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.

Vasoespasmo cerebral y déficit isquémico tardío en la hemorragia subaracnoídea aneurismática: guías para su manejo clínico / Cerebral vasospasm and delayed ischemic deficit in the aneurysmal subarachnoid hemorrhage: guidelines to its clinical management

La presente revisión del tema Vasoespasmo y Déficit Isquémico Cerebral tardío (DIT) en la Hemorragia subaracnoidea aneurismática tiene como objetivo actualizar su manejo, basado en las hipótesis mas aceptadas que se han logrado para explicar su patogénesis. Se efectúa una introducción con conceptos generales, se revisan las bases patogénicas del Vasoespasmo y se plantea su manejo, tomando en cuenta su diagnóstico, monitorización, profilaxis y manejo avanzado de acuerdo a las últimas Guías de Manejo Clínico y según medicina basada en las evidencias.

The objective of the present review on cerebral vasospasm and cerebral delayed isquemic deficit due to subarachnoid haemorrhage secondary to ruptured cerebral aneurysm, is to update their management, based on the most accepted pathophysiological hypotesis explaining their pathogenetic mechanisms. An introduction is performed presenting general concepts, review of the most recent research works explaining their pathogenesis, and the management is stated touching diagnosis, monitoring, prophylaxis, and advanced management according with the last clinical guidelines for his management using medicine based on evidences.

Erythropoietin in vasospasm. From bench to bedside? / Eritropoietina no vasoespasmo. Da bancada do laboratório para a beira do leito?

Aneurysmal subarachnoid haemorrhage is one of the most deleterious acute neurological diseases. The cerebral ischemia secondary to arterial vasospasm occurring after aneurysmal subarachnoid haemorrhage is still responsible for the considerable morbidity and mortality in these patients. Besides the knowledge of basic mechanisms of cerebral vasoespasm following aneurysmal subarachnoid haemorrhage, the prophylaxis and treatment of this pathology however still remain suboptimal. There issome evidence that acute erythropoietin treatment may reduce the severity of cerebral vasospasm and eventually improve outcome in aneurysmal subarachnoid haemorrhage patients. There are underlying mechanisms extend far beyond erythropoiesis: like enhancing neurogenesis, decreasing inflammation and apoptosis inhibition. In this review the authors describe many of the biologic effects, especially experimental studies and clinical studies that reported why the erythropoietin could be beneficial topatients with aneurysmal subarachnoid haemorrhage.

A hemorragia subaracnóidea é uma das doenças neurológicas agudas mais graves. A isquemia cerebral secundária ao vasoespasmo arterial após a hemorragia ainda é responsável por considerável morbidade e mortalidade nesses pacientes. Ao lado do conhecimento dos mecanismos básicos do vasoespasmo na hemorragia subaracnóidea, a profilaxia e o tratamento dessa entidade ainda são insuficientes. Há evidências de que o uso da eritropoietina na fase aguda pode reduzir a gravidade do vasoespasmo e,eventualmente, melhorar o prognóstico desses pacientes. Há mecanismos de ação da eritropoietina que vão além da eritropoiese como neurogênese, redução da inflamação e inibição da apoptose. Nesta revisão, os autores elucidam inúmeros efeitos biológicos, principalmente aqueles demonstrados nos estudos experimentais e clínicos que descrevem por que a eritropoietina pode ser benéfica em pacientes com hemorragia subaracnóidea.

Intraventricular sodium nitroprusside therapy: a future promise for refractory subarachnoid hemorrhage-induced vasospasm.

A prospective study was carried out to evaluate the efficacy of intraventricular sodium nitroprousside (SNP) in the reversal of refractory vasospasm secondary to aneurysmal subarachnoid hemorrhage (SAH). Ten patients of aneurysmal SAH with symptomatic vasospasm, corroborated on Transcranial Doppler (TCD) and/or angiography, were included in the study. The mean age distribution of the patients was 50.8 years (range 33-65 years) with an equal number of males and females. Once vasospasm was refractory even after 12 hours of SAH therapy, intraventricular SNP was instilled in an escalating dose and the reversal of vasospasm was monitored on TCD and/or angiography. All patients showed improvement in TCD velocity on day 0 through day 3. Partial to complete reversal of vasospasm was demonstrated on angiography in all the patients, though not in all the vessels. Two patients who had weakness of limbs due to vasospasm improved following intraventricular SNP therapy. Vomiting was the commonest adverse effect (7/10). Three patients had mild fluctuation in blood pressure. The overall outcome was good in 6 out of 10 patients. The study suggests that intraventricular SNP therapy is effective in reversing the changes even in established cases of SAH-induced vasospasm.

effect of intra-arterial papa verine and/or angioplasty on the cerebral veins in patients with vasospasm following subarachnoid hemorrhage due to ruptured intracranial aneurysms

This study was performed in an attempt to determine if there is a change in intracranial venous diameters following carotid distribution endovascular treatment of vasospasm due to subarachnoid hemorrhage. The venous diameters were measured in all patients who received intra-arterial papaverine and/or balloon angioplasty for treatment of vasospasm from April 1993 to September 1996. The mean measured venous diameters increased significantly following papaverine [10.9%] and following papaverine and angioplasty [4.2%]. There was no statistically significant increase in mean venous diameters following angioplasty alone. Endovascular treatment produces measurable increases in intra-cranial venous diameters. However, these changes do not correlate with changes in ICP