Haptoglobin phenotype predicts the development of focal and global cerebral vasospasm and may influence outcomes after aneurysmal subarachnoid hemorrhage
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 3 years ago
Cerebral vasospasm (CV) and the resulting delayed cerebral ischemia (DCI) significantly contribute to poor outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Free hemoglobin (Hb) within the subarachnoid space has been implicated in the pathogenesis of CV. Haptoglobin (Hp) binds free pro-oxidant Hb, thereby modulating its harmful effects. Humans can be of three Hp phenotypes: Hp1-1, Hp2-1, or Hp2-2. In several disease states, the Hp2-2 protein has been associated with reduced ability to protect against toxic free Hb. We hypothesized that individuals with the Hp2-2 phenotype would have more CV, DCI, mortality, and worse functional outcomes after aSAH. In a sample of 74 aSAH patients, Hp2-2 phenotype was significantly associated with increased focal moderate (P = 0.014) and severe (P = 0.008) CV and more global CV (P = 0.014) after controlling for covariates. Strong trends toward increased mortality (P = 0.079) and worse functional outcomes were seen for the Hp2-2 patients with modified Rankin scale at 6 wk (P = 0.076) and at 1 y (P = 0.051) and with Glasgow Outcome Scale Extended at discharge (P = 0.091) and at 1 y (P = 0.055). In conclusion, Hp2-2 phenotype is an independent risk factor for the development of both focal and global CV and also predicts poor functional outcomes and mortality after aSAH. Hp phenotyping may serve as a clinically useful tool in the critical care management of aSAH patients by allowing for early prediction of those patients who require increased vigilance due to their inherent genetic risk for the development of CV and resulting DCI and poor outcomes.
The present study was conducted to examine the feasibility of nimodipine loaded PLGA microparticles suspended in Tisseel(™) fibrin sealant as an in situ forming depot system. This device locally placed can be used for the treatment of vasospasm after a subarachnoid hemorrhage. Microparticles were prepared via spray drying by using the vibration mesh spray technology of Nano Spray Dryer B-90. Spherically shaped microparticles with different loadings and high encapsulation efficiencies of 93.3% to 97.8% were obtained. Depending on nimodipine loading (10% - 40%) the particle diameter ranged from 1.9 ± 1.2 μm to 2.4 ± 1.3μm. Thermal analyses using DSC revealed that Nimodipine is dissolved in the PLGA matrix. Also fluorescent dye loaded microparticles were encapsulated in Tisseel(™) to examine the homogeneity of particles. 3D-pictures of the in situ forming devices displayed uniform particle homogeneity in the sealant matrix. Drug release was examined by fluorescence spectrophotometry which demonstrated a drug release proportional to the square root of time. A prolonged drug release of 19.5 h was demonstrated under in vitro conditions. Overall, the Nimodipine in situ forming device could be a promising candidate for the local treatment of vasospasm after a subarachnoid hemorrhage.
The goal of this study was to demonstrate the importance of intracoronary nitroglycerin (IC NTG) administration during diagnostic coronary angiography and prior to percutaneous coronary intervention (PCI).
Cerebral vasospasm and sodium and fluid imbalances are common sequelae of aneurysmal subarachnoid hemorrhage (SAH) and cause of significant morbidity and mortality. Studies have shown the benefit of corticosteroids in the management of these sequelae. We have reviewed the literature and analyzed the available data for corticosteroid use after SAH.
OBJECT Studies show that phosphodiesterase-V (PDE-V) inhibition reduces cerebral vasospasm (CVS) and improves outcomes after experimental subarachnoid hemorrhage (SAH). This study was performed to investigate the safety and effect of sildenafil (an FDA-approved PDE-V inhibitor) on angiographic CVS in SAH patients. METHODS A2-phase, prospective, nonrandomized, human trial was implemented. Subarachnoid hemorrhage patients underwent angiography on Day 7 to assess for CVS. Those with CVS were given 10 mg of intravenous sildenafil in the first phase of the study and 30 mg in the second phase. In both, angiography was repeated 30 minutes after infusion. Safety was assessed by monitoring neurological examination findings and vital signs and for the development of adverse reactions. For angiographic assessment, in a blinded fashion, pre- and post-sildenafil images were graded as “improvement” or “no improvement” in CVS. Unblinded measurements were made between pre- and post-sildenafil angiograms. RESULTS Twelve patients received sildenafil; 5 patients received 10 mg and 7 received 30 mg. There were no adverse reactions. There was no adverse effect on heart rate or intracranial pressure. Sildenafil resulted in a transient decline in mean arterial pressure, an average of 17% with a return to baseline in an average of 18 minutes. Eight patients (67%) were found to have a positive angiographic response to sildenafil, 3 (60%) in the low-dose group and 5 (71%) in the high-dose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0-2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%-200%). CONCLUSIONS The results from this Phase I safety and proof-of-concept trial assessing the use of intravenous sildenafil in patients with CVS show that sildenafil is safe and well tolerated in the setting of SAH. Furthermore, the angiographic data suggest that sildenafil has a positive impact on human CVS.
The α2 adrenergic agonist dexmedetomidine (DEX) has huge potential for protecting against cerebral vasospasm, a leading cause of death and disability after subarachnoid hemorrhage (SAH). Biomarker assays for SAH have recently emerged as tools for predicting vasospasm and outcomes. We investigated the effects of DEX on vasospasm and assessed relevant biomarkers in a rat SAH model.
Milrinone is an inotropic and vasodilatory drug proven safe for use in the treatment of cerebral vasospasm. Despite its reported safety profile, its use is not free of side effects. Milrinone-associated cardiomyopathy and arrhythmia can occur in patients with cerebral vasospasm.
Background Delayed cerebral vasospasm (dCVS) following aneurysmal subarachnoid hemorrhage (aSAH) is (next to possible aneurysm rebleeding, cortical spreading depression and early brain injury) one of the main factors contributing to poor overall patient outcome. Since decades intensive research has been ongoing with the goal of improving our understanding of the pathophysiological principles underlying dCVS. Endothelin-1 (ET-1) and prostaglandin F2 alpha (PGF2a) seem to play a major role during dCVS. The synthesis of ET-1 is enhanced after subarachnoid hemorrhage (SAH) to mediate a long-lasting vasoconstriction, and PGF2a contributes to cerebral inflammation and vasoconstriction. Under physiological conditions, levosimendan (LS) demonstrates an antagonistic effect on PGF2a-induced cerebral vasoconstriction. Thus, the intention of the present study was to analyze potentially beneficial interactions in a pathophysiological situation. Methods A modified double hemorrhage model was used. Functional interactions between the calcium-sensitizing action of LS and the vasoconstrictive properties of PGF2a were investigated. Results After pre-incubation with LS, followed by application of PGF2a, a significant decrease in maximum contraction (Emax) for sham-operated animals was found (Emax 28% with LS, Emax 56% without LS). Using the same setting after SAH, the vessel segments did not reach a statistically significant contraction (but similar like the sham-operated vessels), neither for Emax nor pD2 (-log10EC50) nor EC50 (i.e., the concentration at which half of the maximal effect occurs). LS series in sham animals were performed by pre-incubation with PGF2a. The resultant Emax showed a statistically strong significance concerning a higher vasorelaxation compared with a solvent control group. Vessel segment relaxation was significantly stronger in the same experimental setup after SAH. Conclusion Under physiological and pathophysiological circumstances, LS reduced and dose-dependently reversed PGF2a-induced vasoconstriction. These results can be applied to further developing methods to antagonize dCVS after aSAH.
There has been controversy as to whether intraventricular hemorrhage (IVH) after aneurysmal subarachnoid hemorrhage (SAH) contributes to angiographic cerebral vasospasm (aCV) and delayed cerebral ischemia (DCI). CT-based SAH scales that did and did not consider IVH were compared in terms of ability to predict aCV, DCI, and outcome.
Coronary vasospasm in heart transplant recipients occurs through various mechanisms. It has been linked to allograft rejection and coronary vasculopathy, which can result in mortality during follow-up. Here, we investigated the prevalence of coronary vasospasm among heart transplant recipients undergoing surveillance coronary angiography procedures.