001). Further analysis revealed that intraventricular hemorrhage volume was associated with P-LCR and MPV (ρ = 0.34, p < .039; ρ = 0.33, p < .048, respectively), whereas SAH volume with PLT and MPV:PLT ratio (ρ = - 0.40, p < .013; ρ = 0.41, p < .013, respectively). The odds of unfavorable neurological outcome increased 3.95 times per 1 fl of MPV (95% CI 1.19-13.12, p < .025). MPV was independently correlated with SEBES (ρ = 0.44, p < .006). This study demonstrated that the extent and distribution of aneurysmal subarachnoid hemorrhage are related to different types of acute platelet response, which may be interpreted as local and systemic thrombogenicity. Increased mean platelet volume measured in the acute phase of aSAH may identify patients at risk for unfavorable neurological outcomes and may serve as a marker of early brain injury.

Efficacy and safety of Fasudil on vasospasm caused by subarachnoid hemorrhage in elderly patients / 中华老年医学杂志

Objective:To evaluate the efficacy and safety of fasudil on vasospasm caused by subarachnoid hemorrhage in elderly patients.Methods:A total of 100 elderly patients with subarachnoid hemorrhage admitted to our hospital from January 2015 to May 2018 were enrolled as research objects.They were randomly divided into the Fasudil group(n=50, receiving the Rho kinase inhibitor Fasudil therapy)and the Nimodipine group(n=50, receiving Nimodipine therapy). The cerebral vasospasm and cerebral infarction lesions, the ability of daily life, clinical prognostic score, the incidence of symptomatic cerebral vasospasm and adverse reactions during treatment were evaluated and compared between the two groups.Results:After treatment, the incidences of cerebral vasospasm and cerebral infarction in Fasudil group were 2.04%(1/49)and 6.12%(3/49), respectively, which were lower than those in the Nimodipine group[12.50%(6/48)and 20.83%(10/48), respectively]( χ2=6.134 and 6.794, P=0.047 and 0.033). The scores of daily living ability was better in the Fasudil group than in the Nimodipine group(16.09±1.06 vs.22.91±1.66, t=7.721, P=0.026). The incidence of adverse reactions was lower in the Fasudil group than in the Nimodipine group(4.08% or 2/49 vs.16.7% or 8/48, χ2=6.362, P=0.040). There was no statistically significant difference in the proportion of patients with good prognosis between Fasudil group and Nimodipine group. Conclusions:Rho kinase inhibitor Fasudil can effectively prevent and improve cerebral vasospasm caused by subarachnoid hemorrhage, which is beneficial for improving the clinical prognosis and quality of life of the elderly patients with subarachnoid hemorrhage.

Eficácia e segurança da milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea: uma revisão sistemática / Efficacy and safety of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage: a systematic review

RESUMO Objetivo: Revisar sistematicamente a evidência atual da eficácia de milrinona no tratamento do vasoespasmo cerebral após hemorragia subaracnóidea. Métodos: Triaram-se as bases de dados Pubmed®, Cochrane e Embase quanto a artigos publicados entre abril de 2001 e fevereiro de 2019. Dois revisores independentes realizaram uma triagem metodológica da qualidade e a extração dos dados dos estudos. Resultados: Encontraram-se 22 estudos considerados relevantes, sendo que apenas um deles era um ensaio randomizado controlado. Os estudos demonstraram acentuada heterogeneidade e debilidade de seus critérios metodológicos. A maioria dos pacientes apresentava vasoespasmo moderado a grave. O principal método para diagnóstico do vasoespasmo foi a angiografia. Em três estudos, realizou-se administração de milrinona por via intra-arterial; em nove estudos, a administração foi endovenosa, e, em seis estudos, utilizaram-se ambas as vias de administração. A via intratecal foi utilizada em dois estudos, em um estudo, a administração foi realizada via cisterna e, em um estudo, a via de administração foi a endovascular. Os efeitos colaterais de milrinona foram descritos em seis estudos. Vinte e um estudos indicaram a resolução do vasoespasmo. Conclusão: A evidência atual indica que o uso de milrinona teve um papel no tratamento do vasoespasmo após hemorragia subaracnóidea aneurismática. Contudo, só foi realizado um ensaio randomizado controlado, com baixo nível de qualidade. Nossos achados indicam a necessidade de futuros estudos randomizados controlados com desfechos centrados no paciente, com o fim de proporcionar recomendações definitivas.

ABSTRACT Objective: To systematically review the current evidence on the efficacy of milrinone in the treatment of cerebral vasospasm after subarachnoid hemorrhage. Methods: The Pubmed®, Cochrane and Embase databases were screened for articles published from April 2001 to February 2019. Two independent reviewers performed the methodological quality screening and data extraction of the studies. Results: Twenty-two studies were found to be relevant, and only one of these was a randomized control trial. Studies showed marked heterogeneity and weaknesses in key methodological criteria. Most patients presented with moderate to severe vasospasm. Angiography was the main method of diagnosing vasospasm. Intra-arterial administration of milrinone was performed in three studies, intravenous administration was performed in nine studies, and both routes of administration in six studies; the intrathecal route was used in two studies, the cisternal route in one study and endovascular administration in one study. The side effects of milrinone were described in six studies. Twenty-one studies indicated resolution of vasospasm. Conclusion: The current evidence indicates that milrinone may have a role in treatment of vasospasm after aneurysmal subarachnoid hemorrhage. However, only one randomized control trial was performed, with a low quality level. Our findings indicate the need for future randomized control trials with patient-centered outcomes to provide definitive recommendations.

Terapia endovascular múltiple para el manejo del vasoespasmo cerebral refractario / Repeated endovascular therapy for refractory cerebral vasospasm

Resumen El vasoespasmo cerebral es una complicación severa de la hemorragia subaracnoidea. La monitorización y la detección del vasoespasmo por mé- todos no invasivos, así como la terapia endovascular, han revolucionado la atención médica tradicional. Se presenta el caso de un paciente masculino de 45 años con aneurisma roto de la arteria comunicante anterior, quien desarrolló vasoespasmo severo refractario desde el octavo día de hemorragia subaracnoidea. El vasoespasmo fue detectado oportunamente con técnicas no invasivas y tratado en cinco ocasiones mediante terapia endovascular, logrando mejoría inmediata de los síntomas y sin secuelas neurológicas. Este reporte contribuye a demostrar el beneficio de la terapia endovascular múltiple para el manejo del vasoespasmo cerebral refractario, en combinación con la utilización de técnicas no invasivas para la monitorización y detección oportuna del vasoespasmo. Adicionalmente, se revisan las recomendaciones actuales de medicina basada en la evidencia sobre el uso del Doppler transcraneal para la detección del vasoespasmo cerebral.

Abstract Cerebral vasospasm is a severe complication of subarachnoid hemorrhage. Monitoring and detection of vasospasm by non-invasive methods as well as the endovascular therapy have revolutionized healthcare. A 45-years-old male patient presented with a ruptured aneurysm in the anterior communicating artery and developed severe refractory vasospasm since the eighth day of aneurysm rupture. Vasospasm was timely detected with non-invasive techniques and successfully endovascular therapy was provided five times with neurological and radiological recovery each time and no neurological sequelae. This report contributes to current practice as it demonstrates the benefit of repeated endovascular therapy for refractory cerebral vasospasm, especially when clinical and non-invasive monitoring shows persistence of this complication. Furthermore, we review the current evidence-based medicine recommendations about Transcranial Doppler Ultrasonography that support the monitoring and detection of cerebral vasospasm.

Impact of Stereotactic Ventriculocisternostomy on Delayed Cerebral Infarction and Outcome After Subarachnoid Hemorrhage.

Background and Purpose- Delayed cerebral infarction (DCI) is an important cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Stereotactic catheter ventriculocisternostomy (STX-VCS) and fibrinolytic/spasmolytic lavage is a new method for DCI prevention. Here, we assess the effects of implementing STX-VCS in an unselected aSAH patient population of a tertiary referral center. Methods- Retrospective cohort study of all consecutive aSAH patients admitted to a neurosurgical referral center during a 7-year period (April 2012 to April 2019). Midterm STX-VCS was introduced and offered to patients at high risk for DCI. We compared the incidence and burden of DCI, neurological outcome, and the use of induced hypertension and endovascular rescue therapy in this consecutive aSAH population 3.5 years before versus 3.5 years after STX-VCS became available. Results- Four hundred thirty-six consecutive patients were included: 222 BEFORE and 214 AFTER. Fifty-seven of 214 (27%) patients received STX-VCS. Stereotactic procedures resulted in one (2%) subdural hematoma. Favorable neurological outcome at 6 months occurred in 118 (53%) patients BEFORE and 139 (65%) patients AFTER (relative risk, 0.79 [95% CI, 0.66-0.95]). DCI occurred in 40 (18.0%) patients BEFORE and 17 (7.9%) patients AFTER (relative risk, 0.68 [95% CI, 0.57-0.86]), and total DCI volumes were 8933 (100%) and 3329 mL (36%), respectively. Induced hypertension was used in 97 (44%) and 30 (15%) patients, respectively (relative risk, 0.55 [95% CI, 0.46-0.65]). Thirty (13.5%) patients BEFORE versus 5 (2.3%) patients AFTER underwent endovascular rescue therapies (relative risk, 0.17 [95% CI, 0.07-0.42]). Conclusions- Selecting high-risk patients for STX-VCS reduced the DCI incidence, burden, and related mortality in a consecutive aSAH patient population. This was associated with an improved neurological outcome.

[Effectiveness and safety of nimodipine in preventing cerebral vasospasm after subarachnoid hemorrhage in children].

Objective: To evaluate the effect of prophylactic nimodipine in vasospasm prevention and outcome improvement in children with subarachnoid hemorrhage (SAH). Methods: A prospective, randomized controlled clinical trial which enrolled children with SAH who were admitted to pediatric intensive care unit (PICU) of Beijing Children's Hospital from January 2015 to October 2018 was conducted. A total of 43 patients were randomly divided into nimodipine group (24 patients) and control group (19 patients) according to random number table. Transcranial Doppler (TCD) was used to dynamically monitor blood flow velocity and spectrum monography of bilateral middle cerebral artery (MCA) for vasospasm evaluation. Pediatric cerebral performance category (PCPC) scale was used to evaluate patients' brain function on 28(th) day after discharge. Data were analyzed by t test, Mann-Whitney U test, χ(2) test. Results: Except heart rate ((157±26) vs. (137±34) beats/min, t=2.079, P=0.045), no significant differences existed between the two groups in basic demographic characteristics, primary diseases, and clinical manifestations (all P>0.05). The peak velocities of bilateral MCA on the 5(th) day after admission were significantly lower in nimodipine group (left MCA (136±34) vs. (158±23) cm/s, t=-2.890, P=0.006; right MCA (129±34) vs. (176±27) cm/s, t=-3.717, P=0.001). Likewise, a lower peak velocity of left MCA was observed on the 7(th) day after admission in nimodipine group ((127±45) vs. (152±13) cm/s, t=-2.903, P=0.007), but no significant difference existed in that of right MCA ((131±48) vs. (150±22) cm/s, t=-1.760, P=0.090). Eleven patients suffered from vasospasm, 25% (6/24) in nimodipine group and 26% (5/19) in control group (χ(2)=0.010, P=1.000), within whom 8 patients had complete remission after continuing nimodipine treatment, one died in hospital and the other two's vasospasm still existed at the time of discharge. No significant differences were found between the two groups in mean length of hospitalization, proportion of mechanical ventilation, Glasgow coma scale at discharge, survival rate at discharge or survival rate on 28(t)h day after discharge (all P>0.05). However, nimodipine group had a higher proportion of favorable PCPC brain function (92% (22/24) vs. 63% (12/19), χ(2)=5.208, P=0.030). No side effects such as hypotension, rash or injection site erythema were observed. Conclusion: Prophylactic nimodipine cannot reduce vasospasm incidence in children with SAH but may improve short-term brain function, without any significant safety issues.

Effectiveness and safety of nimodipine in preventing cerebral vasospasm after subarachnoid hemorrhage in children / 中华儿科杂志

Objective@#To evaluate the effect of prophylactic nimodipine in vasospasm prevention and outcome improvement in children with subarachnoid hemorrhage (SAH).@*Methods@#A prospective, randomized controlled clinical trial which enrolled children with SAH who were admitted to pediatric intensive care unit (PICU) of Beijing Children′s Hospital from January 2015 to October 2018 was conducted. A total of 43 patients were randomly divided into nimodipine group (24 patients) and control group (19 patients) according to random number table. Transcranial Doppler (TCD) was used to dynamically monitor blood flow velocity and spectrum monography of bilateral middle cerebral artery (MCA) for vasospasm evaluation. Pediatric cerebral performance category (PCPC) scale was used to evaluate patients′ brain function on 28th day after discharge. Data were analyzed by t test, Mann-Whitney U test, χ2 test.@*Results@#Except heart rate ((157±26) vs. (137±34) beats/min, t=2.079, P=0.045), no significant differences existed between the two groups in basic demographic characteristics, primary diseases, and clinical manifestations (all P>0.05). The peak velocities of bilateral MCA on the 5th day after admission were significantly lower in nimodipine group (left MCA (136±34) vs. (158±23) cm/s, t=-2.890, P=0.006; right MCA (129±34) vs. (176±27) cm/s, t=-3.717, P=0.001). Likewise, a lower peak velocity of left MCA was observed on the 7th day after admission in nimodipine group ((127±45) vs. (152±13) cm/s, t=-2.903, P=0.007), but no significant difference existed in that of right MCA ((131±48) vs. (150±22) cm/s, t=-1.760, P=0.090). Eleven patients suffered from vasospasm, 25% (6/24) in nimodipine group and 26% (5/19) in control group (χ2=0.010, P=1.000), within whom 8 patients had complete remission after continuing nimodipine treatment, one died in hospital and the other two′s vasospasm still existed at the time of discharge. No significant differences were found between the two groups in mean length of hospitalization, proportion of mechanical ventilation, Glasgow coma scale at discharge, survival rate at discharge or survival rate on 28th day after discharge (all P>0.05). However, nimodipine group had a higher proportion of favorable PCPC brain function (92% (22/24) vs. 63% (12/19), χ2=5.208, P=0.030). No side effects such as hypotension, rash or injection site erythema were observed.@*Conclusion@#Prophylactic nimodipine cannot reduce vasospasm incidence in children with SAH but may improve short-term brain function, without any significant safety issues.

Effect of nimodipine combined with cerebrospinal fluid replacement by lumbar puncture on hemoglobin concentration, Toll-like receptor 4 expression levels and cerebral vasospasm in patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage / 国际脑血管病杂志

Objective@#To investigate the effect of nimodipine combined with cerebrospinal fluid replacement on hemoglobin concentration, Toll-like receptor 4 (TLR4) expression level and cerebral vasospasm (CVS) in patients with CVS after aneurysmal subarachnoid hemorrhage (aSAH).@*Methods@#One hundred and twenty patients with CVS after aSAH admitted to the Department of Neurosurgery, the Sixth Medical Center of PLA General Hospital from May 2013 to May 2015 were selected. They were randomly divided into control group and observation group (n=60 in each group). The control group received conventional treatment and nimodipine infusion after embolization of the aneurysms, and the observation group underwent cerebrospinal fluid replacement by lumbar puncture on this basis. The clinical efficacy, Glasgow Coma Scale (GCS) scores, hemoglobin concentration and TLR4 expression levels before and after treatment, and adverse reactions were compared between the two groups.@*Results@#One month after treatment, the improvement rate of vasospasm in the observation group was significantly higher than that in the control group (86.7% vs. 60.0%; χ2=9.590, P=0.002). Three months after the treatment, the good rate of clinical outcome (the modified Rankin Scale score 0-2) was significantly higher than that of the control group (88.3% vs. 58.3%; χ2 =13.807, P<0.001). Before treatment, there were no significant differences in hemoglobin concentration and TLR4 expression levels between the two groups; after treatment, the hemoglobin concentration and TLR4 expression levels of both groups were significantly reduced (P<0.05). Compared with the control group, the hemoglobin concentration (119.9±19.8 g/L vs. 137.6±17.8 g/L; t=3.270, P=0.001) and TLR4 expression level (2.5±1.2 vs. 4.5±1.5; t=8.060, P<0.001) in the observation group decreased more significantly. Multivariate logistic regression analysis showed that hypertension (odds ratio [OR] 5.19, 95% confidence interval [CI] 2.31-6.71), hyperlipidemia (OR 2.70, 95% CI 1.93-4.86), previous history of stroke or transient ischemic attack (OR 6.29, 95% CI 3.23-7.32), smoking (OR 4.80, 95% CI 2.18-6.19), and the TLR4 expression level before treatment (OR 3.28, 95% CI 2.87-6.93) were independently correlated with the lack of improvement in CVS, and cerebrospinal fluid replacement was independently correlated with CVS improvement (OR 0.40, 95% CI 0.14-0.89). There was no significant difference in the incidence of adverse reactions such as blood pressure drop, obstructive hydrocephalus and gastrointestinal hemorrhage between the observation group and the control group, but the incidence of delayed CVS (13.3% vs. 36.7%; χ2=7.510, P=0.006) and secondary cerebral infarction (8.3% vs. 31.7%; χ2=8.800, P=0.003) in the observation group were significantly lower than those of the observation group.@*Conclusion@#Nimodipine infusion combined with cerebrospinal fluid replacement by lumbar puncture affected the hemoglobin concentration and TLR4 expression levels, improved the CVS improvement rate, and significantly improved the clinical outcome in patients with CVS after aSAH.

Effect of nimodipine combined with cerebrospinal fluid replacement by lumbar puncture on hemoglobin concentration, Toll-like receptor 4 expression levels and cerebral vasospasm in patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage / 国际脑血管病杂志

Objective To investigate the effect of nimodipine combined with cerebrospinal fluid replacement on hemoglobin concentration,Toll-like receptor 4 (TLR4) expression level and cerebral vasospasm (CVS) in patients with CVS after aneurysmal subarachnoid hemorrhage (aSAH).Methods One hundred and twenty patients with CVS after aSAH admitted to the Department of Neurosurgery,the Sixth Medical Center of PLA General Hospital from May 2013 to May 2015 were selected.They were randomly divided into control group and observation group (n =60 in each group).The control group received conventional treatment and nimodipine infusion after embolization of the aneurysms,and the observation group underwent cerebrospinal fluid replacement by lumbar puncture on this basis.The clinical efficacy,Glasgow Coma Scale (GCS) scores,hemoglobin concentration and TLR4 expression levels before and after treatment,and adverse reactions were compared between the two groups.Results One month after treatment,the improvement rate of vasospasm in the observation group was significantly higher than that in the control group (86.7％ vs.60.0％;x2 =9.590,P =0.002).Three months after the treatment,the good rate of clirnical outcome (the modified Rankin Scale score 0-2) was significantly higher than that of the control group (88.3％ vs.58.3％;x2 =13.807,P＜0.001).Before treatment,there were no significant differences in hemoglobin concentration and TLR4 expression levels between the two groups;after treatment,the hemoglobin concentration and TLR4 expression levels of both groups were significantly reduced (P ＜0.05).Compared with the control group,the hemoglobin concentration (119.9 ± 19.8 g/L vs.137.6 ± 17.8 g/L;t =3.270,P =0.001) and TLR4 expression level (2.5 ± 1.2 vs.4.5 ± 1.5;t =8.060,P ＜0.001) in the observation group decreased more significantly.Multivariate logistic regression analysis showed that hypertension (odds ratio [OR] 5.19,95％ confidence interval [CI] 2.31-6.71),hyperlipidemia (OR 2.70,95％ CI 1.93-4.86),previous history of stroke or transient ischemic attack (OR 6.29,95％ CI 3.23-7.32),smoking (OR 4.80,95％ CI 2.18-6.19),and the TLR4 expression level before treatment (OR 3.28,95％ CI 2.87-6.93) were independently correlated with the lack of improvement in CVS,and cerebrospinal fluid replacement was independently correlated with CVS improvement (OR 0.40,95％ CI 0.14-0.89).There was no significant difference in the incidence of adverse reactions such as blood pressure drop,obstructive hydrocephalus and gastrointestinal hemorrhage betw een the observation group and the control group,but the incidence of delayed CVS (13.3％ vs.36.7％;x2 =7.510,P =0.006) and secondary cerebral infarction (8.3％ vs.31.7％;x2 =8.800,P =0.003) in the observation group were significantly lower than those of the observation group.Conclusion Nimodipine infusion combined with cerebrospinal fluid replacement by lumbar puncture affected the hemoglobin concentration and TLR4 expression levels,improved the CVS improvement rate,and significantly improved the clinical outcome in patients with CVS after aSAH.

Signaling pathways of cerebral vasospasm after aneurysmal subarachnoid hemorrhage / 国际脑血管病杂志

Aneurysmal subarachnoid hemorrhage (aSAH) has high disability and mortality.Cerebral vasospasm is the main cause of ischemic neurological deficit and even cerebral infarction after aSAH.At present,there are many studies on molecular signaling pathways of cerebral vasospasm.This article reviews the signaling pathways of cerebral vasospasm after aSAH.

Whole-Blood miRNA Sequencing Profiling for Vasospasm in Patients With Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- Arterial vasospasm is a well-known delayed complication of aneurysmal subarachnoid hemorrhage (aSAH). However, no validated biomarker exists to help clinicians discriminating patients with aSAH who will develop vasospasm (VSP+) and identifying those who then deserve aggressive preventive therapy. We hypothesized that whole-blood miRNAs could be a source of candidate biomarkers for vasospasm. Methods- Using a next-generation sequencing approach, we performed whole-blood miRNA profiling between VSP+patients with aSAH and patients who did not develop vasospasm (VSP-) in a prospective cohort of 32 patients. Profiling was performed on the admission day and 3 days before vasospasm. Results- Four hundred forty-two miRNAs were highly expressed in whole blood of patients with aSAH. Among them, hsa-miR-3177-3p demonstrated significant ( P=5.9×10-5; PBonferronicorrected=0.03) lower levels in VSP- compared with VSP+ patients. Looking for whole-blood mRNA correlates of hsa-miR-3177-3p, we observed some evidence that the decrease in hsa-miR-3177-3p levels after aSAH was associated with an increase in LDHA mRNA levels in VSP- ( P<10-3) but not in VSP+ ( P=0.66) patients. Conclusions- Whole-blood miRNA levels of hsa-miR-3177-3p could serve as a biomarker for vasospasm. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01779713.

Relation of RhoA in Peripheral Blood Mononuclear Cells With Severity of Aneurysmal Subarachnoid Hemorrhage and Vasospasm.

BACKGROUND AND PURPOSE: Rho-kinase, an effector of RhoA, is associated with various cardiovascular diseases in circulating blood cells. However, the role of RhoA/Rho-kinase in peripheral blood mononuclear cells from patients with spontaneous aneurysmal subarachnoid hemorrhage (aSAH) has not yet been studied in relation to the severity of this disease. Therefore, we analyzed the expression and activity of RhoA as a possible biomarker in aSAH. METHODS: Twenty-four patients with aSAH and 15 healthy subjects were examined. Peripheral blood mononuclear cells were collected, and RhoA activity and expression were determined by RhoA activation assay kit (G-LISA) and enzyme-linked immunosorbent assay tests, respectively. The severity of aSAH was determined from the World Federation of Neurological Surgeon scale, and vasospasm was evaluated using clinical symptoms, arteriography, and sonography. RESULTS: RhoA expression was significantly increased in peripheral blood mononuclear cells from patients on days 0, 2, and 4 after aSAH versus healthy subjects (P=0.036, 0.010, and 0.018, respectively, by U Mann-Whitney analysis). There was a significant correlation between RhoA expression and injury severity on days 2 and 4 (Spearman test, day 2: r=0.682, n=14, P=0.007; day 4: r=0.721, n=14, P=0.004). No significant correlation was observed on day 0 (day 0: r=0.131, n=6, P=0.805). Active RhoA was not significantly different in patients and healthy subjects on days 0, 2, and 4 (P=0.243, 0.222, and 0.600, respectively) nor did it increase significantly on days 0 and 2 in patients with vasospasm versus patients without vasospasm (P=0.064 and 0.519, respectively). In contrast, active RhoA was significantly higher on day 4 in patients who developed vasospasm versus patients without vasospasm (P=0.028). CONCLUSIONS: Our preliminary results indicate that RhoA expression and activity in peripheral blood mononuclear cells might be related with aSAH severity and cerebral vasospasm. RhoA is a potential biomarker of the risks associated with aSAH.