Increased plasma concentration of adrenomedullin in patients with subarachnoid hemorrhage

Adrenomedullin (AM) is a potent hypotensive peptide originally identified in pheochromocytoma tissues. Impaired cardiovascular conditions, such as hypertension, myocardial infarction, and septic shock, stimulate production of AM. This study was performed to determine whether subarachnoid hemorrhage (SAH) altered plasma AM concentration. Plasma concentrations of AM in 17 patients with SAH were measured for 2 wk after the onset of SAH by AM-specific radioimmunoassay. Plasma concentrations of AM were increased in patients with SAH throughout the study period, compared with those in control subjects. Plasma concentrations of AM in patients classified as Hunt and Kosnik grade III or IV were significantly higher than those classified as Hunt and Kosnik grade I or II on the day of and the day after the onset of SAH. However, plasma concentrations of AM were unaffected by angiographic vasospasm. These findings suggest that plasma concentrations of AM are increased in patients with SAH and may reflect the severity of SAH. IMPLICATIONS: Adrenomedullin has been reported to affect the cerebral circulation. This study was performed to determine whether subarachnoid hemorrhage, a typical cerebrovascular disorder, altered plasma adrenomedullin concentrations. We found that plasma adrenomedullin concentrations increased in patients with subarachnoid hemorrhage, although no relationship was found between plasma adrenomedullin concentration and angiographic vasospasm. Plasma adrenomedullin concentration may reflect the severity of hemorrhage.     

Surgical outcome of anterior communicating artery aneurysms

During a 6-year period, 65 consecutive patients who had undergone anterior communicating artery aneurysmal surgery were reviewed at a follow-up examination from 6 to 78 months (mean 35 months) after operation. On admission 69% of cases had a good Hunt and Hess scale (grades I to II) and 31% a poor grade (grades III to V). The degree of subarachnoid hemorrhage (SAH) was determined by Fisher's grade. Sixteen (25%) patients were classified in grades I and II. Forty-six percent of cases had pre-existing hypertension. Early surgery (within the first three days after the bleeding) was performed in 17% of cases. Intraoperative rupture of aneurysm occurred in six (9.2%) patients. Symptomatic cerebral vasospasm was diagnosed in 14 (22%) cases, but only 8 (12%) had evidence of low density on the computerized tomographic scan. Hydrocephalus developed in 16 (25%) cases and 10 needed ventriculoperitoneal shunting. The outcome was determined using the activity of daily life. Sixty-five percent of the patients made a good recovery and 13.8% died. The significant poor prognostic factors included a poor pre-operative grade of the Hunt and Hess scale, the presence of symptomatic cerebral vasospasm, and the Fisher's SAH grade of greater than II. Other factors which apparently were not related to the outcome included age, sex, timing of surgery, history of hypertension, intraoperative rupture, and the development of hydrocephalus.     

Cerebrospinal fluid tissue factor and thrombin-antithrombin III complex as indicators of tissue injury after subarachnoid hemorrhage

BACKGROUND AND PURPOSE: No marker that reflects and predicts brain injury due to subarachnoid hemorrhage (SAH) and cerebral vasospasm has been reported. We hypothesized that membrane-bound tissue factor (mTF) and thrombin-antithrombin III complex (TAT) in the cerebrospinal fluid (CSF) of patients with SAH become markers indicating brain injury. To evaluate the hypothesis, we correlated levels of mTF and TAT in the CSF of patients with SAH with clinical severity, the degree of SAH, and outcome. METHODS: We assayed CSF mTF, TAT and myelin basic protein (MBP) in patients with SAH at intervals that included days 0 to 4 and days 5 to 9 after ictus. Classification of clinical severity of disease on admission was based on Hunt and Hess grade, degree of SAH on CT on Fisher's grading, and outcome 3 months after SAH on the Glasgow Outcome Scale. RESULTS: In the interval from days 0 to 4, mTF and TAT correlated with Hunt and Hess and Fisher grades, and occurrence of cerebral infarction due to vasospasm. Only mTF correlated significantly in this period with outcome. TAT, mTF, and MBP all correlated significantly with each other. From days 5 to 9, only mTF correlated with cerebral infarction, infarction volume, MBP levels, and outcome. CONCLUSIONS: Both mTF and TAT reflected brain injury from SAH and predicted vasospasm, though mTF was more sensitive and a better predictor of outcome. Unlike mTF, TAT did not correlate with vasospasm during the interval when it most commonly occurs, which raised doubt about thrombin activation as a cause.     

Effects of induced hypertension on transcranial Doppler ultrasound velocities in patients after subarachnoid hemorrhage

BACKGROUND AND PURPOSE: Transcranial doppler ultrasound (TCD) is used after subarachnoid hemorrhage to detect cerebral vasospasm and is often treated with induced hypertension. Cerebral autoregulation, however, may be disturbed in this population, raising the possibility that TCD velocities may be elevated by induced hypertension. To study this possibility, we performed continuous TCD monitoring of the middle cerebral artery during the induction and withdrawal of induced hypertension in patients after subarachnoid hemorrhage. METHODS: Twenty-eight patients were studied during the induction and withdrawal of hypertension using primarily phenylephrine. Continuous monitoring was performed on the middle cerebral artery with the highest flow velocity. Treatment was based on rising TCD velocities or clinical evidence for cerebral vasospasm. Mean arterial pressure and mean TCD velocities were recorded every minute. A change of > 15% from starting TCD values was considered significant. Cerebral autoregulation was calculated as a percentage of intact autoregulation. Patients were subsequently divided into groups of disturbed and intact autoregulation. RESULTS: In 10 of 19 patients (53%), TCD velocities changed by > 15% and paralleled changes in mean arterial pressure. This directly altered the TCD interpretation of the grade of vasospasm in 7 of 19 patients (36%). Three additional patients had smaller absolute changes in TCD velocities. No clinical difference could be identified between patients with disturbed and intact autoregulation. CONCLUSIONS: In patients with disturbed autoregulation after subarachnoid hemorrhage, induced hypertension can alter cerebral blood flow velocities. The level of autoregulation needs to be considered when interpreting TCD velocities in patients after subarachnoid hemorrhage.     

Combination of serine protease inhibitor FUT-175 and thromboxane synthetase inhibitor OKY-046 decreases cerebral vasospasm in patients with subarachnoid hemorrhage

The preventive effect of the serine protease inhibitor FUT-175 (nafamostat mesilate), a potent inhibitor of the complement system, against vasospasm was evaluated in 34 high risk patients with thick and diffuse subarachnoid hemorrhage (SAH) demonstrated by computed tomography corresponding to Fisher group 3. All patients underwent surgery within 96 hours following SAH and received the thromboxane A2 synthetase inhibitor, OKY-046, as part of standard care. FUT-175 (40-160 mg/day) was administered during the initial 4 days following surgery. 455 patients treated without FUT-175 in the Nagasaki SAH Data Bank (non-FUT group) formed the control group. FUT-175 significantly decreased the incidence of symptomatic vasospasm in patients with severe neurological grade (Hunt and Hess grade 3, p < 0.02; Hunt and Hess grade 4, p < 0.02). The incidence of favorable outcome was 76.5% in the FUT group and 60.4% in the non-FUT group, but not statistically different. However, when patients of Hunt and Hess grade 5 were excluded, the FUT group had a significantly improved outcome (p < 0.05). This study suggests that FUT-175 has an additive effect to OKY-046 in preventing vasospasm in high risk patients with severe SAH.     

A randomized trial of nicardipine in subarachnoid hemorrhage: angiographic and transcranial Doppler ultrasound results. A report of the Cooperative Aneurysm Study

Calcium antagonist drugs were proposed for use in patients with recent aneurysmal subarachnoid hemorrhage (SAH) because of their ability to block the effects of a wide variety of vasoconstrictor substances on cerebral arteries in vitro. It was suggested that these agents might, therefore, be useful in ameliorating cerebral vasospasm and its ischemic consequences which frequently complicate SAH. This hypothesis was tested in an arm of a randomized double-blind placebo-controlled trial of high-dose intravenous nicardipine in patients with recently ruptured aneurysms. Participating investigators were required to send selected copies of all admission and follow-up angiograms obtained between Days 7 and 11 following hemorrhage (the peak period of risk for vasospasm) to the Central Registry of the Cooperative Aneurysm Study for blinded interpretation and review for the presence and severity of angiographic vasospasm. In centers with transcranial Doppler ultrasound (TCD) capabilities, middle cerebral artery (MCA) mean flow velocities were measured and recorded. Angiograms obtained between Days 7 and 11 were available for 103 (23%) of 449 patients receiving nicardipine and 121 (26%) of 457 receiving placebo. There was a balance of prognostic factors for vasospasm between the groups. Fifty-one percent of placebo-treated patients had moderate or severe vasospasm on "Day 7-11 angiograms" compared to 33% of nicardipine-treated patients. This difference is statistically significant (p < 0.01). Sixty-seven (49%) of 137 placebo-treated patients examined with TCD between Days 7 and 11 had mean MCA flow velocities exceeding 120 cm/sec compared to 26 (23%) of 112 nicardipine-treated patients (significant difference, p < 0.001). These data suggest that high-dose intravenous nicardipine reduces the incidence and severity of delayed cerebral arterial narrowing in patients following aneurysmal SAH.     

Effect of ultra-early referral on management outcome in subarachnoid haemorrhage

A study was conducted to clarify whether ultra-early referral of patients with subarachnoid haemorrhage (SAH) is effective for improving the management outcome. The subjects were 455 patients who were admitted within 6 h after initial SAH. Of these patients, 289 were treated surgically, 159 of them within 24 h. At 6 months, 228 patients (50%) had a favourable outcome including good recovery or moderate disability, 37 (8%) had severe disability, and 190 (42%) had an unfavourable outcome including vegetative state or death. Of 214 patients with an admission grade IV or V, 47 (22%) had a favourable outcome. In 10 patients, emergency procedures such as haematoma removal or ventriculostomy were definitely effective, and in 13, early surgery may have been the reason for the improved outcome. However, in 24 patients, the reasons for a favourable outcome were not related directly to ultra-early referral; in 19 of them, there was spontaneous improvement of clinical grade and/or no SAH on computed tomography. Of 218 patients with admission grade I or II, 30 (14%) had an unfavourable outcome, and in 12 of them, this was ascribed to rebleeding. The rebleeding rate and severity of vasospasm were not significantly reduced by surgery carried out within 24 h after SAH, in comparison with surgery carried out between 24 and 48 h, and there was no significant difference in surgical outcome between them. It is concluded that although ultra-early referral of patients with SAH was expected to improve the outcome in emergency cases, no substantial improvement in overall management outcome seems to have been achieved by this policy.     

Coagulative and fibrinolytic activation in cerebrospinal fluid and plasma after subarachnoid hemorrhage

OBJECTIVE: Intrathecal fibrinolytic therapy has been used as one of the anticerebral vasospasm (VS) preventative therapies in patients with subarachnoid hemorrhage (SAH). However, the changes in coagulation and fibrinolysis in the blood and cerebrospinal fluid (CSF) after SAH remain unknown. METHODS: Fifty patients with SAH caused by ruptured cerebral aneurysms were studied postoperatively to detect the serial changes of the thrombin-antithrombin III complex, active plasminogen activator inhibitor (PAI)-1, and tissue plasminogen activator (tPA)-PAI complex (tPA-PAI) activities in the plasma and CSF collected from cisternal drainage catheters. RESULTS: The CSF levels of all parameters and plasma PAI-1 levels were significantly higher in patients with severe SAH than in those with mild SAH. There was no relationship between the CSF and plasma levels of these parameters (except the CSF levels of tPA-PAI) and the initial neurological statuses. The CSF PAI-1 levels increased to greater than 20 ng/ml near the time of the occurrence of cerebral VS, whereas they remained below 20 ng/ml in patients without VS. The CSF tPA-PAI levels showed the highest peak near the time of VS remission. The CSF PAI-1 and tPA-PAI levels were significantly lower in patients with good outcomes than in those with poor outcomes. CONCLUSION: Both the coagulative and fibrinolytic systems were activated in the CSF and plasma after SAH in correlating to the amount of SAH clot. The intrathecal administration of fibrinolytic agents should be started early after surgery, before CSF PAI-1 levels increase, for patients with severe SAH. Patients with CSF PAI-1 levels greater than 20 ng/ml experienced high incidence of VS and poor outcomes.     

A case of Sj?gren syndrome associated with multiple mononeuritis and dysautonomia including bilateral tonic pupils

In the present study, the feasibility of intrathecal indwelling catheters in the preparation of a repeated subarachnoid hemorrhage (SAH) model in dogs, as well as chronic intrathecal administration of therapeutic agents against the ensuing cerebral vasospasm was examined. Briefly, through a small suboccipital incision, two catheters were introduced into the subarachnoid space so that their tips were positioned in the prepontine cistern. One was used to induce SAH by infusing autologous blood, and the other to administer pharmacological agents (saline and/or saline containing a dye in this study) by means of an osmotic pump. The occurrence of cerebral vasospasm was followed by angiography via the catheter placed in the vertebral artery. The obtained results show: i) the injected blood effectively formed a subarachnoid clot in the prepontine cistern, invariably leading to the occurrence of severe cerebral vasospasm of the basilar artery; ii) the fluid injected by the osmotic pump was evenly distributed in the cisterns around the brain stem; iii) on post mortem pathological examination, no injury of the brain or the major arteries ascribable to the placement of catheters was found. Therefore, the present model is considered to be useful for both the investigation of pathophysiology and therapy of cerebral vasospasm following SAH, to be more favorable from the standpoint of animal protection, and more convenient and reliable than those used until now.     

Understanding the three national databases on collegiate alcohol and drug use

Early admission and medical treatment can improve prognosis in patients with subarachnoid hemorrhage (SAH). In our Centre in 10 years, 595 patients with SAH have been treated: 422 were admitted within 24 hours (71%) and 498 (84%) within 72 hours. 374 underwent surgical treatment: 283 within 48 hours and 91 underwent late surgery. Thirty-three patients underwent emergency surgery for intracranial hematomas, with a mortality rate of 30%. One hundred eighty-one patients in Hunt-Hess grade I-II underwent early surgery. Mortality rate was 7%. Mortality rate for rebleeding, when surgery was delayed was more than 10%. Patients in Hunt-Hess grade III underwent early surgery in the majority of cases (68 out of 111). Only in 52% of cases surgical result was good. Thirty-four out of 108 in grade IV-V underwent early surgery, with a mortality rate of 45%. The analysis of general results shows that early surgery improves prognosis in Hunt-Hess grade III patients. Also patients in Hunt-Hess grade III-IV-V can take advantage of early surgery. Old age, arterial hypertension and angiographical vasospasm do not worsen prognosis even in patients operated on early. Endovascular treatment even in acute phase has improved results especially in cases of certain aneurysms types such as posterior circulation aneurysms.     

Endothelial injury following experimental subarachnoid hemorrhage in rats: effects on brain blood flow

BACKGROUND: The leading cause of death and disability in patients suffering from aneurysmal subarachnoid hemorrhage (SAH) is cerebral vasospasm, a persistent, progressive, and often irreversible constriction of cerebral arteries. A wide array of pathological changes occur in cerebral arteries following SAH, with endothelial injury being the earliest and most consistent one. Since intact endothelium modulates many reflexes that influence vascular tone, damage to them may represent a significant contributor to cerebral vasospasm. METHODS: Changes in local cerebellar blood flow (LCBF) and pathological alterations in major cerebral arteries were studied and compared in rats at various time intervals following SAH. SAH induced by the subarachnoid injection of 0.3 ml of whole blood. Sham rats received a subarachnoid injection of 0.3 ml of isotonic saline. RESULTS: Except for an immediate but transient decrease, LCBF remained unchanged over a 3 day period following saline injection. Likewise, there were no pathological alterations in cerebral arteries of saline-injected rats. In contrast, the subarachnoid injection of whole blood produced significant changes in both LCBF and cerebral arteries. Within 30 minutes post-blood injection, LCBF became significantly decreased and remained so for 4 hours. However, within 24 hours, LCBF had returned to control levels where it remained for 3 days. Endothelial injury was observed in the basilar and middle cerebral arteries from 30 minutes through 4 hours, the same periods in which LCBF was significantly reduced. Within 24 hours, the time period in which LCBF had rebounded to control ranges, cerebral arteries showed no evidence of endothelial damage and resembled control cells. CONCLUSION: The results indicate a direct correlation between changes in LCBF and the structural integrity of endothelial cells in the early stages following SAH. The lack of chronically depressed LCBF (after 1 day) may be related to the quick structural repair of endothelium.     

Prenatal diagnosis of 22q11 microdeletion

It has been recognised that the level of superoxide dismutase (SOD) significantly increases in CSF as the result of cerebral ischaemic damage. The aim of this study was to correlate the CSF levels of SOD enzymatic activity to the patterns of subarachnoid haemorrhage with regards to ischaemic complications due to vasospasm. A series of 78 patients operated on for intracranial aneurysms was studied; all patients were monitored with serial TCD measurements every second day after SAH. CSF samples were obtained at surgery by cisternal puncture of the subarachnoid cistern nearest to the aneurysm. SOD activity was assayed spectrophotometrically. Mean cisternal CSF level of SOD in 12 control cases (12.99 +/- 2.33 U/ml) is significantly higher (p < 0.01) than in 26 patients operated on between day 1 and 3 from last SAH episode (4.44 +/- 0.7 U/ml) and in 40 patients treated by delayed surgery (7.64 +/- 0.92 U/ml). In 13 patients presenting neurological deterioration related to arterial vasospasm mean cisternal SOD level was 12.23 +/- 1.86 U/ml; in 27 cases without vasospasm mean level was 5.43 +/- 0.7 U/ml (p < 001). The present results suggest that (a) cisternal CSF levels of SOD significantly decreases after SAH, probably in relation to an impaired synthesis in the brain compartment and that (b) a substantial elevation of SOD levels is evident in patients suffering ischaemic complications vasospasm-related. Biochemical events in the brain compartment could influence the expression and release of anti-oxidant enzymes in CSF after SAH.     

Failure of platelet angiotensin II binding to predict pregnancy-induced hypertension

OBJECT: Nimodipine therapy has become a standard component of the treatment regimen used in patients with aneurysmal subarachnoid hemorrhage (SAH). Its prescribed use at 60 mg every 4 hours for 21 days is based on reputable, randomized prospective studies. However, because only 20 to 30% of patients with SAH suffer clinical cerebral vasospasm, it is clear that most patients do not actually need the drug. Of course, this fact is not evident until several treatment days have passed. It is common practice, without well-documented consequences, to terminate nimodipine therapy before 21 days in certain clinical circumstances. The aim of this study was to evaluate the effectiveness of abbreviating the duration of nimodipine treatment in the setting of a good-grade aneurysmal SAH. METHODS: A retrospective clinical review was made of 90 consecutive patients who experienced a Hunt and Hess Grade I through III aneurysmal SAH and were treated with nimodipine for 15 days or less. CONCLUSIONS: None of the patients studied suffered a delayed neurological deficit as a result of the abbreviated course of nimodipine.     

Interleukin-6 and development of vasospasm after subarachnoid haemorrhage

The authors characterized the role of interleukins in the cerebrospinal fluid (CSF) in the development of vasospasm after subarachnoid haemorrhage (SAH), particularly interleukin-6 (IL-6). Concentrations of interleukin-1 beta (IL-1 beta), IL-6, and interleukin-8 (IL-8) were measured serially in CSF of 24 patients and in serum of 9 patients with SAH and correlated clinically. Additionally, the effects of the same cytokines on the cerebral arteries of dogs were analyzed on angiograms after intracisternal injection. Changes in levels of eicosanoids, angiogenic factors, and soluble cell adhesion molecules were investigated in the CSF of injected dogs. CSF concentrations of IL-6 and IL-8 were elevated significantly above control levels from the acute stage of SAH until the chronic stage. Patients with symptomatic vasospasm had significantly higher levels of IL-6 as well as IL-8 in CSF on days 5 and 7. Intracisternal injection of IL-6 induced long-lasting vasoconstriction in five out of eight dogs, while IL-8 did not. The diameter of canine basilar artery after IL-6 was reduced 29 +/- 5% from pretreatment diameter at 8 hours. Prostaglandins E2 and I2 were elevated in CSF for the first 4.5 hour of this IL-6-induced vasospasm. Neither angiogenic factors such as platelet-derived growth factor-AB and vascular endothelial growth factor nor soluble cell adhesion molecules were significantly elevated in CSF. IL-6, which increases to very high concentrations in CSF after SAH, may be important in inducing vasospasm, as IL-6 produced long-lasting vasoconstriction in the canine cerebral artery, which may be partly related to activation of the prostaglandin cascade.     

Sample size in clinical trials with dichotomous endpoints: use of covariables

Endothelin participates in regulating the vascular tone, and it is also involved in the pathogenesis of vasospasm following subarachnoid hemorrhage (SAH). Endothelin-1 (ET-1) induced cerebral vasospasm is inhibited by ETA receptors specific antagonist-BQ-123; this protects the neurons from ischemic damage. The present study evaluates the dynamics of ET-1 concentration changes in the plasma of rats in the acute phase of vasospasm after SAH, which was induced by administering 100 microliters non-heparinized fresh autologous arterial blood into the brain cisterna magna (CM). The study also assesses the effect of blocking ETA receptors on the changes in ET-1 level. BQ-123, the specific ETA receptors antagonist, was administered to cerebrospinal fluid (CSF) through a cannula inserted into CM; the antagonist--40 nmol in 50 microliters CSF--was given 20 minutes prior to SAH. In the control group, sham SAH was induced by administering 100 microliters artificial CSF (aCSF) to CM. ET-1 concentration in the plasma of rats in the acute phase of vasospasm was assessed by radioimmunoassay 30 and 60 minutes after SAH or sham SAH. It has been showed that both SAH and sham SAH cause significant increase in the ET-1 concentration (p < 0.05) in the rat plasma after 30 minutes; the concentration returns to an initial value after following 30 minutes, which may suggest that ET-1 released binds to its receptors in the acute phase of the vasospasm. On the other hand, in the two groups of rats with blocked ETA receptors there was a significant rise in ET-1 concentration 30 minutes after SAH or sham SAH, and a still further rise was observed 60 minutes after the procedure. The rise was significantly higher in animals with SAH (p < 0.05). The dynamics of the ET-1 concentration changes observed in rats with blocked ETA receptor suggests that SAH is an ET-1 production stimulator significantly more potent than other factors assessed in the study, such as a rise in the intracranial pressure resulting from administering aCSF to CM. Blocking ETA receptors makes it impossible for the ET-1 released to bind to the receptors, which may be a factor preventing the occurrence of cerebral vasospasm following SAH.     

Vasospasm diagnosis: theoretical and real transcranial Doppler sensitivity

In 40 patients middle cerebral artery trunk (M1) flow velocity was recorded just before 54 carotid angiography in 54 cases exhibiting vasospasm after aneurysm rupture. Angiographic vasospasm distribution was studied; cases of symptomatic vasospasm were noted and were compared with transcranial Doppler data. Angiographic vasospasm was present in M1 in 41/54 carotid angiograms. Postulating that all the cases of M1 angiographic vasospasm should be identified by transcranial Doppler, the theoretical sensitivity of TCD was 76%. In this series however the real sensitivity of TCD in vasospasm diagnosis was only 70%: besides 13 cases where vasospasm was not present in M1 (mainly after ACoA Aneurysm rupture), TCD failed to identify 3 cases of M1 angiographic vasospasm. Vasospasm may not be located in M1 even when severe and symptomatic (4 cases in this series). Transcranial Doppler remains a mediocre tool for identifying vasospasm after anterior communicating artery aneurysm rupture (sensitivity: 55%). Its reliability is better after internal carotid aneurysm rupture (sensitivity: 72%) and excellent after middle cerebral artery aneurysm rupture (sensitivity: 93%). In order to test the drugs or methods used to prevent or combat vasospasm, angiography has to be considered when during the vasospasm risk period TCD does not demonstrate vasospasm in M1, either in patients in whom clinical deterioration is occurring without other obvious explanation, or in all patients.     

CO2 reactivity in patients after subarachnoid haemorrhage

CO2 reactivity was tested in patients with transcranial Doppler sonography (TCD) and endtidal CO2 measurements after an average time interval of ten months after subarachnoid haemorrhage (SAH). After deliberately changing breathing there was a significant change in endtidal CO2 and in flow velocities in all three examination groups. Comparing 27 patients with SAH and 5 patients treated for incidental aneurysms and 20 patients without cerebrovascular disease there were no significant differences in CO2 reactivity. Furthermore, there were no right to left differences. In 12 patients with vasospasm, two of them treated by percutaneous transluminal angioplasty for delayed ischaemic deficits, CO2 reactivity was normal at the time of investigation. Furthermore, normal CO2 reactivity was found in patients after SAH and surgery for ruptured aneurysms regardless of the severity of the SAH.     

Monoclonal antibodies against ICAM-1 and CD18 attenuate cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits

BACKGROUND AND PURPOSE: Inflammatory responses have been implicated in the elaboration of several forms of central nervous system injury, including cerebral vasospasm after subarachnoid hemorrhage (SAH). A critical event participating in such responses is the recruitment of circulating leukocytes into the inflammatory site. Two of the key adhesion molecules responsible for the attachment of leukocytes to endothelial cells are intercellular adhesion molecule-1 (ICAM-1) and the common beta chain of the integrin superfamily (CD18). This study examined the effects of monoclonal antibodies on ICAM-1 and the effects of CD18 on cerebral vasospasm after SAH. METHODS: A rabbit model of SAH was utilized to test the influence of intracisternally administered antibodies to ICAM-1 and CD18 on cerebral vasospasm. Antibodies were administered alone or in combination, and the cross-sectional area of basilar arteries was assessed histologically on day 2 post-SAH. RESULTS: Treatment with antibodies to ICAM-1 or CD18 inhibited vasospasm by 22% and 27%, respectively. When administered together, the attenuation of vasospasm increased to 56%. All of these effects achieved statistical significance. CONCLUSIONS: These findings provide the first evidence that the severity of cerebral vasospasm can be attenuated using monoclonal antibodies against ICAM-1 and CD18. The results reinforce the concept that cell-mediated inflammation plays an important role in cerebral vasospasm after SAH and suggest that therapeutic targeting of cellular adhesion molecules can be of benefit in treating cerebral vasospasm.     

Subarachnoid haemorrhage: what happens to the cerebral arteries?

1. Subarachnoid haemorrhage (SAH) is a unique disorder and a major clinical problem that most commonly occurs when an aneurysm in a cerebral artery ruptures, leading to bleeding and clot formation. Subarachnoid haemorrhage results in death or severe disability of 50-70% of victims and is the cause of up to 10% of all strokes. Delayed cerebral vasospasm, which is the most critical clinical complication that occurs after SAH, seems to be associated with both impaired dilator and increased constrictor mechanisms in cerebral arteries. Mechanisms contributing to development of vasospasm and abnormal reactivity of cerebral arteries after SAH have been intensively investigated in recent years. In the present review we focus on recent advances in our knowledge of the roles of nitric oxide (NO) and cGMP, endothelin (ET), protein kinase C (PKC) and potassium channels as they relate to SAH. 2. Nitric oxide is produced by the endothelium and is an important regulator of cerebral vascular tone by tonically maintaining the vasculature in a dilated state. Endothelial injury after SAH may interfere with NO production and lead to vasoconstriction and impaired responses to endothelium-dependent vasodilators. Inactivation of NO by oxyhaemoglobin or superoxide from erythrocytes may also occur in the subarachnoid space after SAH. 3. Nitric oxide stimulates activity of soluble guanylate cyclase in vascular muscle, leading to intracellular generation of cGMP and relaxation. Subarachnoid haemorrhage appears to cause impaired activity of soluble guanylate cyclase, resulting in reduced basal levels of cGMP in cerebral vessels and often decreased responsiveness of cerebral arteries to NO. 4. Endothelin is a potent, long-lasting vasoconstrictor that may contribute to the spasm of cerebral arteries after SAH. Endothelin is present in increased levels in the cerebrospinal fluid of SAH patients. Pharmacological inhibition of ET synthesis or of ET receptors has been reported to attenuate cerebral vasospasm. Production of and vasoconstriction by ET may be due, in part, to the decreased activity of NO and formation of cGMP. 5. Protein kinase C is an important enzyme involved in the contraction of vascular muscle in response to several agonists, including ET. Activity of PKC appears to be increased in cerebral arteries after SAH, indicating that PKC may be critical in the development of cerebral vasospasm. Recent evidence suggests that PKC activation may occur in cerebral arteries after SAH as a result of decreased negative feedback influence of NO/cGMP. 6. Cerebral arteries are depolarized after SAH, possibly due to decreased activity of potassium channels in vascular muscle. Decreased basal activation of potassium channels may be due to several mechanisms, including impaired activity of NO (and/or cGMP) or increased activity of PKC. Vasodilator drugs that produce hyperpolarization, such as potassium channel openers, appear to be unusually effective in cerebral arteries after SAH. 7. Thus, endothelial damage and reduced activity of NO may contribute to cerebral vascular dysfunction after SAH. Potassium channels may represent an important therapeutic target for the treatment of cerebral vasospasm after SAH.     

The false-positive rate of thoracic outlet syndrome shoulder maneuvers in healthy subjects

Cytokines are considered as mediators of immune and inflammatory responses. Cisternal CSF levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and of the soluble adhesion molecule E-selectin were evaluated in patients operated on for intracranial aneurysms. Cisternal CSF samples were obtained at surgery in 41 selected patients (31 with diagnosis of subarachnoid hemorrhage (SAH) and 10 control patients operated on for incidental unruptured aneurysms); 14 patients were operated within 72 h after SAH (early surgery) and 17 were operated after day 10 after the hemorrhage (delayed surgery). The CSF levels of cytokines were evaluated using radioimmunoassay and their concentrations were related to the timing of surgery, the amount of cisternal subarachnoid blood clots and the onset of clinical and angiographical evidence of arterial vasospasm. Mean cisternal CSF levels of IL-6, IL-8 and AMCP-1 are significantly higher in samples obtained from patients early operated after SAH, while levels of E-selectin were below the threshold value of the method in all 41 cases. In the early operated group 7 patients presented symptomatic vasospasm: levels of IL-8 and MCP-1 were not significantly different were compared to those of uncomplicated cases; on the other hand, significantly higher levels of IL-6 were shown in the subgroup of patients operated within 72 h after SAH and developing vasospasm. Among the patients undergoing delayed surgery 5 presented symptomatic vasospasm, but no significant difference was shown in cisternal CSF levels of cytokines measured. The results of the present study show that in patients with unruptured aneurysms cytokines are present in cisternal CSF in scarce quantities and that in subarachnoid spaces after SAH there is an impressive increase of IL-6, IL-8 and MCP-1. Moreover, the higher cisternal CSF levels of IL-6 found in the early stage after SAH might have a predictive value regarding the occurrence of symptomatic vasospasm.