Cause Of Cerebral Vasospasm Research Articles

Symptomatic cerebral vasospasm after posterior fossa surgery in pediatric patients: single-center study and systematic literature review.

The most common cause of cerebral vasospasm is subarachnoid hemorrhage, less frequently it occurs after trauma, infection, and tumor resection. Vasospasm in children is rare and has not been systematically investigated in posterior fossa surgery. The authors undertook a single-center retrospective study of all the pediatric patients who underwent surgery on the posterior fossa and presented with postoperative symptomatic vasospasm in the period from January 2018 to February 2024. Subsequently, a systematic literature review in accordance with the PRISMA guidelines was performed in the PubMed and Scopus databases to identify the published papers on symptomatic vasospasm after posterior fossa surgery in children. Of the 178 patients who underwent surgery on the posterior fossa, only one patient was diagnosed with symptomatic diffuse vasospasm on postoperative day 21. The systematic literature review provided further 9 children. The underlying pathology comprised 8 intra-axial lesions with 4 medulloblastomas, 1 schwannoma in the medulla oblongata, 1 pilocytic astrocytoma, 1 primitive neuroectodermal tumor, and 1 arteriovenous malformation. The extra-axial lesions were 1 hypoglossal schwannoma and 1 oculomotor nerve schwannoma. Iatrogenic symptomatic vasospasm after posterior fossa surgery in children is a rare complication with an outcome ranging from complete recovery to the death of the patient. It is important for all staff involved in the care of patients undergoing surgery on the posterior fossa to be aware of this rare postoperative complication. The small number of patients affected does not allow a substantiated conclusion to be drawn about predictive risk factors.

Unusual cause of cerebral vasospasm after pituitary surgery

Cerebral vasospasm (CVS) was described in patients after trans-sphenoidal pituitary surgery due to intra-operative trauma of arteries or blood clots around the arteries of Willis' circle. We consider that in the two presented cases the main cause of CVS in early postoperative period was meningitis. Two patients with pituitary adenomas were operated with trans-sphenoidal approach. CVS developed in early postoperative period. Meningitis was revealed in both cases. CVS regressed only after successful treatment of meningitis. In the first case empiric antibiotic therapy was ineffective and CVS remained until Klebsiella pneumonia was detected in CSF and specific therapy was performed. In the second case empiric therapy was effective and CVS vasospasm regressed in 12days. These cases show that meningitis can be a leading cause of CVS in early postoperative period in trans-sphenoidal pituitary surgery. Adequate treatment of meningitis shortens duration of CVS in these patients.

Involvement of phospholipase C in endothelin 1–induced stimulation of Ca++ channels and basilar artery contraction in rabbits

Endothelin 1 (ET-1) is a major cause of cerebral vasospasm after subarachnoid hemorrhage (SAH), and extracellular Cal++ influx plays an essential role in ET-1-induced vasospasm. The authors recently demonstrated that ET-1 activates two types of Ca"-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Cal++ channel (SOCC) in vascular smooth-muscle cells located in the basilar arteries (BAs) of rabbits. In the present study, they investigate the effects of phospholipase C (PLC) on ET-1-induced activation of these Ca++ channels and BA contraction by using the PLC inhibitor U73122. Methods. To determine which Cal++ channels are activated via a PLC-dependent pathway, these investigators monitored the intracellular free Cal++ concentration ([Ca++]i). The role of PLC in ET-1-induced vascular contraction was examined by performing a tension study of rabbit BA rings. The U73122 inhibited the ET-1-induced transient increase in [Ca++]i, which resulted from mobilization of Ca++ from the intracellular store. Phospholipase C also inhibited ET-1-induced extracellular Ca++ influx through the SOCC and NSCC-2, but not through the NSCC-1. The U73122 inhibited the ET-1-induced contraction of the rabbit BA rings, which depended on extracellular Cal++ influx through the SOCC and NSCC-2. Conclusions. These results indicate the following. (1) The SOCC and NSCC-2 are stimulated by ET-1 via a PLC-dependent cascade whereas NSCC-1 is stimulated via a PLC-independent cascade. (2) The PLC is involved in the ET-1-induced contraction of rabbit BA rings, which depends on extracellular Ca++ influx through the SOCC and NSCC-2.

Evolution of the treatment of cerebral vasospasm

Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a disease process for which the lack of effective treatments has plagued neurosurgeons for decades. Historically, successful treatment after SAH in the acute setting was often followed by a rapid, uncontrollable deterioration in the subacute interval. Little was known regarding the nature and progression of this condition until the mid-1800s, when the disease was first described by Gull. Insight into the origin and natural history of cerebral vasospasm came slowly over the next 100 years, until the 1950s. Over the past five decades our understanding of cerebral vasospasm has expanded exponentially. This newly discovered information has been used by neurosurgeons worldwide for successful treatment of complications associated with vasospasm. Nevertheless, although great strides have been made toward elucidating the causes of cerebral vasospasm, a lasting cure continues to elude experts and the disease continues to wreak havoc on patients after aneurysmal SAH.

Increased levels of lipid peroxides as predictive of symptomatic vasospasm and poor outcome after aneurysmal subarachnoid hemorrhage.

Cerebral vasospasm remains a devastating medical complication of aneurysmal subarachnoid hemorrhage (SAH). Reactive oxygen species and subsequent lipid peroxidation are reported to participate in the causes of cerebral vasospasm. This clinical study was performed to investigate the relationships between levels of lipid peroxides in cerebrospinal fluid (CSF) and both delayed cerebral vasospasm and clinical outcome after SAH. Levels of phosphatidylcholine hydroperoxide (PCOOH) and cholesteryl ester hydroperoxide (CEOOH) in the CSF were measured in 20 patients with aneurysmal SAH. The patients' CSF was collected within 48 hours of hemorrhage onset and on Day 6 or 7 post-SAH. On Day 7, angiography was performed to verify the degree and extent of the vasospasm. The relationship between the patients' clinical profiles and the levels of lipid peroxides in the CSF were investigated. Both PCOOH and CEOOH were detectable in CSF, and their levels decreased within 7 days after onset of SAH. The levels of CEOOH within 48 hours after onset of hemorrhage were significantly higher in patients in whom symptomatic vasospasm later developed than in patients in whom symptomatic vasospasm did not develop (p = 0.002). Levels of PCOOH measured within 48 hours after onset of hemorrhage were significantly higher in patients with poor outcomes than in patients with good outcomes (p = 0.043). Increased levels of lipid peroxides measured in the CSF during the acute stage of SAH were predictive of both symptomatic vasospasm and poor outcome. Measurements of lipid peroxides in the CSF may be useful prognostically for patient outcomes as well as for predicting symptomatic vasospasm.

Effects of Extracellular Superoxide Dismutase on Arterial Vascular Structural Changes After Acute Subarachnoid Hemorrhage in the Mouse

P113 Background and Purpose: Subarachnoid hemorrhage (SAH) is a known cause of cerebral vasospasm. Vasopasm may result from loss of endothelial NO synthesis. There is also evidence that Hgb products released after SAH bind NO and deplete its extracellular bioavailability. Cu/Zn superoxide dismutase (SOD) overexpression has been shown to provide protection against vasospasm presumably by reducing available superoxide to react with and deplete NO thereby increasing NO concentration. This study characterized the effects of extracellular SOD (EC-SOD) on vasospasm comparing transgenic EC-SOD overexpressing mice to wild type (WT) counterparts. Methods: Mice underwent halothane anesthesia and endovascular perforation of the right proximal anterior cerebral artery (ACA) using a 5–0 monofilament. Sham mice underwent surgery but no vascular perforation. Temperature, blood gases, & blood pressure were maintained within normal ranges. Three days after recovery, brains were sectioned and Gomori’s trichromic stained. Vascular wall thickness was measured in triplicate sections from the proximal and distal segments of the ACA with the observer blinded to genotype. N=5 per group. Results: There was no difference in wall thickness between EC-SOD overexpressors and wild type shams in either ACA segment (Proximal: EC-SOD = 64±22μm, WT = 72±8μm, p=0.62; Distal: EC-SOD = 77±13μm, WT = 68±9μm, p=0.2). For both genotypes, SAH caused increased wall thickness which was greater in the EC-SOD vs. wild type SAH groups in the proximal (EC-SOD = 164±9μm, WT = 108±27μm, p=0.01) but not distal (EC-SOD =136±37μm, WT = 106±38μm, p=0.28) ACA segments. Conclusions: We were unable to demonstrate amelioration of vasospasm by the five-fold increase of brain EC-SOD known to occur in these mutants. In fact, in the proximal ACA, wall thickness was greater in the EC-SOD overexpressors subjected to SAH. Absence of a beneficial EC-SOD effect might be attributable to the post-SAH measurement interval when processes other than NO metabolism are likely to account for vasospasm. The reason for the pattern of an adverse effect of EC-SOD overexpression is unknown.

Mechanism of endothelin-1-induced contraction in rabbit basilar artery.

Endothelin-1 (ET-1) is suggested to be a major cause of cerebral vasospasm after subarachnoid hemorrhage. However, the mechanism of ET-1-induced contraction in cerebral arteries remains unclear. This study was undertaken to demonstrate the possible role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in ET-1-induced contraction. PD-98059, damnacanthal, wortmannin, AG-490, genistein, calphostin C, and staurosporine were used to inhibit, or relax, the ET-1-induced contraction of basilar artery, studied with an isometric tension system. Immunoprecipitation of MAPK in ET-1-stimultated rings of basilar artery without or with the above inhibitors was studied with Western blot. (1) ET-1 produced concentration-dependent contraction and MAPK immunoprecipitation in rabbit basilar artery by activation of ET(A) but not ET(B) receptors. (2) MAPK inhibitors PD-98059 and U-0126 produced dose-dependent inhibition of ET-1-induced contraction. (3) The Src tyrosine kinase inhibitor damnacanthal, the phosphatidylinositol-3 kinase inhibitor wortmannin, and the Janus tyrosine kinase(2) inhibitor AG-490 abolished ET-1-induced contraction. (4) The PKC inhibitor staurosporine but not calphostin C abolished ET-1-induced contraction, and the PTK inhibitor genistein partially reduced ET-1-induced contraction. (5) In arteries precontracted by ET-1, PD-98059, U-0126, wortmannin, AG-490, genistein, and staurosporine produced concentration-dependent relaxation. (6) ET-1 induced a biphasic and time-dependent MAPK immunoprecipitation. (7) PD-98059, U-0126, genistein, AG-490, and damnacanthal, but not staurosporine or wortmannin, abolished the effect of ET-1 on MAPK immunoreactivity. This study demonstrated that MAPK may be involved in ET-1-induced contraction in rabbit basilar artery. MAPK is downstream of PTK, Src, and Janus tyrosine kinase pathways but may not be downstream of phosphatidylinositol-3 kinase pathways. The possible involvement of PKC in ET-1-induced contraction requires further investigation. Inhibition of these pathways may offer alternative treatment for ET-1-induced contraction and cerebral vasospasm.

Effects of Extracellular Superoxide Dismutase on Arterial Vascular Structural Changes After Acute Subarachnoid Hemorrhage in the Mouse

P113 Background and Purpose: Subarachnoid hemorrhage (SAH) is a known cause of cerebral vasospasm. Vasopasm may result from loss of endothelial NO synthesis. There is also evidence that Hgb products released after SAH bind NO and deplete its extracellular bioavailability. Cu/Zn superoxide dismutase (SOD) overexpression has been shown to provide protection against vasospasm presumably by reducing available superoxide to react with and deplete NO thereby increasing NO concentration. This study characterized the effects of extracellular SOD (EC-SOD) on vasospasm comparing transgenic EC-SOD overexpressing mice to wild type (WT) counterparts. Methods: Mice underwent halothane anesthesia and endovascular perforation of the right proximal anterior cerebral artery (ACA) using a 5–0 monofilament. Sham mice underwent surgery but no vascular perforation. Temperature, blood gases, & blood pressure were maintained within normal ranges. Three days after recovery, brains were sectioned and Gomori’s trichromic stained. Vascular wall thickness was measured in triplicate sections from the proximal and distal segments of the ACA with the observer blinded to genotype. N=5 per group. Results: There was no difference in wall thickness between EC-SOD overexpressors and wild type shams in either ACA segment (Proximal: EC-SOD = 64±22μm, WT = 72±8μm, p=0.62; Distal: EC-SOD = 77±13μm, WT = 68±9μm, p=0.2). For both genotypes, SAH caused increased wall thickness which was greater in the EC-SOD vs. wild type SAH groups in the proximal (EC-SOD = 164±9μm, WT = 108±27μm, p=0.01) but not distal (EC-SOD =136±37μm, WT = 106±38μm, p=0.28) ACA segments. Conclusions: We were unable to demonstrate amelioration of vasospasm by the five-fold increase of brain EC-SOD known to occur in these mutants. In fact, in the proximal ACA, wall thickness was greater in the EC-SOD overexpressors subjected to SAH. Absence of a beneficial EC-SOD effect might be attributable to the post-SAH measurement interval when processes other than NO metabolism are likely to account for vasospasm. The reason for the pattern of an adverse effect of EC-SOD overexpression is unknown.

Oxyhemoglobin as the principal cause of cerebral vasospasm: a holistic view of its actions.

While oxyhemoglobin (oxyHb) is deemed to be the principal cause of cerebral vasospasm following subarachnoid hemorrhage, the mechanism(s) whereby it leads to vasospasm is by no means clear. Of importance is the fact that prolonged contraction of arterial smooth muscle is not the sole feature of cerebral vasospasm, particularly in humans. Vasospasm is also associated with the occurrence of organic changes in the arterial wall as well as the derangement of cerebral microcirculation. These additional features may play a pivotal role when vasospasm in the proximal arteries incurs delayed ischemic neurological deficits and cerebral infarction. The question then arises as to whether or not all the features of vasospasm are attributable to the actions of oxyHb. In this regard, owing to the recent advances in vascular physiology, it has become clear that the cerebral vasculature should be regarded as an organ, not a mere conduit, in which all intracellular mechanisms are functionally integrated for the maintenance and regulation of cerebral blood flow (CBF). In the sense that the arterial function is not simply a sum of the individual cellular functions, it may be described as "holistic". According to extant literature, oxyHb has multifarious actions that can be divided into the following three categories: (1) scavenging of nitric oxide (NO), (2) generation of reactive oxygen species (ROS), (3) activation of the tyrosine kinase/mitogen-activated kinase (TK/MAPK) pathway. Based on such knowledge, the present review aims at a speculative synthesis in terms of how oxyHb pertains to the occurrence of vasospasm, in which the highly integrated, holistic mechanisms within the cerebral artery are perturbed for a prolonged period.

Endothelin and subarachnoid hemorrhage: an overview.

Delayed cerebral vasospasm occurring after subarachnoid hemorrhage (SAH) is still responsible for a considerable percentage of the morbidity and mortality in patients with aneurysms. It has been suggested that the pathogenesis of delayed cerebral vasospasm is related to a number of pathological processes, including endothelial damage and smooth muscle cell contraction resulting from spasmogenic substances generated during lysis of subarachnoid blood clots, changes in vascular responsiveness, and inflammatory or immunological reactions of the vascular wall. It has been recognized that the endothelium plays an important role in the regulation of the cerebral vascular tone. In 1988, endothelin (ET)-1, a potent vasoconstrictor, was isolated from cultured porcine aortic endothelial cells. ET-1, which is one of three distinct isoforms of ETs (ET-1, ET-2, and ET-3), has a more marked effect on cerebral arteries than do the other two isoforms. Elevated levels of ETs have been demonstrated in the cerebrospinal fluid and plasma of patients after SAH and cerebral infarction. ETs act by at least three different receptor subtypes, the ET(A) receptor, which is localized in vascular smooth muscle cells and mediates vasoconstriction, and two different ET(B) receptor subtypes. The ET(B1) receptor subtype is present in vascular endothelial cells and mediates the endothelium-dependent vasodilation. The ET(B2) receptor subtype is present in smooth muscle cells causing vasoconstriction. ET-1 acts from the adventitial but not from the luminal side of cerebral arteries. In vivo and in vitro ET-1 causes a dose-dependent and long-lasting vasoconstriction, similar to cerebral vasospasm after SAH. The vasoconstriction caused by ET-1 can be reversed by selective ET(A) receptor antagonists or combined ET(A) and ET(B) receptor antagonists. The results of current clinical and experimental investigations support the hypothesis that ET-1 is a major cause of cerebral vasospasm after SAH. Other studies indicate that SAH causes complex changes in the ET system and increased ET-1 levels after SAH, which are not solely responsible for the development of vasospasm but may occur after cerebral ischemia. Further investigations are therefore needed to clarify these different hypotheses.

Abstracts of Literature

Abstracts of Literature

Reversal and prevention of cerebral vasospasm by intracarotid infusions of nitric oxide donors in a primate model of subarachnoid hemorrhage.

Decreased endothelium-derived relaxing factor, nitric oxide (NO), in the arterial wall has been hypothesized to be a potential cause of cerebral vasospasm following subarachnoid hemorrhage (SAH). The authors sought to determine whether intracarotid infusions of newly developed NO-donating compounds (NONOates) could reverse vasospasm or prevent the occurrence of cerebral vasospasm in a primate model of SAH. Twenty-one cynomolgus monkeys were studied in two experimental settings. In an acute infusion experiment, saline or NONOate was infused intracarotidly in four normal monkeys and in four monkeys after onset of SAH. During the infusions regional cerebral blood flow (rCBF) was measured in eight animals and CBF velocity in two. In a chronic infusion experiment, saline (four animals) or NONOate (diethylamine-NO [three animals] or proli-NO [six animals]) was infused intracarotidly in monkeys for 7 days after SAH. In acute infusion experiments, 3-minute intracarotid diethylamine-NO infusions reversed arteriographically confirmed vasospasm of the right middle cerebral artery (MCA) (as viewed on anteroposterior projection, the decrease in area was 8.4+/-4.3% in the treatment group compared with 35+/-12% in the control group; p < 0.004), increased rCBF by 31+/-1.9% (p < 0.002), and decreased the mean systolic CBF velocity in the right MCA. In a long-term infusion experiment, the area of the right MCA in control animals decreased by 63+/-5%. In animals undergoing a 7-day continuous glucantime-NO intracarotid infusion, the area of the right MCA decreased by 15+/-6.2%, and in animals undergoing a 7-day proli-NO infusion, the area of the right MCA decreased by 11+/-2.9% (p < 0.05). The mean arterial blood pressure decreased in the glucantime-NO group from 75+/-12 mm Hg (during saline infusion) to 57+/-10 mm Hg (during glucantime-NO infusion; p < 0.05), but it was unchanged in animals undergoing proli-NO infusion (76+/-12 mm Hg vs. 78+/-12 mm Hg). Results of these experiments show that cerebral vasospasm is both reversed and completely prevented by NO replacement. However, only the use of regional infusion of the NONOate with an extremely short half-life avoided a concomitant decrease in arterial blood pressure, which could produce cerebral ischemia in patients with impaired autoregulation of CBF after the rupture of an intracranial aneurysm.

Attenuation of cerebral vasospasm by systemic administration of an endothelin-A receptor antagonist, TBC 11251, in a rabbit model of subarachnoid hemorrhage.

Cerebral vasospasm is a major complication of subarachnoid hemorrhage (SAH) after the rupture of an intracranial aneurysm. Although the cause of cerebral vasospasm has not been fully established, several lines of evidence suggest that the vasoconstrictor peptide endothelin (ET) may play a crucial role. In the present study the potential of TBC 11251 (TBC), a newly developed ET(A) receptor antagonist, to prevent and/or reverse cerebral vasospasm was examined in a well-established rabbit model of SAH. Sixty-five New Zealand White rabbits were assigned to one of six groups. Experimental SAH was induced in rabbits comprising five of the groups by injecting autologous arterial blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH); 2) SAH only; 3) SAH + placebo at 24 and 36 hours (24/36); 4) SAH + TBC (24/36); 5) SAH + placebo twice daily (BID); and 6) SAH + TBC BID. All drug-treated animals received an intravenous dosage of 5 mg/kg TBC. After 48 hours, the animals were killed by intracardiac perfusion with fixative. The brainstems were removed and the basilar arteries (BAs) were prepared for histological examination. The cross-sectional area of each BA was measured using computer-assisted videomicroscopy by an investigator blind to the group from which it came. A one-way analysis of variance and paired group mean comparisons with the post-hoc Fisher least significant difference test were used for analysis of BA diameters and physiological parameters. The model provided reliable vasospasm, with the mean BA cross-sectional area constricting from 0.388 mm2 in the control group to 0.106 mm2 (27.4% of control) in the SAH only group. Treatment with TBC (24/36) after SAH (reversal protocol) produced a mean BA area of 0.175 mm2 (44.2% of control) which, although larger than the placebo group value of 0.135 mm2 (39.9% of control), was not statistically significant. However, treatment with TBC BID (prevention protocol) produced a mean BA area of 0.303 mm2 (78.1% of control) compared with the placebo BID value of 0.134 mm2 (34.6% of control); this effect was statistically significant (p < 0.01). There were no side effects noted and no differences in the mean arterial pressures between drug and placebo groups. These findings demonstrate that systemic administration of the ET(A) receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH when given as a preventative therapy, and they provide additional support for the role of ET in the establishment of vasospasm.

Outcome of carpal tunnel release surgery in patients with diabetes.

The surgical outcomes in 149 patients with diabetes and carpal tunnel syndrome who underwent transverse carpal ligament release surgery are reported. Associated factors such as insulin dependence, length of time with diabetes, electrodiagnostic studies, severity of neurological deficit, presence of polyneuropathy, and cervical disc disease were considered. Analysis of preoperative and postoperative symptoms, clinical findings, diagnostic studies, and patient self-assessment indicated that the majority of patients with diabetes experienced a favorable surgical outcome, regardless of any associated factors. Eighty-four percent of the patients reported good to excellent postoperative results in their hands. Further analysis of the subpopulation of insulin-dependent diabetics showed that 81% experienced good to excellent postoperative results. These results compare favorably with those of the control group: 200 nondiabetic patients, of whom 90% rated their results from carpal tunnel release surgery as good to excellent. There were no major complications in any group.

Source and cause of endothelin-1 release into cerebrospinal fluid after subarachnoid hemorrhage.

Despite years of research, delayed cerebral vasospasm remains a serious complication of subarachnoid hemorrhage (SAH). Recently, it has been proposed that endothelin-1 (ET-1) mediates vasospasm. The authors examined this hypothesis in a series of experiments. In a primate model of SAH, serial ET-1 levels were measured in samples from the perivascular space by using a microdialysis technique and in cerebrospinal fluid (CSF) and plasma during the development and resolution of delayed vasospasm. To determine whether elevated ET-1 production was a direct cause of vasospasm or acted secondary to ischemia, the authors also measured ET-1 levels in plasma and CSF after transient cerebral ischemia. To elucidate the source of ET-1, they measured its production in cultures of endothelial cells and astrocytes exposed to oxyhemoglobin (10 microM), methemoglobin (10 microM), or hypoxia (11% oxygen). There was no correlation between the perivascular levels of ET-1 and the development of vasospasm or its resolution. Cerebrospinal fluid and plasma levels of ET-1 were not affected by vasospasm (CSF ET-1 levels were 9.3 +/- 2.2 pg/ml and ET-1 plasma levels were 1.2 +/- 0.6 pg/ml) before SAH and remained unchanged when vasospasm developed (7.1 +/- 1.7 pg/ml in CSF and 2.7 +/- 1.5 pg/ml in plasma). Transient cerebral ischemia evoked an increase of ET-1 levels in CSF (1 +/- 0.4 pg/ml at the occlusion vs. 3.1 +/- 0.6 pg/ml 4 hours after reperfusion; p < 0.05), which returned to normal (0.7 +/- 0.3 pg/ml) after 24 hours. Endothelial cells and astrocytes in culture showed inhibition of ET-1 production 6 hours after exposure to hemoglobins. Hypoxia inhibited ET-1 release by endothelial cells at 24 hours (6.4 +/- 0.8 pg/ml vs. 0.1 +/- 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05) and at 48 hours (6.4 +/- 0.6 pg/ml vs. 0 +/- 0.1 pg/ml, control vs. hypoxic endothelial cells; p < 0.05), but in astrocytes hypoxia induced an increase of ET-1 at 6 hours (1.5 +/- 0.6 vs. 6.4 +/- 1.1 pg/ml, control vs. hypoxic astrocytes; p < 0.05). Endothelin-1 is released from astrocytes, but not endothelial cells, during hypoxia and is released from the brain after transient ischemia. There is no relationship between ET-1 and vasospasm in vivo or between ET-1 and oxyhemoglobin, a putative agent of vasospasm, in vitro. The increase in ET-1 levels in CSF after SAH from a ruptured intracranial aneurysm appears to be the result of cerebral ischemia rather than reflecting the cause of cerebral vasospasm.

Paraplegia, epidural analgesia, and thoracic aneurysmectomy.

Paraplegia, epidural analgesia, and thoracic aneurysmectomy.

Absence of elevation of big endothelin in subarachnoid hemorrhage.

Endothelin peptides are potent vasoconstrictors and thus are seen as potential cause of cerebral vasospasm after subarachnoid hemorrhage (SAH). Earlier reports showed elevated or normal endothelin levels in plasma and cerebrospinal fluid in patients suffering from SAH. The present study was designed to determine whether endothelin is a causal factor in SAH. We studied 11 patients with acute SAH. Seven of these 11 patients had a proven aneurysm and six had experienced vasospasm. Big endothelin levels were determined by a radioimmunoassay recognizing the C-terminal peptide (normal range, 1-11 fmol/ml). There were no elevations of big endothelin in the 59 plasma samples and the 17 simultaneously estimated cerebrospinal fluid samples. Differences between plasma and cerebrospinal fluid did not reach significant levels. Big endothelin values between patients with and without vasospasm showed no significant differences. Our findings suggest that plasma elevation of the endothelins is not reproducible in SAH and that big endothelin is unlikely to be a causal plasma factor in the complex multifactorial development of vasospasm after SAH.

Neuropeptide Y in the primate model of subarachnoid hemorrhage.

The cause of cerebral vasospasm after subarachnoid hemorrhage (SAH) remains unknown. Recently, an association between the potent vasoconstricting peptide, neuropeptide Y, and delayed cerebral vasospasm after SAH has been postulated. This was based on the findings of increased neuropeptide Y levels in the cerebrospinal fluid (CSF) and plasma after SAH in animals and humans. For this study, the primate model of SAH was used to assess the possible role of neuropeptide Y in delayed vasospasm after SAH. Fifteen cynomolgus monkeys underwent placement of a clot of either whole blood or red blood cells in the subarachnoid space around the middle cerebral artery (MCA). Sequential arteriography for assessment of MCA diameter and sampling of blood and CSF for neuropeptide Y were performed: before SAH (Day 0); 7 days after SAH, when signs of delayed cerebral vasospasm peak in this model and in humans; 12 days after SAH; and 28 days after SAH. Subarachnoid hemorrhage did not evoke changes in CSF or plasma levels of neuropeptide Y. Nine monkeys had arteriographic evidence of vasospasm on Day 7, but no change in neuropeptide Y levels occurred in plasma or CSF. In addition, neuropeptide Y levels did not change, even after resolution of vasospasm on Day 12 or Day 28. Neuropeptide Y levels were substantially higher in CSF than in arterial plasma (p less than 0.003 at each interval). No correlation was found between neuropeptide Y levels in CSF and in plasma. These results do not confirm a relationship between neuropeptide Y levels in the CSF or peripheral plasma and delayed cerebral vasospasm in SAH.

Levels of catecholamine in plasma and cerebrospinal fluid in aneurysmal subarachnoid hemorrhage.

Despite intensive investigation into the cause of cerebral vasospasm (focal ischemic deficit) after subarachnoid hemorrhage, the morbidity and mortality associated with this condition remain high. Various studies have shown levels of catecholamine in plasma and cerebrospinal fluid (CSF) to be increased in subarachnoid hemorrhage, and it is possible that these vasoactive substances play an important role in the subsequent vasospasm. In an attempt to elucidate this possibility, the study presented here was undertaken to investigate the relationship between catecholamine levels in plasma and CSF and focal ischemic deficit (FID); the rupture of aneurysms on blood vessels supplying the hypothalamus as compared with the rupture of aneurysms on blood vessels supplying other areas of the brain; and the clinical outcome of the patients. Concentrations of adrenaline and noradrenaline in plasma and CSF samples obtained from 21 patients who had suffered aneurysmal subarachnoid hemorrhage were determined by a radioenzymatic technique. Significantly higher levels of adrenaline were found at the time of surgery in the CSF of patients with FID. A similar trend, though not statistically significant, was also observed for plasma. Patients with a rupture of aneurysms on blood vessels supplying the hypothalamus showed a tendency towards higher catecholamine levels in plasma and CSF. Subjects with a bad clinical outcome (i.e., those who were severely disabled or had died) had significantly higher levels of catecholamine in plasma than did those with a good clinical outcome (i.e., those with moderate or no disability). Further detailed analysis of the interrelationships showed that, within the group of patients with FID, those with rupture of aneurysms on blood vessels supplying the hypothalamus had significantly higher catecholamine levels in plasma than did those with rupture of aneurysms on other cerebral vessels. Furthermore, in the group of patients with rupture of aneurysms on blood vessels supplying the hypothalamus, those with a bad clinical outcome had significantly higher catecholamine levels in plasma than did those with a good clinical outcome. These findings lend support to the possibility that damage to the hypothalamus and subsequent elevations in catecholamine levels may be associated with FID and poor clinical outcome.

Etiology of cerebral vasospasm in primates

A primate model was used to determine whether oxyhemoglobin (OxyHb), methemoglobin (MetHb), or bilirubin is likely to be responsible for cerebral vasospasm following subarachnoid hemorrhage (SAH). Forty cynomolgus monkeys were randomly assigned to one of five groups. On Day 0, each animal underwent angiography followed by right craniectomy and placement of an Ommaya reservoir with its catheter adjacent to the right middle cerebral artery (MCA). The animals received intrathecal injections twice a day for 6 days of one of the following solutions: mock cerebrospinal fluid (CSF); OxyHb; MetHb; bilirubin; or supernatant fluid from an incubated mixture of autologous blood and mock CSF. On Day 7, angiography was repeated and the animals were killed. Comparison of angiograms obtained on Day 0 and Day 7 of the experiment showed significant vasospasm of the right MCA and the right anterior cerebral and internal carotid arteries in the animal groups that had received OxyHb or supernatant fluid. There was a smaller reduction in diameter of the same vessels in the bilirubin group (not statistically significant), while no effects were observed in the groups receiving MetHb or mock CSF. Electron microscopy of the right MCA's gave results consistent with the angiographic findings. One monkey in the OxyHb group developed a delayed-onset right MCA infarction. These data suggest that OxyHb is the cause of cerebral vasospasm following SAH.