The evolution of invasive cerebral vasospasm treatment in patients with spontaneous subarachnoid hemorrhage and delayed cerebral ischemia—continuous selective intracarotid nimodipine therapy in awake patients without sedation

Neurosurgical Review - Cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) are major factors that limit good outcome in patients with spontaneous subarachnoid hemorrhage (SAH). Continuous...     

Review of aneurysmal subarachnoid hemorrhage—Focus on treatment,anesthesia, cerebral vasospasm prophylaxis,and therapy

Aneurysmal subarachnoid hemorrhage (aSAH) is a serious and debilitating condition that leads to the development of many complications, which are followed by mortality and morbidity. As anesthesiologists, we may require to manage aSAH at various settings such as in the perioperative period or in a nonoperative setting such as the neuroradiology suite for diagnostic and therapeutic interventions. Therefore, it is important to understand the pathophysiology of aSAH and anesthetic management for operations and interventions. For decades, early brain injury and cerebral vasospasm have played major roles in the outcome following aSAH. The purpose of this article is to review recent advances and future perspectives in the treatment of aSAH, early brain injury, and cerebral vasospasm.     

Products of hemolysis in the subarachnoid space inducing spreading ischemia in the cortex and focal necrosis in rats: a model for delayed ischemic neurological deficits after subarachnoid hemorrhage?

OBJECT: The pathogenesis of delayed ischemic neurological deficits after subarachnoid hemorrhage has been related to products of hemolysis. Topical brain superfusion of artificial cerebrospinal fluid (ACSF) containing the hemolysis products K+ and hemoglobin (Hb) was previously shown to induce ischemia in rats. Superimposed on a slow vasospastic reaction, the ischemic events represent spreading depolarizations of the neuronal-glial network that trigger acute vasoconstriction. The purpose of the present study was to investigate whether such spreading ischemias in the cortex lead to brain damage. METHODS: A cranial window was implanted in 31 rats. Cerebral blood flow (CBF) was measured using laser Doppler flowmetry, and direct current (DC) potentials were recorded. The ACSF was superfused topically over the brain. Rats were assigned to five groups representing different ACSF compositions. Analyses included classic histochemical and immunohistochemical studies (glial fibrillary acidic protein and ionized calcium binding adaptor molecule) as well as a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Superfusion of ACSF containing Hb combined with either a high concentration of K+ (35 mmol/L, 16 animals) or a low concentration of glucose (0.8 mmol/L, four animals) reduced CBF gradually. Spreading ischemia in the cortex appeared when CBF reached 40 to 70% compared with baseline (which was deemed 100%). This spreading ischemia was characterized by a sharp negative shift in DC, which preceded a steep CBF decrease that was followed by a slow recovery (average duration 60 minutes). In 12 of the surviving 14 animals widespread cortical infarction was observed at the site of the cranial window and neighboring areas in contrast to findings in the three control groups (11 animals). CONCLUSIONS: The authors conclude that subarachnoid Hb combined with either a high K+ or a low glucose concentration leads to widespread necrosis of the cortex.     

The role of the alphaVbeta3 integrin in the development of osteolytic bone metastases: a pharmacological target for alternative therapy?

Common cancers frequently develop bone metastases, which are often osteolytic in nature due to activation of osteoclast differentiation and bone resorption. This may result from direct stimulation of these cells by the metastasis, or may be due to indirect enhancement of osteoclast activity by osteoblasts. A further feature of the bone metastasis is an extensive medullary angiogenesis which supports tumor growth. The alphaVbeta3 integrin is highly expressed in bone metastatic cells, as well as in osteoclasts and in the activated endothelium, where it plays a major role in cell function. In contrast, this receptor is barely expressed in other cell types. Our hypothesis is that inhibition of this mechanism, which is not widespread in most tissues and at the same time is common to several steps of cancer-induced osteolysis (i.e., homing, growth, and survival of metastatic cells, osteoclast bone resorption, and angiogenesis), should represent a suitable target to block the development of bone spreading of metastatic tumors. We extend this hypothesis to downstream signalling molecules activated by ligation of the alphaVbeta3 integrin, some of which (i.e., Src, PYK2, and Shc) could have similar specific roles in tumor cells, activated endothelium and osteoclasts, but not in other cell types.     

A restricted subarachnoid hemorrhage in the cortical sulcus in cerebral amyloid angiopathy: could it be a warning sign?

BACKGROUND: Cerebral amyloid angiopathy is a well-known disease that is predominantly recognized in elderly people and repeatedly causes large subcortical hemorrhages. These hemorrhages may be derived from vessel wall weakness because of Abeta depositions in the wall of the cortical and leptomeningeal arteries. Although vessel ruptures in CAA have been thought to occur in cortical arteries, it was recently demonstrated that the primary hemorrhage occurs in the subarachnoid space, particularly the cerebral sulci, as a result of multiple ruptures of meningeal arteries in some cases of subcortical hematoma caused by CAA. CASE DESCRIPTION: Case patient 1 was a 74-year-old woman who presented with epileptic seizure. A restricted SAH in the right frontal lobe was observed on MRI. Thirty-three days later, left hemiparesis occurred suddenly and a huge subcortical hematoma was observed in the right frontal lobe on CT. The hematoma was removed, and the patient was pathologically diagnosed with amyloid angiopathy. Case patient 2 was a 73-year-old man who presented with epileptic seizure. A restricted SAH in the right frontal lobe was observed on MRI. Twenty days later, left hemiparesis occurred suddenly and a huge subcortical hematoma was observed in the right frontoparietal area on CT. Hematoma removal was performed on both patients, and they were diagnosed pathologically with amyloid angiopathy. CONCLUSIONS: We report on the cases of 2 patients with CAA who presented with epileptic seizure and were found to have a restricted subarachnoid hematoma in the cerebral sulcus on MRI before their subcortical hemorrhages occurred. Both cases were diagnosed pathologically. This demonstrated that vessel ruptures in CAA can occur in the subarachnoid space, particularly the cerebral sulci, as a result of ruptures of meningeal arteries. A restricted SAH on CT/MRI could be a warning sign of a huge subcortical hemorrhage in CAA.     

No role of adjuvant systemic therapy after complete metastasectomy in metastatic renal cell carcinoma?

ObjectiveTo compare the effects of metastasectomy combined with immunotherapy and metastasectomy alone in the treatment of patients with metastatic renal cell carcinoma.Materials and MethodsA total of 93 patients who had undergone metastasectomy were included in the study. Patients were categorized according to immunotherapy status, including the immunotherapy group (n = 70) and the no immunotherapy group (n = 23).ResultsIn the immunotherapy group, median overall survival was 56.1 months (95% confidence interval [CI] 34.1–78.2), whereas the no immunotherapy group reached a median overall survival of 21.3 months (95% CI 3.4–39.2), respectively. The 1, 3, and 5-year overall survival rates were calculated at 67.1% and 56.5%, 30.0% and 34.8%, and 7.1% and 19.0%, for the immunotherapy group and the no immunotherapy group, respectively (P = 1.000). When patients were stratified according to the time of metastasis, overall survival was not significantly different among the groups in patients with synchronous metastasis or in those with metachronous metastasis. Multivariate Cox proportional hazards model analysis showed that multiplicity of metastasis (odds ratio 3.68; 95% CI 1.85–7.34; P < 0.001) and metastatic sites (odds ratio 2.12; 95% CI 1.15–3.90; P = 0.016) were independent predictors of overall survival.ConclusionsMetastasectomy combined with adjuvant immunotherapy did not result in a significantly higher overall survival rate as compared with metastasectomy alone. Our findings raise the question of “Is there a role of adjuvant immunotherapy after complete metastasectomy in patients with metastatic renal cell carcinoma?”     

Neurological outcome after experimental cardiopulmonary resuscitation: a result of delayed and potentially treatable neuronal injury?

BACKGROUND: In experimental cardiopulmonary resuscitation (CPR) aortic balloon occlusion, vasopressin, and hypertonic saline dextran administration improve cerebral blood flow. Free radical scavenger alpha-phenyl-N-tert-butyl-nitrone (PBN) and cyclosporine-A (CsA) alleviate neuronal damage after global ischemia. Combining these treatments, we investigated neurological outcome after experimental cardiac arrest. METHODS:: Thirty anesthetized piglets, randomly allocated into three groups, were subjected to 8 min of ventricular fibrillation followed by 5 min of closed-chest CPR. The combined treatment (CT) group received all the above-mentioned modalities; group B was treated with balloon occlusion and epinephrine; and group C had sham balloon occlusion with epinephrine. Indicators of oxidative stress (8-iso-PGF(2 alpha)), inflammation (15-keto-dihydro-PGF(2 alpha)), energy crisis (hypoxanthine and xanthine), and anoxia/hypoxia (lactate) were monitored in jugular bulb venous blood. Neurological outcome was evaluated 24 h after CPR. RESULTS:: Restoration of spontaneous circulation (ROSC) was more rapidly achieved and neurological outcome was significantly better in the CT group, although there was no difference in coronary perfusion pressure between groups. The jugular venous PCO2 and cerebral oxygen extraction ratio were lower in the CT group at 5-15 min after ROSC. Jugular venous 8-iso-PGF(2 alpha) and hypoxanthine after ROSC were correlated to 24 h neurological outcome CONCLUSIONS:: A combination of cerebral blood flow promoting measures and administration of alpha-phenyl-N-tert-butyl-nitrone and cyclosporine-A improved 24 h neurological outcome after 8 min of experimental normothermic cardiac arrest, indicating an ongoing neuronal injury in the reperfusion phase.     

Mortality, malnutrition, and atherosclerosis in ESRD: what is the role of interleukin-6?

There is growing evidence that increased plasma concentrations of CRP strongly predict cardiovascular death in both non-renal and renal patient populations. The interleukin-6 (IL-6) system activity, which is the major mediator of the acute phase response, is often markedly up-regulated in uremic patients and has also been shown to predict outcome. This raises the issue of whether or not IL-6 per se may contribute to increased mortality from malnutrition and atherosclerotic cardiovascular disease in uremic patients. The causes of elevated IL-6 levels in the uremic circulation are not fully understood, although a number of factors prevalent in uremic patients, such as hypertension, adiposity, infections, and chronic heart failure may all contribute. However, factors associated with the dialysis procedure, such as bioincompatibility and non-sterile dialysate, may stimulate IL-6 production. Furthermore, available evidence suggests that genetic factors may also have an impact on circulating plasma IL-6 levels. We advance the hypothesis that IL-6 may play a central role in the genesis of inflammatory-driven malnutrition and that it may be regarded as a significant proatherogenic cytokine. This hypothesis may provide a rationale to test if targeted anti-cytokine therapy may be one way to combat the unacceptable high cardiovascular mortality rate among dialysis patients.     

Does administration of recombinant human erythropoietin attenuate the increase of S-100 protein observed in cerebrospinal fluid after experimental subarachnoid hemorrhage?

OBJECT: Results of recent studies indicate that erythropoietin (EPO) produces a neuroprotective effect on experimental subarachnoid hemorrhage (SAH). It has been reported that S-100 protein levels increase in cerebrospinal fluid (CSF) after SAH, providing a highly prognostic indication of unfavorable outcome. This study was conducted to validate further the findings of S-100 protein as an index of brain damage and to assess whether treatment with recombinant human EPO (rhEPO) would limit the increase of S-100 protein level in CSF following experimental SAH. METHODS: Thirty-two rabbits were each assigned to one of four groups: Group 1, control; Group 2, SAH; Group 3, SAH plus placebo; and Group 4, SAH plus rhEPO (each group consisted of eight rabbits). The rhEPO and placebo were administered to the rabbits after SAH had been induced, and S-100 protein levels in the CSF of these animals were measured at 24, 48, and 72 hours after the experimental procedure. In each group of animals levels of S-100 protein were compared with the mortality rate, neurological outcome, and neuronal ischemic damage. High S-100 protein levels were found in rabbits in Groups 2 and 3, which exhibited poor neurological status and harbored a high number of damaged cortical neurons. Favorable neurological outcome and significant reductions in total numbers of damaged neurons were observed in animals in Group 4 in which there were significantly lower S-100 protein concentrations compared with animals in Groups 2 and 3 (p < 0.001). CONCLUSIONS: The results of this study support the concept that determination of the S-100 protein level in CSF has prognostic value after SAH. The findings also confirm that rhEPO acts as a neuroprotective agent during experimental SAH.     

Endogenous calcitonin gene-related peptide in cerebrospinal fluid and early quality of life and mental health after good-grade spontaneous subarachnoid hemorrhage—a feasibility series

The vasodilatory calcitonin gene-related peptide (CGRP) is excessively released after spontaneous subarachnoid hemorrhage (sSAH) and modulates psycho-behavioral function. In this pilot study, we prospectively analyzed the treatment-specific differences in the secretion of endogenous CGRP into cerebrospinal fluid (CSF) during the acute stage after good-grade sSAH and its impact on self-reported health-related quality of life (hrQoL). Twenty-six consecutive patients (f:m?=?13:8; mean age 50.6 years) with good-grade sSAH were enrolled (drop out 19% (n?=?5)): 35% (n?=?9) underwent endovascular aneurysm occlusion, 23% (n?=?6) microsurgery, and 23% (n?=?6) of the patients with perimesencephalic SAH received standardized intensive medical care. An external ventricular drain was inserted within 72 h after the onset of bleeding. CSF was drawn daily from day 1–10. CGRP levels were determined via competitive enzyme immunoassay and calculated as “area under the curve” (AUC). All patients underwent a hrQoL self-report assessment (36-Item Short Form Health Survey (SF-36), ICD-10-Symptom-Rating questionnaire (ISR)) after the onset of sSAH (t₁: day 11–35) and at the 6-month follow-up (t₂). AUC CGRP (total mean ± SD, 5.7?±?1.8 ng/ml/24 h) was excessively released into CSF after sSAH. AUC CGRP levels did not differ significantly when dichotomizing the aSAH (5.63?±?1.77) and pSAH group (5.68?±?2.08). aSAH patients revealed a higher symptom burden in the ISR supplementary item score (p?=?0.021). Multiple logistic regression analyses corroborated increased mean levels of AUC CGRP in CSF at t₁ as an independent prognostic factor for a significantly higher symptom burden in most ISR scores (compulsive-obsessive syndrome (OR 5.741, p?=?0.018), anxiety (OR 7.748, p?=?0.021), depression (OR 2.740, p?=?0.005), the supplementary items (OR 2.392, p?=?0.004)) and for a poorer performance in the SF-36 physical component summary score (OR 0.177, p?=?0.001). In contrast, at t₂, CSF AUC CGRP concentrations no longer correlated with hrQoL. To the best of our knowledge, this study is the first to correlate the levels of endogenous CSF CGRP with hrQoL outcome in good-grade sSAH patients. Excessive CGRP release into CSF may have a negative short-term impact on hrQoL and emotional health like anxiety and depression. While subacutely after sSAH, higher CSF levels of the vasodilator CGRP are supposed to be protective against vasospasm-associated cerebral ischemia, from a psychopathological point of view, our results suggest an involvement of CSF CGRP in the dysregulation of higher integrated behavior.