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Current Neurology and Neuroscience... Jul 2021Aneurysmal subarachnoid hemorrhage remains a devastating disease process despite medical advances made over the past 3 decades. Much of the focus was on prevention and... (Review)
Review
PURPOSE OF REVIEW
Aneurysmal subarachnoid hemorrhage remains a devastating disease process despite medical advances made over the past 3 decades. Much of the focus was on prevention and treatment of vasospasm to reduce delayed cerebral ischemia and improve outcome. In recent years, there has been a shift of focus onto early brain injury as the precursor to delayed cerebral ischemia. This review will focus on the most recent data surrounding the pathophysiology of aneurysmal subarachnoid hemorrhage and current management strategies.
RECENT FINDINGS
There is a paucity of successful trials in the management of subarachnoid hemorrhage likely related to the targeting of vasospasm. Pathophysiological changes occurring at the time of aneurysmal rupture lead to early brain injury including cerebral edema, inflammation, and spreading depolarization. These events result in microvascular collapse, vasospasm, and ultimately delayed cerebral ischemia. Management of aneurysmal subarachnoid hemorrhage has remained the same over the past few decades. No recent trials have resulted in new treatments. However, our understanding of the pathophysiology is rapidly expanding and will advise future therapeutic targets.
Topics: Brain Ischemia; Humans; Inflammation; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 34308493
DOI: 10.1007/s11910-021-01136-9 -
Reviews on Recent Clinical Trials 2023Cerebral vasospasm is one of the frequent complications that can occur following subarachnoid hemorrhage (SAH). With new protocols in the management of SAH, the combined... (Review)
Review
BACKGROUND
Cerebral vasospasm is one of the frequent complications that can occur following subarachnoid hemorrhage (SAH). With new protocols in the management of SAH, the combined risk of death and long-term disability have been reduced by about 10% compared with the past.
OBJECTIVE
This work aims to report the latest updates on the vasospasm developing after the SAH in patients in the ICU department. In this short review, we reviewed the latest scientific findings on the mechanisms of vasospasm, and in addition, we considered it necessary to review the literature to report the tools for early diagnosis of vasospasm and the best treatment strategies to prevent the negative outcome in patients admitted to ICU.
AIM
The aim of this narrative review is to report the main characteristics of vasospasm, new diagnostic methods, and, especially, more effective treatment of vasospasm.
MATERIALS AND METHODS
The peer-reviewed articles analyzed were selected from PubMed, Google scholar, Embase, and Scopus databases published in the previous 20 years using the keywords "vasospasm", "vasospasm diagnosis", "vasospasm and SAH", "vasospasm treatment", and nontraumatic brain injury. Among the 78 papers identified, 43 articles were selected; after the title - abstract examination and removing the duplicates, only 31 articles were examined.
RESULTS
Vasospasm can be classified according to clinical (asymptomatic vs. symptomatic) and diagnostic (angiographic vs. ultrasound) methods. Various procedures such as TCD and CT perfusion are used for early diagnosis and close monitoring of this condition. The treatment of vasospasm consists of both prevention (nimodipine, statitis, and magnesium sulphate) and active treatment (mainly endovascular).
CONCLUSION
As the review shows, vasospasm is a complication of SAH, a complication that is difficult to recognize early and treat with the best outcome. However, with the equipment we have, it has been possible to improve the outcome, even if it is still not ideal, in patients who develop vasospasm. Several studies are in the final stages to improve the outcome of this unfortunately frequent condition.
Topics: Humans; Vasospasm, Intracranial; Brain Injuries; Subarachnoid Hemorrhage; Nimodipine; Treatment Outcome
PubMed: 35950252
DOI: 10.2174/1574887117666220810121048 -
Journal of Neurosurgery Dec 2022Clazosentan has been investigated globally for the prevention of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). The authors evaluated its effects on... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of clazosentan on cerebral vasospasm-related morbidity and all-cause mortality after aneurysmal subarachnoid hemorrhage: two randomized phase 3 trials in Japanese patients.
OBJECTIVE
Clazosentan has been investigated globally for the prevention of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). The authors evaluated its effects on vasospasm-related morbidity and all-cause mortality following aSAH in Japanese patients.
METHODS
Two similar double-blind, placebo-controlled phase 3 studies were conducted in 57 Japanese centers in patients with aSAH, after aneurysms were secured by endovascular coiling in one study and surgical clipping in the other. In each study, patients were randomly administered intravenous clazosentan (10 mg/hr) or placebo (1:1) starting within 48 hours of aSAH and for up to 15 days after aSAH. Stratified randomization based on World Federation of Neurosurgical Societies grade was performed using a centralized interactive web response system. Vasospasm-related morbidity and all-cause mortality within 6 weeks post-aSAH, including new cerebral infarcts and delayed ischemic neurological deficits as well as all-cause mortality, were the first primary endpoint in each study. The second primary endpoint was all-cause morbidity (new cerebral infarct or delayed ischemic neurological deficit from any causes) and all-cause mortality (all-cause morbidity/mortality) within 6 weeks post-aSAH. The incidence of individual components of the primary morbidity/mortality endpoints within 6 weeks and patient outcome at 12 weeks post-aSAH (including the modified Rankin Scale scores) were also evaluated. The above analyses were also performed in the population pooled from both studies.
RESULTS
In each study, 221 patients were randomized and 220 were included in the full analysis set of the primary analysis (109 in each clazosentan group, 111 in each placebo group). Clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality after aneurysm coiling (from 28.8% to 13.6%; relative risk reduction 53%; 95% CI 17%-73%) and after clipping (from 39.6% to 16.2%; relative risk reduction 59%; 95% CI 33%-75%). All-cause morbidity/mortality and poor outcome (dichotomized modified Rankin Scale scores) were significantly reduced by clazosentan after preplanned study pooling. Treatment-emergent adverse events were similar to those reported previously.
CONCLUSIONS
Clazosentan significantly reduced the combined incidence of vasospasm-related morbidity and all-cause mortality post-aSAH with no unexpected safety findings. Clinical trial registration nos.: JapicCTI-163368 and JapicCTI-163369 (https://www.clinicaltrials.jp).
Topics: Humans; Vasospasm, Intracranial; Subarachnoid Hemorrhage; Japan; Cerebral Infarction; Morbidity; Treatment Outcome
PubMed: 35364589
DOI: 10.3171/2022.2.JNS212914 -
Neurologic Clinics Feb 2020Transcranial Doppler ultrasonography (TCD) is a noninvasive, bedside, portable tool for assessment of cerebral hemodynamics. Modern TCD head frames allow continuous... (Review)
Review
Transcranial Doppler ultrasonography (TCD) is a noninvasive, bedside, portable tool for assessment of cerebral hemodynamics. Modern TCD head frames allow continuous hands-free emboli detection for risk stratification and assessment of treatment efficacy in several cardiovascular diseases. Identifying a focal stenosis, arterial occlusion, and monitoring the treatment effect of intravenous tissue plasminogen activator can easily be accomplished by assessing TCD waveforms and determining prestenotic and poststenotic mean flow velocities. TCD is an excellent screening tool for vasospasm in aneurysmal subarachnoid hemorrhage. The use of intraoperative TCD during carotid endarterectomy and stenting allows optimal intraoperative hemodynamic management. Other applications are also discussed.
Topics: Humans; Intracranial Embolism; Subarachnoid Hemorrhage; Tissue Plasminogen Activator; Ultrasonography, Doppler, Transcranial; Vasospasm, Intracranial
PubMed: 31761060
DOI: 10.1016/j.ncl.2019.09.006 -
Neurocritical Care Oct 2019Intrathecal nicardipine has been shown to have some efficacy for the treatment of symptomatic cerebral vasospasm in aneurysmal subarachnoid hemorrhage (aSAH). We...
Intrathecal nicardipine has been shown to have some efficacy for the treatment of symptomatic cerebral vasospasm in aneurysmal subarachnoid hemorrhage (aSAH). We performed a PRISMA-based systematic review of intrathecal nicardipine for the treatment of cerebral vasospasm in aneurysmal subarachnoid hemorrhage. A total of 825 articles were reviewed. After duplicates were removed and the search criteria was applied, 9 articles remained that were eligible for inclusion and analysis. 377 patients received a total of 6,596 injections of intrathecal nicardipine for aSAH-related cerebral vasospasm. The cumulative ventriculostomy-associated infection risk was 6%. Intrathecal nicardipine injections for aSAH-related cerebral vasospasm appears efficacious and safe. Administration of 4 mg of nicardipine every 12 hours was the most commonly reported dosing regimen. Intrathecal nicardipine decreases mean flow velocities on transcranial Doppler and reduces angiographic and clinical vasospasm. The infection risk appears to be in-line with studies in which rates of EVD-related infections have been reported.
Topics: Blood Flow Velocity; Cerebrovascular Circulation; Humans; Injections, Intraventricular; Injections, Spinal; Nicardipine; Subarachnoid Hemorrhage; Treatment Outcome; Ultrasonography, Doppler, Transcranial; Vasodilator Agents; Vasospasm, Intracranial; Ventriculostomy
PubMed: 30607826
DOI: 10.1007/s12028-018-0659-9 -
International Journal of Stroke :... Dec 2023Reversible segmental narrowing of the intracranial arteries has been described since several decades in numerous clinical settings, using variable nosology. Twenty-one... (Review)
Review
Reversible segmental narrowing of the intracranial arteries has been described since several decades in numerous clinical settings, using variable nosology. Twenty-one years ago, we tentatively proposed the unifying concept that these entities, based on similar clinical-imaging features, represented a single cerebrovascular syndrome. This "reversible cerebral vasoconstriction syndrome" or RCVS has now come of age. A new International Classification of Diseases code, (ICD-10, I67.841) has been established, enabling larger-scale studies. The RCVS2 scoring system provides high accuracy in confirming RCVS diagnosis and excluding mimics such as primary angiitis of the central nervous system. Several groups have characterized its clinical-imaging features. RCVS predominantly affects women. Recurrent worst-ever (thunderclap) headaches are typical at onset. While initial brain imaging is often normal, approximately one-third to half develop complications such as convexity subarachnoid hemorrhages, lobar hemorrhages, ischemic strokes located in arterial "watershed" territories and reversible edema, alone or in combination. Vasoconstriction evolves over hours to days, first affecting distal and then the more proximal arteries. An overlap between RCVS and primary thunderclap headache, posterior reversible encephalopathy syndrome, Takotsubo cardiomyopathy, transient global amnesia, and other conditions has been recognized. The pathophysiology remains largely unknown. Management is mostly symptomatic: headache relief with analgesics and oral calcium-channel blockers, removal of vasoconstrictive factors, and avoidance of glucocorticoids that can significantly worsen outcome. Intra-arterial vasodilator infusions provide variable success. Overall, 90-95% of admitted patients achieve complete or major resolution of symptoms and clinical deficits within days to weeks. Recurrence is exceptional, although 5% can later develop isolated thunderclap headaches with or without mild cerebral vasoconstriction.
Topics: Humans; Female; Vasoconstriction; Posterior Leukoencephalopathy Syndrome; Stroke; Cerebrovascular Disorders; Headache; Vasospasm, Intracranial
PubMed: 37246916
DOI: 10.1177/17474930231181250 -
Drugs Apr 2022Clazosentan (PIVLAZ) is a small molecule, endothelin (ET) A receptor-selective antagonist being developed by Idorsia Pharmaceuticals. ET receptor inhibition by... (Review)
Review
Clazosentan (PIVLAZ) is a small molecule, endothelin (ET) A receptor-selective antagonist being developed by Idorsia Pharmaceuticals. ET receptor inhibition by clazosentan decreases ET-related cerebral vasospasm, which may occur after an aneurysmal subarachnoid haemorrhage. Clazosentan has been approved in Japan for use in the prevention of cerebral vasospasm, vasospasm-related cerebral infarction and cerebral ischaemic symptoms after aneurysmal subarachnoid haemorrhage, following the results from the JapicCTI163369 and JapicCTI163368 phase III trials. This article summarises the milestones in the development of clazosentan leading to this first approval in this indication.
Topics: Dioxanes; Endothelin A Receptor Antagonists; Humans; Pyridines; Pyrimidines; Subarachnoid Hemorrhage; Sulfonamides; Tetrazoles; Vasospasm, Intracranial
PubMed: 35362854
DOI: 10.1007/s40265-022-01708-0 -
Innere Medizin (Heidelberg, Germany) Jun 2022Vascular acrosyndromes are characterized by sparse, uniform clinical manifestations and a variety of possible pathomechanisms. The present article focuses on the... (Review)
Review
Vascular acrosyndromes are characterized by sparse, uniform clinical manifestations and a variety of possible pathomechanisms. The present article focuses on the functional entities. Raynaud phenomenon is based on cold- or stress-induced vasospasms of acral arteries. It is defined by the color changes of the skin, in the typical case white-blue-red (tricolore). The long fingers are most commonly affected. The etiology is unknown, and the pathophysiology is poorly understood. A distinction is made between primary and a secondary Raynaud phenomenon. The most important underlying diseases include collagenosis, primarily systemic sclerosis, and malignancies; furthermore, medications and drugs may promote vasospasm. Treatment is aimed at preventing or breaking the vasospasm, but has been only partially effective in doing so. Acrocyanosis is a vasospastic dystonic acral disorder that results in permanent reddish-livid discoloration, especially of the hands and feet. Secondary forms occur in collagenosis, malignancies, and myelodysplastic syndromes. The etiology and pathophysiology are virtually unknown. Targeted pharmacological intervention is not possible. Unlike all other vascular acrosyndromes, erythromelalgia is characterized by hyperemia. The primary form is a genetic sodium channelopathy, while secondary forms include malignancies, connective tissue diseases, and myelodysplastic syndromes. The symptoms are often distressing and disabling. Therapy requires a multimodal approach that includes both nonpharmacological and pharmacological strategies. Close interdisciplinary collaboration is essential for the management of this disease.
Topics: Cyanosis; Erythromelalgia; Humans; Myelodysplastic Syndromes; Raynaud Disease; Vascular Diseases
PubMed: 35925129
DOI: 10.1007/s00108-022-01340-w -
Neurosurgery Dec 2023Clazosentan has been studied to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH).This meta-analysis of randomized controlled trials updates the... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
Clazosentan has been studied to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH).This meta-analysis of randomized controlled trials updates the current knowledge regarding the efficacy and safety of clazosentan compared with placebo after aSAH.
METHODS
Databases were systematically searched for randomized controlled trials directly comparing the use of clazosentan and placebo for the treatment of cerebral vasospasm after aSAH. Additional eligibility criteria were the report of any of the outcomes of interest (vasospasm, morbidity, functional outcome, or mortality). The primary outcome was vasospasm-related delayed cerebral ischemia (DCI). The analyses were stratified by clazosentan dosage (low or high dose) and aneurysm treatment modality (clipping or coiling). The Cochrane RoB-2 tool was used for studies quality assessment.
RESULTS
Six studies comprising 7 clinical trials were included, involving 2778 patients. Clazosentan decreased the risk of vasospasm-related DCI (risk ratio [RR] 0.56, 95% CI 0.38-0.81) and delayed ischemic neurological deficit (RR 0.63, 95% 0.50-0.80). Angiographic vasospasm (RR 0.54, 95% CI 0.47-0.61) was also decreased. Functional outcomes (favorable Glasgow Outcome Scale, RR 0.99, 95% CI 0.79-1.24) and death (RR 1.03, 95% CI 0.71-1.49) did not change. Meanwhile, adverse events were increased by clazosentan (RR 1.54, 95% CI 1.35-1.76).
CONCLUSION
Clazosentan decreased vasospasm-related DCI and angiographic vasospasm but did not improve functional outcomes or mortality. Adverse events were increased by clazosentan.
Topics: Humans; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial; Dioxanes; Brain Ischemia; Cerebral Infarction
PubMed: 37462365
DOI: 10.1227/neu.0000000000002601 -
CNS Neuroscience & Therapeutics Jun 2022Subarachnoid hemorrhage (SAH) is a common acute and severe disease worldwide, which imposes a heavy burden on families and society. However, the current therapeutic... (Review)
Review
Subarachnoid hemorrhage (SAH) is a common acute and severe disease worldwide, which imposes a heavy burden on families and society. However, the current therapeutic strategies for SAH are unsatisfactory. Hydrogen sulfide (H S), as the third gas signaling molecule after carbon monoxide and nitric oxide, has been widely studied recently. There is growing evidence that H S has a promising future in the treatment of central nervous system diseases. In this review, we focus on the effects of H S in experimental SAH and elucidate the underlying mechanisms. We demonstrate that H S has neuroprotective effects and significantly reduces secondary damage caused by SAH via antioxidant, antiinflammatory, and antiapoptosis mechanisms, and by alleviating cerebral edema and vasospasm. Based on these findings, we believe that H S has great potential in the treatment of SAH and warrants further study to promote its early clinical application.
Topics: Animals; Antioxidants; Humans; Hydrogen Sulfide; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 35315575
DOI: 10.1111/cns.13828