cardiovascular-agents and Subarachnoid-Hemorrhage

To compare the effectiveness of various drug interventions in improving the clinical outcome of postoperative patients after aneurysmal subarachnoid hemorrhage (aSAH) and assist in determining the drugs of definite curative effect in improving clinical prognosis.. Eligible Randomized Controlled Trials (RCTs) were searched in databases of PubMed, EMBASE, and Cochrane Library (inception to Sep 2020). Glasgow Outcome Scale (GOS) score, Extended Glasgow Outcome Scale (GOSE) score or modified Rankin Scale (mRS) score was used as the main outcome measurements to evaluate the efficacy of various drugs in improving the clinical outcomes of postoperative patients with aSAH. The network meta-analysis (NMA) was conducted based on a random-effects model, dichotomous variables were determined by using odds ratio (OR) with 95% confidence interval (CI), and a surface under the cumulative ranking curve (SUCRA) was generated to estimate the ranking probability of comparative effectiveness among different drug therapies.. From the 493 of initial citation screening, forty-four RCTs (n = 10,626 participants) were eventually included in our analysis. Our NMA results showed that cilostazol (OR = 3.35,95%CI = 1.50,7.51) was the best intervention to improve the clinical outcome of patients (SUCRA = 87.29%, 95%CrI 0.07-0.46). Compared with the placebo group, only two drug interventions [nimodipine (OR = 1.61, 95%CI 1.01,2.57) and cilostazol (OR = 3.35, 95%CI 1.50, 7.51)] achieved significant statistical significance in improving the clinical outcome of patients.. Both nimodipine and cilostazol have exact curative effect to improve the outcome of postoperative patients with aSAH, and cilostazol may be the best drug to improve the outcome of patients after aSAH operation. Our study provides implications for future studies that, the combination of two or more drugs with relative safety and potential benefits (e.g., nimodipine and cilostazol) may improve the clinical outcome of patients more effectively.

Topics: Cardiovascular Agents; Cilostazol; Humans; Intracranial Aneurysm; Network Meta-Analysis; Neuroprotective Agents; Nimodipine; Postoperative Period; Prognosis; Randomized Controlled Trials as Topic; Subarachnoid Hemorrhage; Treatment Outcome

Delayed cerebral ischemia seriously affects the prognosis of patients surviving the initial aneurysmal subarachnoid hemorrhage. Application of cilostazol was reported to ameliorate vasospasm and improve outcomes in series and clinical trials. But the effectiveness and feasibility of cilostazol on aneurysmal subarachnoid hemorrhage remained controversial. We performed a systematic review to clarify this issue.. PubMed, Ovid and Cochrane library database were systematically searched up to May 2018 for eligible publications in English. Quality assessment was conducted for included studies. Meta-analysis was conducted to evaluate the overall effect on events of interest. Subgroup analyses and sensitivity analyses were used to check whether the results were robust. Publication bias was evaluated with the funnel plot.. Pooled analyses found cilostazol significantly reduced incidences of severe angiographic vasospasm (p = 0.0001), symptomatic vasospasm (p < 0.00001), new cerebral infarction (p < 0.00001) and the poor outcome (p < 0.0001). Subgroup and sensitivity analyses achieved consistent results. There was no statistical difference between cilostazol and the control group in reducing mortality (p = 0.07). But sensitivity analysis changed the result after excluding one study. Under the prescribed dosage, complication was few and non-lethal.. Cilostazol was effective and safe to reduce incidences of severe angiographic vasospasm, symptomatic vasospasm, new cerebral infarction and poor outcome in patients after aneurysmal subarachnoid hemorrhage. However, its effect on mortality and the interactive effect with nimodipine warranted further research.

Topics: Brain Ischemia; Cardiovascular Agents; Cerebral Infarction; Cilostazol; Humans; Intracranial Aneurysm; Outcome Assessment, Health Care; Subarachnoid Hemorrhage; Vasospasm, Intracranial

The purpose of this article is to describe the modern management of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (SAH). SAH causes an inflammatory reaction to blood products in the basal cisterns of the brain, which may produce cerebral ischemia and strokes through progressive narrowing of the cerebral artery lumen. This process, known as cerebral vasospasm, is the most common cause of DCI after SAH. Untreated DCI may result in strokes, which account for a significant portion of the death and long-term disability after SAH.. A number of publications, including two recent consensus statements, have clarified many best practices for defining, diagnosing, monitoring, preventing, and treating DCI. DCI is best defined as new onset of focal or global neurologic deficits or strokes not attributable to another cause. In addition to the clinical examination, radiographic studies such as transcranial Doppler ultrasonography, CT angiography, and CT perfusion may have a role in determining which patients are at high risk for developing DCI. The mainstay of prevention and treatment of DCI is maintenance of euvolemia, which can be a difficult therapeutic target to measure. Hemodynamic augmentation with induced hypertension with or without inotropic support has become the first-line treatment of DCI. The ideal method of measuring hemodynamic values and volume status in patients with DCI remains elusive. In patients who do not adequately respond to or cannot tolerate hemodynamic augmentation, endovascular therapy (intraarterial vasodilators and balloon angioplasty) is a complementary strategy. Optimal triggers for escalation and de-escalation of therapies for DCI have not been well defined.. Recent guidelines and consensus statements have clarified many aspects of prevention, monitoring, and treatment of DCI after SAH. Controversies continue regarding the optimal methods for measurement of volume status, the role of invasive neuromonitoring, and the targets for hemodynamic augmentation therapy.

Topics: Angioplasty, Balloon; Brain Ischemia; Calcium Channel Blockers; Cardiovascular Agents; Cerebral Angiography; Combined Modality Therapy; Consensus Development Conferences as Topic; Disease Management; Fluid Therapy; Hemodynamics; Humans; Hypertension; Intracranial Aneurysm; Neuroimaging; Nimodipine; Practice Guidelines as Topic; Rupture, Spontaneous; Subarachnoid Hemorrhage; Ultrasonography, Doppler, Transcranial; Vasospasm, Intracranial

The vast amount of literature on the pharmaceutical treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage remains daunting. Optimal treatment regimens for patients can be obscured by studies not statistically powered to draw evidenced-based conclusions.. In this chapter, we reviewed the English literature using the National Library of Medicine for studies regarding pharmacotherapies for the treatment of cerebral vasospasm. These studies were then categorized according to the US Preventative Services Task Force ranking system for evidence based medicine and reviewed each pharmacotherapy for its efficacy in the treatment of cerebral vasospasm.. Nimodipine (Nimotop), HMG Co-A reductase inhibitor (statins) and enoxaparin (Lovenox) were the only drugs with level-1 evidence available for the treatment of vasospasm from aneurysmal subarachnoid hemorrhage as defined by the US Preventative Services Task Force.. As the understanding of the pathophysiological mechanisms of vasospasm after aneurysmal subarachnoid hemorrhage evolves in the basic science laboratory, novel medications are being trialed in humans. However, significantly more work must be carried out in this area before we have an effective medical treatment that can prevent or reverse the devastating events of cerebral vasospasm.

Topics: Animals; Cardiovascular Agents; Enoxaparin; Evidence-Based Medicine; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Nimodipine; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Subarachnoid haemorrhage (SAH) from a ruptured cerebral aneurysm carries high morbidity and mortality. Despite huge advances in techniques to secure the aneurysm, there has been little progress in the treatment of the deleterious effects of the haemorrhage.Sulforaphane is an Nrf2 inducer with anti-oxidant and anti-inflammatory properties. It has been shown to improve clinical outcome in experimental models of SAH, but is unstable. SFX-01 (Evgen Pharma) is a novel composition comprised of synthetic sulforaphane stabilised within an α-cyclodextrin complex. On ingestion, the complex releases sulforaphane making SFX-01 an ideal vehicle for delivery of sulforaphane.. The objective of the study is to assess the safety, pharmacokinetics and efficacy of SFX-01. This is a prospective, multicentre, randomised, double-blind placebo-controlled trial in patients aged 18-80 years with aneurysmal subarachnoid haemorrhage in the previous 48 hours. 90 patients will be randomised to receive SFX-01 (300 mg) or placebo two times per day for up to 28 days.Safety will be assessed using blood tests and adverse event reporting.Pharmacokinetics will be assessed based on paired blood and cerebrospinal fluid (CSF) sulforaphane levels on day 7. A subgroup will have hourly samples taken during 6 hours post-dosing on days 1 and 7. Pharmacodynamics will be assessed by haptoglobin and malondialdehyde levels, and maximum flow velocity of middle cerebral artery will be measured by transcranial Doppler ultrasound.Clinical outcomes will be assessed at days 28, 90 and 180 with modified Rankin Scale, Glasgow Outcome Score, SAH Outcome Tool, Short Form-36, Brain Injury Community Rehabilitation Outcome Scales and Check List for Cognitive and Emotional consequences following stroke. MRI at 6 months including quantitative susceptibility mapping and volumetric T1 will measure iron deposition and cortical volume.Safety, CSF sulforaphane concentration and middle cerebral artery flow velocity will be primary outcomes and all others secondary.. Ethical approval was obtained from South Central Hampshire A committee. Outcomes of the trial will be submitted for publication in a peer-reviewed journal.. NCT02614742.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; alpha-Cyclodextrins; Cardiovascular Agents; Clinical Protocols; Dosage Forms; Double-Blind Method; Drug Delivery Systems; Drug Stability; Female; Humans; Isothiocyanates; Male; Middle Aged; Prospective Studies; Subarachnoid Hemorrhage; Sulfoxides; Treatment Outcome; Young Adult

The sphingosylphosphorylcholine-Rho-kinase pathway plays an important role in Ca(2+) sensitization of vascular smooth muscle contraction. Eicosapentaenoic acid (EPA) inhibits sphingosylphosphorylcholine -Rho-kinase-activated Ca(2+)-sensitization in vitro and in subarachnoid hemorrhage (SAH) models in vivo and has also been shown to inhibit the occurrence of cerebral vasospasm (CIV) after the onset of SAH in a prospective, nonrandomized study. The current prospective, multicenter, randomized study was performed to confirm the preventive effects of EPA on CIV in patients with SAH.. The trial population comprised 162 patients who underwent surgical clipping within 72 hours of the onset of SAH. Of these patients, 81 received 2700 mg/day EPA from the day after surgery until day 30 (EPA group), and 81 did not receive EPA (control group). The primary end point was the occurrence of symptomatic vasospasm (SV) or cerebral infarction caused by CIV.. The occurrences of SV (15% vs. 30%; P = 0.022) and CIV (7% vs. 21%; P = 0.012) were lower in the EPA group. Multivariate analysis revealed an adjusted odds ratio of 0.39 (95% confidence interval, 0.17-0.89; P = 0.028) for SV inhibition by EPA and 0.27 (95% confidence interval, 0.09-0.72; P = 0.012) for CIV inhibition.. These results indicate that oral EPA reduces the frequency of SV and CIV after the onset of aneurysmal SAH.

Topics: Aged; Arachidonic Acid; Cardiovascular Agents; Combined Modality Therapy; Eicosapentaenoic Acid; Female; Humans; Male; Middle Aged; Odds Ratio; Phosphorylcholine; Prospective Studies; rho-Associated Kinases; Signal Transduction; Sphingosine; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Late cerebral vasospasm after subarachnoid hemorrhage (SAH) is a disastrous phenomenon for the patients and a definite treatment has not been established. We studied 48 consecutive patients receiving high-dose diltiazem (5 micrograms/kg/min) injection combined with dextran and hydrocortisone to late cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). All but 2 patients underwent surgery within 72 hours after SAH. Diltiazem was continuously given via a central venous line for up to 2 weeks in conjunction with simple cisternal drainage. 5% of dextran solution (500 ml/day) was infused for 7-10 days. Hydrocortisone was given 1,600 mg on the first day, then the dose was gradually decreased over 14 days. Symptomatic vasospasm (SVS) occurred in 5 patients (10.4%), 4 patients recovered, but 1 had severe neurological deficit. A low density area on CT-scan was observed in 2 patients. Thirty patients (62.5%) had good recovery, 10 patients (20.8%) had moderate disability, 3 (6.3%) had severe disability and 3 (6.3%) had vegetative survival. Two patients died of the initial brain damage. There were no severely hypotensive side effects. However, 3 patients showed atrioventricular blockage on electrocardiogram. These side effects subsided after the dose of the drug was decreased or administration was stopped altogether. These findings show that high-dose calcium antagonist diltiazem therapy combined with dextran and hydrocortisone injection is safe and effective for prevention of late cerebral symptomatic vasospasm after SAH.

Topics: Adult; Aged; Aged, 80 and over; Aneurysm, Ruptured; Anti-Inflammatory Agents; Anticoagulants; Blood Pressure; Cardiovascular Agents; Dextrans; Diltiazem; Drug Therapy, Combination; Female; Heart Rate; Humans; Hydrocortisone; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Subarachnoid Hemorrhage; Tomography, X-Ray Computed

Human Albumin is a unique pleiotropic protein with multiple properties. Previous clinical and laboratory studies have indicated a possible beneficial effect of Albumin in subarachnoid hemorrhage (SAH). The present study aimed to further define the preclinical characteristics of Albumin. SAH was induced by endovascular perforation in Sprague-Dawley rats. In the dose-escalation study, Albumin ranging from 0.02g/kg to 1.0g/kg was intravenously infused immediately after SAH. In the therapeutic window study, 1.0g/kg Albumin was administered at 0h, 2h, 4h or 8h after SAH. Physiologic variables were monitored in different Albumin treatment regimens. One day after SAH, neurological scores, SAH scores, blood-brain barrier permeability, neural degeneration and apoptosis were examined. The efficacy of Albumin for SAH was also determined in female rats and in spontaneously hypertensive rats. We found that 0.2g/kg and 1.0g/kg Albumin significantly attenuated sensorimotor deficits, brain edema, IgG leakage, and neuronal degeneration after SAH. The benefits of Albumin existed even when the administration was delayed to 4h after SAH onset. No significant difference was found between 0.2g/kg and 1.0g/kg Albumin groups. In female rats and spontaneously hypertensive rats, Albumin likewise improved neurological outcomes and early brain injury. In conclusion, Albumin could reduce both cerebral lesions and functional deficits in the early stage of SAH. The beneficial regimen occurs within a favorable therapeutic window and is reproducible in different high-risk subjects.

Topics: Albumins; Animals; Brain; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; Hypertension; Male; Neuroprotective Agents; Random Allocation; Rats, Inbred SHR; Rats, Sprague-Dawley; Severity of Illness Index; Subarachnoid Hemorrhage; Time Factors

Our previous findings indicated that in rats subjected to subarachnoid hemorrhage (SAH), suppression of post-SAH neuroinflammation via vascular adhesion protein-1 (VAP-1) blockade provides significant neuroprotection. We and others have reported that neuroinflammation contributes to cerebral microvascular impairment. Thus, in the present study, we tested the hypotheses that: (1) treatment with LJP-1586, a selective VAP-1 blocker, prevents SAH-associated pial arteriolar dilating dysfunction; and (2) the vasculoprotective effect of LJP-1586 arises from inhibiting SAH-elicited neutrophil recruitment. We utilized an endovascular perforation model of SAH. Rats subjected to SAH were either treated with LJP-1586 or rendered neutropenic via anti-neutrophil-antibody treatment. Findings from these groups were compared to their respective control groups. At 48 h post-SAH, rats were evaluated for neurobehavioral function, pial venular leukocyte trafficking, and pial arteriolar reactivity to topically-applied acetylcholine (ACh) and S-nitroso-N-acetyl penicillamine (SNAP). Pial arteriolar responses decreased at 48 h post-SAH. However, in the presence of LJP-1586, those responses were significantly preserved. Neutrophil-depletion yielded a substantial suppression of SAH-associated leukocyte adhesion and infiltration. This was accompanied by a significant preservation of pial arteriolar dilating function, suggesting a direct link between neutrophil recruitment and the loss of cerebral microvascular reactivity. Moreover, neutrophil depletion also was associated with significant protection of neurobehavioral function. The present findings suggest that attenuating SAH-linked elevation in neutrophil trafficking will protect against the development of microvascular dysfunction and subsequent neurological impairment.

Topics: Acetylcholine; Allylamine; Amine Oxidase (Copper-Containing); Animals; Arterioles; Cardiovascular Agents; Cell Adhesion Molecules; Cerebrovascular Circulation; Cholinergic Agonists; Disease Models, Animal; Leukocytes; Male; Neuroimmunomodulation; Neutrophil Infiltration; Neutrophils; Nitric Oxide Donors; Pia Mater; Rats, Sprague-Dawley; Regional Blood Flow; S-Nitroso-N-Acetylpenicillamine; Subarachnoid Hemorrhage; Venules

Cardiac abnormalities attributed to adrenergic surge are common after aneurysmal subarachnoid hemorrhage. Prescribed medications that block adrenergic stimulation may suppress the onset of cardiopulmonary compromise in patients after aneurysmal subarachnoid hemorrhage.. To compare the incidence of early cardiac complications between patients who reported prescribed use of β-blockers and/or angiotensin-converting enzyme inhibitors before aneurysmal subarachnoid hemorrhage and patients who did not.. A retrospective review of 254 adult patients after acute aneurysmal subarachnoid hemorrhage who were enrolled in an existing R01 study. Demographic data and history were obtained from patients'/proxies' reports and charts. Cardiac enzyme levels, 12-lead electrocardiograms, and chest radiographs were obtained on admission. Holter monitoring and echocardiograms were completed as a part of the R01 study.. Patients reporting prescribed use of angiotensin-converting enzyme inhibitors or β-blockers before aneurysmal subarachnoid hemorrhage had more ventricular and supraventricular ectopy on a Holter report than did patients who did not (P < .05). When age, race, sex, and injury (Fisher grade) were controlled for, patients reporting use of β-blockers were 8 times more likely than others to have occasional to frequent ventricular ectopy (P = .02).. No concrete evidence was found that exposure to adrenergic blockade before aneurysmal subarachnoid hemorrhage provides protection from neurocardiac injury.

Topics: Adrenergic beta-Antagonists; Adult; Age Distribution; Aged; Aneurysm, Ruptured; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Female; Heart; Heart Diseases; Humans; Intracranial Aneurysm; Male; Middle Aged; Retrospective Studies; Sex Distribution; Subarachnoid Hemorrhage; Survival Analysis; Young Adult

Topics: Cardiovascular Agents; Eicosapentaenoic Acid; Female; Humans; Male; Subarachnoid Hemorrhage; Vasospasm, Intracranial

The information on the existence of sex differences in management of stroke patients is scarce. We evaluated whether sex differences may influence clinical presentation, resource use, and outcome of stroke in a European multicenter study.. In a European Concerted Action involving 7 countries, 4499 patients hospitalized for first-in-a-lifetime stroke were evaluated for demographics, risk factors, clinical presentation, resource use, and 3-month survival, disability (Barthel Index), and handicap (Rankin Scale).. Overall, 2239 patients were males and 2260 females. Compared with males, female patients were significantly older (mean age 74.5+/-12.5 versus 69.2+/-12.1 years), more frequently institutionalized before stroke, and with a worse prestroke Rankin score (all values P<0.001). History of hypertension (P=0.007) and atrial fibrillation (P<0.001) were significantly more frequent in female stroke patients, as were coma (P<0.001), paralysis (P<0.001), aphasia (P=0.001), swallowing problems (P=0.005), and urinary incontinence (P<0.001) in the acute phase. Brain imaging, Doppler examination, echocardiogram, and angiography were significantly less frequently performed in female than male patients (all values P<0.001). The frequency of carotid surgery was also significantly lower in female patients (P<0.001). At the 3-month follow-up, after controlling for all baseline and clinical variables, female sex was a significant predictor of disability (odds ratio [OR], 1.41; 95% CI 1.10 to 1.81) and handicap (OR, 1.46; 95% CI 1.14 to 1.86). No significant gender effect was observed on 3-month survival.. Sex-specific differences existed in a large European study of hospital admissions for acute stroke. Both medical and sociodemographic factors may significantly influence stroke outcome. Knowledge of these determinants may positively impact quality of care.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alcohol Drinking; Atrial Fibrillation; Brain Damage, Chronic; Brain Ischemia; Cardiovascular Agents; Case Management; Comorbidity; Diabetes Mellitus; Diagnostic Imaging; Europe; Female; Follow-Up Studies; Glasgow Coma Scale; Humans; Hypertension; Hypoglycemic Agents; Institutionalization; Length of Stay; Male; Middle Aged; Myocardial Infarction; Patient Discharge; Prognosis; Registries; Risk Factors; Severity of Illness Index; Sex Factors; Smoking; Stroke; Stroke Rehabilitation; Subarachnoid Hemorrhage; Survival Analysis; Treatment Outcome