Systemic Administration of Mexiletine for Attenuation of Cerebral Vasospasm Following Experimental Subarachnoid Haemorrhage

Mexiletine is a class Ib drug that is widely used to treat ventricular arrhythmias. This compound is mainly known as a sodium channel blocker, but studies have demonstrated that it can also activate ATP-sensitive K+ channels and block Ca2+ channels. Recent in vitro data from experiments on liposomes indicate that mexiletine is also a potent antioxidant. The unique activity profile of this drug raised the possibility that it might be of benefit in limiting cerebral vasospasm. Our first series of experiments assessed the effects of mexiletine on transclivally exposed rabbit basilar arteries. The arteries were treated with 50-mM KCl, 20-nM endothelin-1 (ET-1), or 100-microM lysophosphatidic acid (LPA) in the presence or absence of 400-mM mexiletine. Vasoconstriction caused by KCl, ET-1, and LPA was inhibited by mexiletine. In a second series of experiments, subarachnoid haemorrhage (SAH) was induced in rabbits by injecting 3-ml of autologous arterial blood into the cisterna magna. Forty-eight hours after SAH induction, transclivally exposed basilar arteries exhibited a spastic constriction that was partially reversed by topical application of 400-microM mexiletine. In a third set of experiments, mexiletine was administered orally at dosages of 80-, 20, and 5-mg/kg/day t.i.d., beginning 3 hours before SAH to study the prevention of vasospasm. In a separate group of animals, 80- and 20-mg/kg/day t.i.d. of mexiletine was administered 21 hours post-SAH induction, to study the reversal of vasoconstriction. Microscopic analysis of vessels from controls (no SAH), SAH-only, and SAH + mexiletine groups indicated there was 71.43% vascular constriction in the SAH-only group compared with controls. Considerable vasorelaxation was seen in the prevention study, in which average arterial cross-sectional areas were reduced by only 17.86% and 39.29% in the mexiletine 80- and 20-mg/kg/day groups, respectively, compared with controls (p < 0.001). Compared with controls, average arterial cross-sectional areas were reduced by 53.58% and 64.29% in the mexiletine 80- and 20-mg/kg/day reversal groups, respectively. Our findings indicate that mexiletine induces potent relaxation in cerebrovascular arteries contracted with various agents, and that it prevents and partially reverses SAH-induced vasoconstriction.     

Basilar Vasospasm Following Spontaneous and Traumatic Subarachnoid Haemorrhage: Clinical Implications

Summary. Summary.   Background: Cerebral vasospasm has been commonly described following subarachnoid haemorrhage (SAH) though its impact on neurological outcome, especially in head trauma, has not been yet elucidated. The purpose of this study was to monitor and correlate neurological condition and flow velocities (FVs) in the arteries of the brain after SAH and more particularly to investigate the influence of basilar artery (BA) vasospasm on neurological outcome.   Methods: Daily transcranial Doppler (TCD) evaluations were conducted in 116 consecutive patients with subarachnoid haemorrhage. SAH was of traumatic origin (tSAH) in 59 patients and spontaneous (sSAH) in 57 patients. Vasospasm in the MCA and ACA was defined by a mean FV exceeding 120 cm/s and three times the mean FV of the ipsilateral ICA. Basilar artery (BA) vasospasm was defined as moderate whenever the FV was higher than 60 cm/s and severe above 85 cm/s.   Findings: Sixty-two patients (53.4%) had elevated FVs in the BA, among these 34 (29.3%) had FVs above 85 cm/s. Basilar vasospasm was significantly more common in tSAH (59.7%) than in sSAH (40.3%, P=0.041). In patients with moderate and severe BA vasospasm, FVs in the BA increased on the third day after admission and remained elevated for a week before returning to normal value by the end of the second week. This elevation in BA FVs in patients with BA vasospasm was followed by a significant and progressive worsening in the neurological condition at the end of the first week. Permanent neurological deficit was associated with elevated BA FVs consistent with moderate BA vasospasm whereas patients who remained in persistent vegetative state, had FVs consistent with severe BA vasospasm (P=0.00019).   Interpretation: The present results further support that BA vasospasm may act as an independent factor of ischaemic brain damage following SAH, especially in head trauma.     

Intra-Aortic Balloon Counterpulsation: Augmentation of Cerebral Blood Flow after Aneurysmal Subarachnoid Haemorrhage

 Objective. To measure cerebral blood flow before and after intra-aortic balloon counterpulsation (IABC) in patients at high risk of developing delayed cerebral ischaemia after aneurysm surgery following subarachnoid haemorrhage.  Methods. Six prospectively selected patients at high risk of developing delayed ischaemia had elective IABC after clipping of their cerebral aneurysm(s). The IAB inflates in early diastole and deflates at the end of diastole to increase cardiac perfusion and decrease afterload. This results in enhanced cardiac efficiency. It also augments cerebral blood flow (CBF).  Results. We demonstrated a significant increase in the mean hemispheric CBF from the preoperative (preIABC) value of 35.6 mls/100 g/min to 50.9±12.3 mls/100 g/min (p=0.0042) as a result of balloon augmentation. Each patient developed a neurological deficit as a result of delayed cerebral ischaemia. These were reversed in 5 patients with increased CBF. There were minimal balloon related complications.  Conclusion. IABC consistently enhanced CBF in these patients and resulted in stable cardiovascular parameters. This represents a possible new technique in the management of cerebral ischaemia following subarachnoid haemorrhage and needs further assessment to ascertain its role.     

Long-Term Functional Effects of Aneurysmal Subarachnoid Haemorrhage with Special Emphasis on the Patient's View

Summary  Although physical and emotional dysfunction appears to be quite frequent even among independent survivors of aneurysmal subarachnoid haemorrhage (SAH), these symptoms may easily be missed on routine follow-up examinations. To assess the long-term functional effects of SAH and to outline possible treatment approaches, a cross-sectional study using multidimensional measures of relevant areas of function was performed on 40 independent survivors. After an average follow-up period of 22 months, patients were selected and enrolled following a pre-designed protocol. The comprehensive test battery consisted of subjective and objective measures of physical, psychological and social function and relationships between the different levels of assessment were calculated. We found a considerable proportion of cognitive, emotional and physical dysfunction in this sample, but on the subjective level, the majority of the patients stated satisfaction with life in general. Mild cognitive dysfunction was frequently missed and causes distress in the family. Mild to moderate depression was underdiagnosed, although such an emotional dysfunction influences working capacity and quality of life. Referral to rehabilitation centers appears to be restricted to patients with severe impairments. Our results help to alert the neurosurgeon to these possible symptoms and show the urgent need for a prospective, interdisciplinary and multidimensional follow-up of SAH survivors.     

Intra-Arterial Infusion of Fasudil Hydrochloride for Treating Vasospasm Following Subarachnoid Haemorrhage

Summary  In this pilot study we treated cerebral vasospasm in patients with subarachnoid haemorrhage to assess intra-arterial fasudil hydrochloride. We analysed effects of intra-arterial infusion on angiographically evident cerebral vasospasm in 10 patients including 3 with symptoms of vasospasm. Over 10 to 30 min 15 to 60 mg was administered via the proximal internal carotid artery or vertebral artery following standard angiography, without superselective techniques. A total of 24 arterial territories (21 internal carotid, 3 vertebral) were treated. Angiographic improvement of vasospasm was demonstrated in 16 arterial territories (local dilation in 2, diffuse dilation in 14) in 9 patients. In 2 symptomatic patients, intra-arterial fasudil hydrochloride was associated with resolution of symptoms without sequelae. In the third symptomatic patient the benefit of fasudil hydrochloride was only temporary, and a large cerebral infarction occurred. All asymptomatic patients showed no progression of angiographic to symptomatic vasospasm after treatment with intra-arterial fasudil hydrochloride. No adverse effect was encountered.     

Outcome After Aneurysmal Subarachnoid Haemorrhage: The use of a Graphical Model in the Assessment of Risk Factors

Summary  In 102 consecutive prospectively identified patients with subarachnoid haemorrhage (SAH) we have analysed the severity of the initial haemorrhage and the direct and indirect effects of adverse factors on outcome.  The data we recorded included delay in diagnosis, risk groups, Doppler measurements, angiographic findings, surgical events and outcome at 1 year. By using a temporal graphical chain model, the associations between all variables and possible causal pathways were statistically determined.  The severity of the initial haemorrhage, as determined by means of a clinical assessment and CT scanning, allowed low-, medium- and high-risk patient groups and a statistically predictable outcome to be identified.  The overall management mortality was 13.7% at 1 year; 70.6% had a favourable outcome and 15.7% were severely disabled. Outcome was directly associated with risk group (p=0.0038) and rebleeding (p=0.0000). Delayed diagnosis led to a poorer outcome (p=0.014) – an indirect association probably due to rebleeding. Adverse surgical events led to a significantly poorer outcome in high-risk patients.  No significant relationship was found either between age and risk group (p=0.7784) or between age and outcome (p=0.6418). Preoperative clinical (WFNS) grade was unreliable in predicting outcome. It is the particular risk group, determined by the initial SAH, that indicates the individual patient's outcome.  Management strategies can reduce preventable adverse events such diagnostic delay and rebleeding. Future studies should stratify patients according to risk group, delay in diagnosis and rebleeding in order to enable a clearer comparison to be made of treatment methods.     

Spinal Arachnoiditis Following Subarachnoid Haemorrhage: Report of two Cases and Review of the Literature

Summary  Two patients with spinal arachnoiditis following subarachnoid haemorrhage are described. A complete spinal block was seen at the mid thoracic level with characteristics of spinal arachnoiditis. Only one patient had severe symptoms. Both patients were treated conservatively. Signs and symptoms diminished in time. A review of the literature is given and the aetiology is discussed.     

Advantage of Intravenous Anaesthesia for Acute Stage Surgery of Aneurysmal Subarachnoid Haemorrhage

Summary  To investigate the clinical effects of intravenous anaesthesia on surgical procedure and the outcome in acute stage surgery for aneurysmal subarachnoid haemorrhage (SAH), pre-, intra-, and post-operative factors were analyzed to compare between inhalational (IA, n=38) and intravenous (IVA, n=37) anaesthesia. IVA significantly shortened the duration of surgery (p<0.05) and the duration of hospital stay (p<0.01). These results suggest that IVA may be more suitable than IA for acute stage surgery of aneurysmal SAH. These effects may be mainly caused by IVA's pharmakokinetics, by effects on intracranial homeostasis and metabolism, and neuroprotective properties.     

Subarachnoid Haemorrhage as Initial Symptom of Multiple Brain Abscesses

The case of evolving multiple brain abscesses which became symptomatic with a sudden hemianopsia and the clinical and radiological signs of a subarachnoid haemorrhage, is reported. A common pathomechanism which could explain both the sudden focal neurological deficit and the subarachnoid bleeding is discussed.     

Circulating Blood Volume in Patients with Subarachnoid Haemorrhage

Summary  To establish the fluid management for patients with subarachnoid haemorrhage (SAH), circulating blood volume (BV) was measured by pulse-spectrophotometry using indocyanine green (ICG) in 34 cases with SAH and 20 cases with neurosurgical disorders as control. BV measured immediately after induction of anaesthesia was lower in cases with SAH than that in controls. (62.8±12.3 vs. 73.3±11.2 ml/kg, p<0.01). In cases with SAH, the BV was significantly decreased in females (p<0.05) but not so significantly in males. In female cases with SAH, reduced BV was increased 3 days after operation (p<0.01). In conclusion BV is decreased in cases with SAH, especially in females. Active fluid therapy may be necessary when temporary vascular occlusion is required during aneurysm surgery. Since hypovolaemia may cause symptomatic vasospasm, BV measurement with pulse-spectrophotometry may provide useful information to insure normovolaemia.     

Radiation-Induced Aneurysm and Moyamoya Vessels Presenting with Subarachnoid Haemorrhage

A rare case of a ruptured internal carotid artery (ICA) aneurysm, with ICA stenosis and moyamoya vessels, was diagnosed in a young female patient after radiotherapy for optic glioma. Retrospective analysis revealed that an extraordinarily high dose of radiation (110 Gy) had been delivered to the area around the ICA in two therapeutic sessions. Clipping and wrapping of the aneurysm were performed and the patient made a good recovery. A review of the literature suggested that rupture of radiation-induced aneurysms is a rare event, but may be fatal. Considerable care must therefore be taken when delivering high-dose radiation to cerebral arteries. We suggest that the incidence of radiation-induced moyamoya vessels is higher in younger patients.     

Transcranial Cerebral Oximetry Related to Transcranial Doppler After Aneurysmal Subarachnoid Haemorrhage

Summary  Noninvasive methods for detecting cerebral artery vasospasm, still a serious complication following aneurysmal subarachnoid haemorrhage, are of vital interest. Up-to-date transcranial Doppler ultrasound (TCD) has proved to be sensitive in detecting vasospasm in the middle cerebral artery, but has less accuracy for other cerebral arteries. Transcranial cerebral oximetry (TCCO) is a new noninvasive technique which may increase the reliability for detecting cerebral ischaemia. The purpose of the present study was to evaluate a putative correlation between TCCO and TCD.  We examined the two hemispheres in 14 patients with the aim of evaluating a proposed correlation between TCD and TCCO.  Analysis of all absolute values (maximum TCD mFV and minimum TCCO saturation, respectively) in all series indicate a correlation between TCCO and TCD, p<0.01, r=−0.62. All patients with TCD mean flow velocity >120 cm/s also presented TCCO saturation<60%. Conversely, all patients with normal TCCO saturation (≥63%) presented normal or moderately increased TCD velocities.  In clinical neurosurgical practice it is of great interest if a true correlation between TCD and TCCO exists. The present results support the assumption that TCCO may enhance the reliability for detecting cerebral ischaemia after aneurysmal subarachnoid haemorrhage.     

Subarachnoid Heamorrhage-Induced Chronic Cerebral Vasospasm in the Rabbit: IV-DSA Versus IA-DSA

Summary.  Background: Chronic cerebral vasospasm is delayed-onset cerebral arterial narrowing in response to blood clots left in the subarachnoid space after aneurysmal subarachnoid haemorrhage (SAH). Rabbit models of vasospasm have been developed as in vivo experimental pathogenesis and the treatments of cerebral vasospasm using human vessels are not possible. The present study assessed the diagnostic accuracy of the intravenous digital subtraction angiography (IV-DSA) in chronic cerebral arterial spasm following induced SAH in the rabbit.  Method: Ten rabbits' left leg veins catheterised by intravascular access needle and 3F catheters introduced to the right leg arteries probing the proximal of the vertebral arteries. Initially IV-DSA and intra-arterial digital subtraction angiography (IA-DSA) was performed. Three millilitres of fresh autologous arterial blood was injected into the cisterna magna of the ten rabbits' in order to produce in vivo model of chronic SAH. Angiograms were obtained 15 minutes and 72 hours after the SAH.  Findings: Diameters of the basilar arteries were similar to each other in both methods and reduced after the SAH.  Interpretation:The present study shows that IV-DSA is a relatively simple and effective method for demonstrating cerebral vessels, especially the basilar artery. Published online September 2, 2002 Correspondence: Tanzer Sancak M.D., Mesa Camyolu sitesi, B1 Blok A17 Yenikent, Cayyolu, Ankara, Turkey.     

Platelet-Derived Growth Factor (PDGF-AB) like Immune Reactivity in Serum and in Cerebral Spinal Fluid Following Experimental Subarachnoid Haemorrhage in Dogs

Summary  The aim of this study was to evaluate the following questions: Can the platelet-derived growth factor (PDGF-AB) be identified in the serum and cerebro spinal fluid (CSF) of dogs? Is there an increase in the concentration of PDGF-AB following experimental subarachnoid haemorrhage (SAH)? Is the increase in concentration related to the angiographic cerebral vasospasm of the basilar artery. The “double haemorrhage” model was applied in seven dogs to produce experimental SAH with determination of angiographic vasospasm in the basilar artery. Blood and CSF samples were taken on the first, third and eighth days. The analyses were performed with an ELISA human PDGF-AB antibody kit (quantikine human PDGF-AB, R&D Systems, Minneapolis, USA).  The average PDGF-AB base value in the serum on the day before the SAH was 410.77±177.56 pg/ml, in the CSF it was 6.43±3.19 pg/ml. There was a significant (p=0.05) increase in the concentration of PDGF-AB (third day 717.35 pg/ml, eighth day 918.07 pg/ml) in the serum of all animals. No significant increase was found in the CSF samples of any animal. In summary, a PDGF-AB like immune reactivity was found in the serum of dogs with the human PDGF-AB ELISA kit and the concentration of PDGF-AB in the serum increased after experimental SAH but not in CSF, but there was no relationship between the increase in PDGF-AB serum concentration and angiographic vasospasm.     

Plasma and Cerebrospinal Fluid Endogenous Digoxin-Like Immunoreactivity in Patients with Aneurysmal Subarachnoid Haemorrhage

Summary  Recent evidence indicates the presence of naturally occurring digitalis-like compounds in mammals, collectively known as either digitalis-like (DLF) or ouabain-like (OLF) factors, presumed to be endogenous hormones regulating the biological activity of the NA⁺/K⁺-ATPase and its isoforms. This substance has been postulated to enhance renal tubular sodium excretion and to increase peripheral vascular resistance. Digoxin-like immunoreactive substance (DLIS) was observed in plasma of some patients with spontaneous subarachnoid haemorrhage (SSAH). Accumulating evidence suggests the central nervous system as a site of synthesis, but also as a site of hypertensinogenic action of endogenous cardioglycosides. The present study intends to establish the ratio of the DLIS in plasma to that in cerebrospinal fluid (CSF) in patients with SSAH and to investigate possible connection of this substance with development of arterial vasospasm. A prospective analysis of DLIS levels was performed on plasma and CSF samples obtained in 40 patients who had suffered a recent SSAH. DLIS levels were determined by the fluorescence polarisation immuno-assay method immediately after the admission to the Ward, and again seven days later. The comparison of CSF and plasma DLIS levels did not show statistically significant differences between the results – neither for the first (Z=0.530; P=0.591) nor for the seventh day after the disease onset (Z=0.448; P=0.654). Three possible hypothetical explanations of these results are offered: a) substance determined by digoxin immuno-assay has no essential likeness to digoxin; b) loss of the haemato-encephalic barrier integrity enabling free substance exchange between plasma and central nervous system; c) digoxin-like substance production within the central nervous system. Further, comparison of DLIS plasma levels (7^th day from onset of SSAH) with angiography results showed that patients with multiple vasospasm had essentially higher plasma DLIS levels compared to patients with no vasospasms (Z=2.59; P=0.0097). The amount of extravasated blood, assessed on the basis of cranial CT scanning, was also connected with higher plasma DLIS levels (X²=3.29; P=0.0305). The enhanced arterial narrowing which occurs in SSAH may be in part mediated by increased digitalis-like factor activity.     

Carotid Rete Mirabile Presenting Subarachnoid Haemorrhage. Report of Two Cases

Carotid rete mirabile (CRM) consists of arterial channels between the internal and external carotid arteries in some lower mammals. It is a very rare pathological condition in humans. We report two patients who presented with clinical signs of subarachnoid haemorrhage (SAH). Their sudden-onset SAH was thought to have been due to rupture of cerebral aneurysms, however, angiograms revealed an abnormal vascular network around the cavernous sinus. To our knowledge, 2 of 7 reported patients with CRM presented with SAH, however, only one of these patients had a probable cerebral aneurysm. We suggest that in patients with CRM, the rupture of anastomosing vessels be a probable cause of SAH.     

Decrease in Intraoperative Brain Surface Temperature in Patients with Subarachnoid Haemorrhage

Summary  Background. Recent experimental and clinical evidence of hypothermic protection against neuronal injury creates new interests regarding human brain temperature. However, very little information is available for the brain temperature under certain pathological conditions. In this study, intra-operative brain temperature in patients with subarachnoid haemorrhage (SAH) is particularly addressed.  Methods. Brain surface temperature and oxygen saturation of jugular bulb (SjO₂) were monitored during early surgery undergone within 48 hours after the onset in patients with SAH (n=16). Those were also measured in patients with unruptured aneurysms during elective surgery as control (n=15).  Findings. The brain surface temperature was significantly lower in SAH than control (35.3±0.8 vs. 36.1±0.5°C, P<0.01). The reduction in brain surface temperature was correlated with the severity of the Hunt and Kosnik's aneurysmal grade (r=0.837, P<0.01). SjO₂ was significantly lower in SAH than control (51.5±7.3 vs. 68.5±7.6%, P<0.01), and was positively correlated with brain surface temperature (r=0.642, P<0.01).  Interpretation. These results suggest that the brain temperature and/or the temperature gradient within the brain may be altered in an early period after SAH. Since brain temperature is determined by cerebral blood flow (CBF), metabolism, temperature of both circulating blood and surrounding environment, the brain surface temperature reduction may be explained by depressed CBF and metabolism in SAH.     

Systemic and Cerebral Haemodynamics During Craniotomy Under Mild Hypothermia in Patients with Acute Subarachnoid Haemorrhage

Summary ? Background. Mild hypothermia provides cerebral protection against ischaemic insults in various animal models. We compared systemic and cerebral oxygenation between mild hypothermic and normothermic management in 60 patients with acute subarachnoid haemorrhage who underwent clipping of cerebral aneurysms.  Method. The temperature in the pulmonary artery was maintained at 36°C in 28 patients and was reduced to 34°C in 32 patients. Parameters in the systemic and cerebral haemodynamics from pulmonary artery and internal jugular vein catheters were compared between the two groups immediately after the induction of anaesthesia (T1), and just before temporary occlusion or aneurysm clipping (T2).  Findings. Cardiac index, oxygen delivery index, oxygen consumption index, and oxygen saturation of the jugular bulb were significantly lower at T2 in hypothermic group (H) (2.9±0.6 L/min/m², 400.8±106.3 ml/min·m², 87.0±14.8 ml/min·m², 55.2±6.6%, respectively) than in normothermic group (N) (3.7±0.6, 521.0±105.5, 109.9±21.7, 60.9±6.6) (p<0.05). The arterial lactate and arteriojugular difference in oxygen content were significantly higher in H (2.3±1.3 mmol/L, 6.5±1.5 ml/dl, respectively) than in N (1.7±1.0, 5.6±1.2) (p<0.05). Arteriojugular differences in carbon dioxide tension and hydrogen ion content were significantly lower at T2 in H (−10.8±2.1 mm Hg, −6.4±1.3 nmol/L, respectively) than in N (−8.9±2.8, −5.3±1.0) (p<0.05).  Interpretation. The balance between oxygen supply and demand systemically and in the brain may worsen during aneurysm surgery for patients with acute subarachnoid haemorrhage under mild hypothermia. Oxygenation of the brain and the whole body should be monitored closely during this surgery, and adequate circulatory assistance is recommended under mild hypothermia.     

Cerebral Blood Flow and Oxygen Metabolism During Mild Hypothermia in Patients with Subarachnoid Haemorrhage

Cerebral blood flow and O2 metabolism during hypothermia (33-34 degrees C) was evaluated in 5 patients with aneurysmal subarachnoid haemorrhage by positron emission tomography (PET). Their preoperative clinical condition was WFNS scale IV or V. The patients received surface cooling postoperatively, and were maintained in a hypothermic state during transfer for radiological examination. Positron emission tomography revealed a decrease in cerebral blood flow and O2 metabolic rate. Cerebral blood flow was 34.8+/-15.1 ml/100 ml/min and the O2 metabolic rate was 1.85+/-0.61 ml/100 ml/min in areas of the middle cerebral artery ipsilateral to the ruptured aneurysms, whereas these values were 30.8+/-7.1 and 2.21+/-0.45 ml/100 ml/min, respectively, on the contralateral side. This represents a decrease of 37+/-27% compared to normal cerebral blood flow and 52+/-16% compared to normal O2 metabolic rate (p < 0.02) in the ipsilateral areas, and decreases of 44+/-13% and 43+/-12%, respectively, on the contralateral side. The present results reflected the luxury perfusion state in almost all cases and provide the first PET evidence of decreased cerebral blood flow and metabolic rate of O2 during hypothermia in humans.