Superoxide dismutase does not prevent delayed hypoperfusion after incomplete cerebral ischaemia in the rat

Summary Local cerebral blood flow (1CBF) was measured autoradiographically 60 minutes after 15 minutes of forebrain ischaemia in rats treated with superoxide dismutase (SOD) before (50 mg · kg^–1 body weight) or at the end of the ischaemia period (4mg·kg^–1 body weight). Incomplete forebrain ischaemia was produced by a combination of common carotid artery occlusion and bleeding to a mean arterial blood pressure of 50 mmHg. During ischaemia the 1CBF values in cortical areas were less than 3% of the preischaemic values and treatment with SOD prior to ischaemia did not influence 1CBF during ischaemia. Sixty minutes after termination of cerebral ischaemia the 1CBF values were decreased to between 40 and 60% of values found in control animals. Neither form of treatment improved the postischaemic cerebral blood flows. The results imply that postischaemic flow disturbances in the brain may not be due to extracellular superoxide production.     

The effect of nimodipine on autoregulation of cerebral blood flow after subarachnoid haemorrhage in rat

Summary Disturbance of the autoregulation of the cerebral blood flow (CBF) is frequently seen following subarachnoid haemorrhage (SAH) and is possibly partly caused by cerebral ischaemia. It is well-known, that the calcium channel blocker nimodipine reduces the incidence of cerebral infarction and ischaemic dysfunction after SAH.The aim of the present study was to investigate the effect of nimodipine on autoregulation of CBF in an experimental model of SAH. The autoregulation was investigated in 10 control rats with SAH and in 10 nimodipine treated rats with SAH by serial measurements of CBF using a¹³³Xenon intracarotid injection method during controlled blood pressure manipulations.In the control rats the autoregulation was severely disturbed, no plateau was found where CBF was independent of changes in the arterial blood pressure (MABP). In rats treated with intravenous nimodipine (0.03 mg/kg bodyweight/h), CBF was 33.0% higher and MABP 5.3% higher compared with the controls. CBF was found constant in the MABP interval between 60 and 100 mmHg which indicates, that nimodipine improves the autoregulation of CBF after SAH.     

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.     

Blood Flow Velocities in the Basal Vein after Subarachnoid Haemorrhage A Prospective Study Using Transcranial Duplex Sonography

Summary. Summary. Background: Early recognition of emerging delayed neurological deficits (DND) in patients after subarachnoid haemorrhage (SAH) is not always possible by transcranial Doppler sonography. Aim of this study was to investigate a) whether determination of blood flow velocities in deep cerebral basal veins can predict DND in these patients b) the correlation of venous flow velocity to cerebral blood flow (CBF). Methods: a) We prospectively investigated the mean flow velocity in the basal vein (V_BVR), in the middle cerebral artery (V_MCA) and in the extracranial internal carotid artery (V_ICA) in 66 patients after spontaneous SAH. Examinations were performed daily during the first 10 days, using transcranial duplex sonography. Thirty-seven patients had V_MCA exceeding 120 cm/s. They were categorised in three groups: I: no delayed neurological deficit; II: transient DND; III: permanent DND or death associated with vasospasm. b) In another group of 14 patients, interdiane variations in global cerebral blood flow (CBF) measured by the Kety-Schmidt-method were correlated with variations in V_BVR, V_MCA, and V_ICA. Findings: a) In patients without deficit, V_BVR was significantly elevated above normal values the first day (p<0.05), and days 5 and 6 (p<0.1) after V_MCA exceeding 120 cm/s. In group III (permanent deficit), flow velocities in the BVR were significantly below normal on day 5 (p<0.05) and 9 (p<0.1). b) The correlation between changes in V_BVR to changes in CBF (r=0.78, p<0.001) was closer than between changes in V_MCA to the changes in CBF (r=0.54, p<0.05). Interpretation: In case of elevated V_MCA, patients with higher V_BVR seem to have a better outcome. Changes in CBF correlate better with V_BVR than with arterial flow velocities.     

Pression tissulaire cérébrale en oxygène : pour quoi faire et pour qui ?

The main purpose of neurointensive care is to fight against cerebral ischaemia. Ischaemia is the cell energy failure following inadequacy between supply of glucose and oxygen and demand. Ischemia monitoring starts with a global approach, especially with cerebral perfusion pressure (CPP) determined by mean arterial pressure and intracranial pressure (ICP). However, global monitoring is insufficient to detect “regional” ischaemia, leading to development of local monitoring such as brain oxygen partial pressure (PtiO₂). PtiO₂ is measured on a volume of a few mm³ from a probe implanted in the cerebral tissue. The normal value is classically included between 25 and 35 mmHg and critical ischemic threshold is 10 mmHg. Understanding what exactly is PtiO₂ is still a matter of debate. PtiO₂ is more an indicator of oxygen diffusion depending of oxygen arterial pressure (PaO₂) and local cerebral blood flow (CBF). Increase PaO₂ to treat PtiO₂ would hide information about local CBF. PtiO₂ is useful for the detection of low local CBF even when ICP is low as in hypocapnia-induced vasoconstriction. PtiO₂-guided management could lead to a continuous optimization of arterial oxygen transport for an optimal cerebral tissue oxygenation. Finally, PtiO₂ has probably a global prognostic value because studies showed that hypoxic values for a long period of time lead to an unfavourable neurologic outcome. In conclusion, PtiO₂ provides additional information for regional monitoring of cerebral ischaemia and deserves more intensive use to better understand it and probably improve neurointensive care management.     

Effect of controlled blood pressure increase on cerebral blood flow velocity and oxygenation in patients with subarachnoid haemorrhage

Background

Patients with aneurysmal subarachnoid haemorrhage (SAH) might have impaired cerebral autoregulation, that is, CBF – and thereby oxygen delivery – passively increase with an increase in CPP. This physiological study aimed to investigate the cerebral haemodynamic effects of controlled blood pressure increase in the early phase after SAH before any signs of delayed cerebral ischaemia (DCI) occurred.

Methods

The study was carried out within 5 days after ictus. Data were recorded at baseline and after 20 min of noradrenaline infusion to increase mean arterial blood pressure (MAP) by a maximum of 30 mmHg and to an absolute level of no more than 130 mmHg. The primary outcome was the difference in middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler (TCD), while differences in intracranial pressure (ICP), brain tissue oxygen tension (PbtO₂), and microdialysis markers of cerebral oxidative metabolism and cell injury were assessed as exploratory outcomes. Data were analysed using Wilcoxon signed-rank test with correction for multiplicity for the exploratory outcomes using the Benjamini-Hochberg correction.

Results

Thirty-six participants underwent the intervention 4 (median, IQR: 3–4.75) days after ictus. MAP was increased from 82 (IQR: 76–85) to 95 (IQR: 88–98) mmHg (p-value: <.001). MCAv remained stable (baseline, median 57, IQR: 46–70 cm/s; controlled blood pressure increase, median: 55, IQR: 48–71 cm/s; p-value: .054), whereas PbtO₂ increased significantly (baseline, median: 24, 95%CI: 19–31 mmHg; controlled blood pressure increase, median: 27, 95%CI: 24–33 mmHg; p-value <.001). The remaining exploratory outcomes were unchanged.

Conclusion

In this study of patients with SAH, MCAv was not significantly affected by a brief course of controlled blood pressure increase; despite this, PbtO₂ increased. This suggests that autoregulation might not be impaired in these patients or other mechanisms could mediate the increase in brain oxygenation. Alternatively, a CBF increase did occur that, in turn, increased cerebral oxygenation, but was not detected by TCD. Trial registration: clinicaltrials.gov (NCT03987139; 14 June 2019).     

Cerebral blood flow and cerebral blood flow velocity during angiotensin-induced arterial hypertension in dogs

Pressure-passive perfusion beyond the upper limit of cerebral blood flow (CBF) autoregulation may be deleterious in patients with intracranial pathology. Therefore, monitoring of changes in CBF would be of clinical relevance in situations where clinical evaluation of adequate cerebral perfusion is impossible. Noninvasive monitoring of cerebral blood flow velocity using transcranial Doppler sonography (TCD) may reflect relative changes in CBF. This study correlates the effects of angiotensininduced arterial hypertension on CBF and cerebral blood flow velocity in dogs. Heart rate (HR) was recorded using standard ECG. Catheters were placed in both femoral arteries and veins for measurements of mean arterial blood pressure (MAP), blood sampling and drug administration. A left ventricular catheter was placed for injection of microspheres. Cerebral blood flow velocity was measured in the basilar artery through a cranial window using a pulsed 8 MHz transcranial Doppler ultrasound system. CBF was measured using colour-labelled microspheres. Intracranial pressure (ICP) was measured using an epidural probe. Arterial blood gases, arterial pH and body temperature were maintained constant over time. Two baseline measures of HR, MAP, CBF, cerebral blood flow velocity and ICP were made in all dogs (n = 10) using etomidate infusion (1.5 mg · kg^?1 · hr^?1) and 70% N₂O in O₂ as background anaesthesia. Following baseline measurements, a bolus of 1.25 mg angiotensin was injected iv and all variables were recorded five minutes after the injection. Mean arterial blood pressure was increased by 76%. Heart rate and ICP did not change. Changes in MAP were associated with increases in cortical CBF (78%), brainstem CBF (87%) and cerebellum CBF(64%). Systolic flow velocity increased by 27% and Vmean increased by 31% during hypertension (P < 0.05). Relative changes in CBF and blood flow velocity were correlated (CBF cortex — Vsyst: r = 0.94, CBF cortex — Vmean: r = 0.77; P < 0.001; CBF brainstem — Vsyst: r = 0.82, CBF brainstem — Vmean: r = 0.69; P < 0.05). Our results show that increases in arterial blood pressure beyond the upper limit of cerebral autoregulation increase CBF in dogs during etomidate and N₂O anaesthesia. The changes in CBF are correlated with increases in basilar artery blood flow velocity. These data suggest that TCD indicates the upper limit of the cerebral autoregulatory response during arterial hypertension. However, the amount of CBF change may be underestimated with the TCD technique.     

Sequential changes in cerebral blood flow and metabolism in patients with subarachnoid haemorrhage

Summary Haemodynamic and metabolic sequences were investigated in nine patients having subarachnoid haemorrhage (SAH) up to 3 months following aneurysmal rupture, using positron emission tomography (PET). In the pre-spasm stage (2–4 days after SAH) cerebral blood flow (CBF, ml/100 ml/min) was 45±11, the cerebral metabolic rate of oxygen (CMRO₂, ml/100 ml/min) was 2.68±0.50, and cerebral blood volume (CBV, ml/100 ml) was 5.5±1.2. CBF within the normal range and a relatively low CMRO₂, indicated relative hyperaemia. This was possibly due to the direct toxic effect of SAH on the brain metabolism. CBV was considerably elevated. The spasm stage (6–15 days after SAH) showed CBF values of 39±7, CMRO₂ values of 2.42±0.50, and CBV values of 5.4±1.7. CBF decreased significantly (p<0.05 vs pre-spasm stage), and CMRO₂ also tended to decrease, while they were coupling. It is likely that this may have been induced by vasospasm. Thereafter, the PET parameters normalized gradually. During all the stages studied, significant laterality of the PET parameters was not observed. This may be because SAH and vasospasm provide diffuse pathophysiological conditions for the entire brain and cerebral arteries.     

In Vivo Effects of Dexmedetomidine on Laser-Doppler Flow and Pial Arteriolar Diameter

Background: The alpha2 -adrenergic agonist dexmedetomidine alters global cerebral blood flow (CBF). However, few studies have investigated the action of dexmedetomidine on the cerebral microcirculation. This investigation examined the effects of dexmedetomidine on (1) regional CBF in the rat cerebral cortex using laser-Doppler flowmetry and (2) on pial arteriolar diameter.

Methods: Halothane-anesthetized rats were fitted with instruments to measure CBF as determined by laser-Doppler flow (CBFldf) or to measure pial arteriolar diameter by preparing a cranial hollow deepened until a translucent plate of skull remained, thereby maintaining the integrity of the cranial vault. In both groups, 20 micro gram/kg dexmedetomidine was infused intravenously. Thirty minutes later, the mean arterial pressure was restored to control values with an infusion of phenylephrine (0.5 to 5 micro gram/kg/min).

Results: Administration of dexmedetomidine was associated with decreases in end-tidal and arterial carbon dioxide. The CBFldf and pial arteriolar diameter were measured during normocapnia (controlled carbon dioxide) and during dexmedetomidine-induced hypocapnia. Intravenous administration of dexmedetomidine significantly decreased systemic arterial pressure concurrent with a decrease in CBFldf (22% in normocapnic animals, 36% in hypocapnic animals). Restoration of mean arterial pressure increased CBFldf in normocapnic but not in hypocapnic animals. Similarly, dexmedetomidine significantly reduced pial vessel diameter in both normocapnic (9%) and hypocapnic animals (17%). However, vessel diameters remained decreased in the normocapnic and hypocapnic animals after the mean arterial pressure was restored.     

Posttraumatic cerebral arterial spasm: transcranial Doppler ultrasound, cerebral blood flow, and angiographic findings.

Thirty patients admitted after suffering closed head injuries, with Glasgow Coma Scale scores ranging from 3 to 15, were evaluated with transcranial Doppler ultrasound monitoring. Blood flow velocity was determined in the middle cerebral artery (MCA) and the intracranial portion of the internal carotid artery (ICA) in all patients. Because proximal flow in the extracranial ICA declines in velocity when arterial narrowing becomes hemodynamically significant, the extracranial ICA velocity was concurrently monitored in 19 patients. To assess cerebral perfusion, cerebral blood flow (CBF) measurements obtained with the intravenous 133Xe technique were completed in 16 patients. Vasospasm, designated as MCA velocity exceeding 120 cm/sec, was found in eight patients (26.7%). Severe vasospasm, defined as MCA velocity greater than 200 cm/sec, occurred in three patients, and was confirmed by angiography in all three. Subarachnoid hemorrhage (SAH) was documented by computerized tomography in five (62.5%) of the eight patients with vasospasm. All cases of severe vasospasm were associated with subarachnoid blood. The time course of vasospasm in patients with traumatic SAH was similar to that found in patients with aneurysmal SAH; in contrast, arterial spasm not associated with SAH demonstrated an uncharacteristically short duration (mean 1.25 days), suggesting that this may be a different type of spasm. A significant correlation (p less than 0.05) was identified between the lowest CBF and highest MCA velocity in patients during the period of vasospasm, indicating that arterial narrowing can lead to impaired CBF. Ischemic brain damage was found in one patient who had evidence of cerebral infarction in the territories supplied by the arteries affected by spasm. These findings demonstrate that delayed cerebral arterial spasm is a frequent complication of closed head injury and that the severity of spasm is, in some cases, comparable to that seen in aneurysmal SAH. This experience suggests that vasospasm is an important secondary posttraumatic insult that is potentially treatable.     

Nitric Oxide Synthase Inhibition Attenuates Vasoactive Response to Spinal Cord Stimulation in an Experimental Cerebral Vasospasm Model

Summary  Background. The basic mechanism of delayed cerebral vasospasm following subarachnoid haemorrhage (SAH) has been intensively investigated. It is thought that nitric oxide (NO) is a basic mediator of the cerebral vasodilator mechanism. Previous clinical and experimental studies have shown a cerebral vasodilator effect of high cervical spinal cord stimulation (SCS) however, the mechanism of this effect is still controversial. We investigated the contribution of the vasodilator effect of NO to this mechanism in an experimental SAH model using rabbits.  Method. Four experimental groups, were designated: Group 1. Cerebral blood flow (CBF) was evaluated by transcranial Doppler ultrasonography (TDU) in 8 rabbits. Group 2. In 4 animals, intracisternal saline injection and cervical epidural electrode placement without SCS were performed before TDU. Group 3. TDU was performed before and after SCS on the fourth day of SAH in 8 rabbits. Group 4. In 8 animals, N-Nitro-L-Arginine Methyl Esther (L-NAME) was administered intracisternally on the fourth day of SAH, at a dose of 0.6 mg/kg, 45 minutes before SCS. CBF parameters, obtained via measurements or calculations from TDU data, were compared.  Findings. The occurrence of vasospasm after SAH was demonstrated with significant changes in TDU parameters (high peak systolic velocity and positive values of the degree of stenosis). In all SAH animals, SCS resulted in significant vasodilation. Even after the injection of L-NAME, SCS still had a significant vasodilatory effect in SAH animals, but there was also a significant difference in CBF parameters in the SCS-only group when compared with the L-NAME treatment before SCS group.  Interpretation. The mechanism of the cerebral vasodilatory effect of SCS remains controversial. Our results revealed the contribution of a neurohumoral effect which can be partially prevented by use of an NO synthase inhibitor.     

Blood flow velocity changes in carotid and vertebral arteries with stellate ganglion block: Measurement by magnetic resonance imaging using a direct bolus tracking method

Background and Objectives. Stellate ganglion block (SGB) leads to vasodilation of the head and neck, as a result of a regional sympathetic blockade. However, in such cases, controversy remains concerning changes in cerebral and extracerebral blood flow in the head. We estimated the effect of SGB on blood flow in the head by measuring the blood flow velocity in cervical vessels, using magnetic resonance imaging and the direct bolus tracking method. This noninvasive method is free from potential artifacts of bones and other connective tissues. Methods. Seven adult patients with acute or chronic pain in the head or neck underwent SGBs, using an anterior paratracheal approach with 6–8 mL of 1% mepivacaine (3 right and 4 left SGBs). Blood flow velocity in common carotid and vertebral arteries (CCA and VA) was measured simultaneously before and after SGB, using the direct bolus tracking method. Results. On the side of SGB, blood flow velocity in CCA significantly increased (P < .002), whereas velocity in VA was unchanged after SGB. On the side contralateral to the SGB, significant changes in blood flow velocity in CCA and VA were never observed. Conclusions. Blood from the VA flows primarily to cerebral vessels, whereas that from CCA goes to both cerebral and extracerebral vessels. Given the presumed differences in blood flow distribution through the VA and CCA, we assume that the observed CCA blood flow increases, ipsilateral to the SGB, primarily as a result of vasodilation of extracerebral vessels and independent of changes in brain blood flow.     

Anesthésie pour chirurgie vasculaire cérébrale anévrismale

The two major neurological complications of subarachnoid haemorrhage (SAH) due to an intracranial aneurysm are rebleeding and delayed cerebral ischaemia related to cerebral vasospasm. The best way to prevent rebleeding is early surgery. Even when surgery is performed within the first 72 hours posthaemorrhage, the risk of cerebral ischaemia due to vasospasm is high. Conventional medical treatment of cerebral vasospasm includes haemodilution, hypervolaemia and increase of arterial blood pressure. Haemodilution is of limited value as the patients suffering from SAH have usually a low haematocrit. The effectiveness of hypervolaemia is controversial and it may worsen cerebral and pulmonary oedema. Systemic hypertension is an effective therapy of vasospasm, but which can only be used once the aneurysm is controlled. Nimodipine and nicardipine, two calcium antagonists, have a beneficial effect on neurologic outcome following SAH. Today, it is still debated whether the beneficial effect of nimodipine results from the vascular effect of the drug or from a direct cerebral cytoprotective mechanism. Early surgery implies that surgeons operate on brains in acute inflammatory state. Thus, it is mandatory to use peroperative techniques improving cerebral exposure. These techniques include infusion of mannitol, lumbar cerebrospinal fluid (CSF) drainage, administration of anaesthetic agents known to decrease cerebral blood flow (CBF) and hypocapnia. Usually, the effect of CSF drainage is very effective and sufficient by itself. The second objective in the peroperative period is to avoid ischaemia. In areas with decreased flow distal to vasospasm, autoregulation is impaired and CBF is directly dependent on cerebral perfusion pressure. Furthemore, the safe practice of transient clipping of vessels supplying the aneurysm has dramatically reduced the indications of controlled hypotension. During temporary clipping, some authors recommend a pharmacological brain protection using barbiturates, etomidate or propofol, but this practice has not been validated by randomized studies. However, it is generally agreed that the arterial pressure should be increased during temporary clipping to improve collateral blood flow and to maintain it after the aneurysm has been secured. To conclude, together with lumbar CSF drainage and transient clipping, the anaesthetic management of the patients should include : maintenance of the arterial blood pressure close to its preoperative level, maintenance of Paco₂ between 30 and 35 mmHg and of normovolaemia through replacement of fluid and blood losses. After completion of surgery, recovery from anaesthesia should be rapid to allow fast diagnosis of neurological complications. The monitoring of the status of consciousness is the key of the diagnosis of early postoperative complications.     

Disturbance of Cerebral Blood Flow Autoregulation in Hypertension is Attributable to Ischaemia Following Subarachnoid Haemorrhage in Rats: A PET Study

The effects of subarachnoid haemorrhage (SAH) on cerebral blood flow (CBF) autoregulation during induced hypertension were studied by positron emission tomography (PET) during chronic vasospasm in anaesthetized Sprague-Dawley rats. SAH was induced by intracisternal injection of autologous blood. In the control animals saline was injected instead. This method produced angiographical vasospasm of major arteries 48 h after injection. During this period, CBF was measured at each side of fronto-parietal and occipital sections using PET with or without induced hypertension. Mean arterial blood pressure (MABP) was increased from 94+/-2.4 to 140+/-0.3 mmHg by the injection of phenylephrine. An autoregulatory index (AI) expressed as delta CBF (%) per 10-mmHg increase in MABP was employed to analyse CBF response. SAH significantly reduced (p<0. 0001) basal CBF (ml/100 g/min) by 26.2% (control 60.0+/-1.9 n=24, SAH 44.3+/-4.5 n=20). A territorial CBF that decreased by 50% or more over the mean control value was used to define ischaemia and was identified in five out of 20 regions (25%) in the SAH group. AI (%/10-mmHg) was 13.5+/-2.4 in the control group (n=24). In the SAH group, AI decreased (p<0.05) to 4.5+/-2.5 in non-ischaemic areas (n=15), while in the ischaemic areas (n=5) AI increased (p<0.05) to 25.2+/-4.1. Since the spastic artery is intrinsically resistant to hypertension, the marked increase in CBF during hypertension can be attributable to ischaemia following SAH.     

Internal carotid artery volume flow correlates to rCBF measurements

Summary ¶Background. There is no simple, cost effective bedside method available for measuring global cerebral blood flow (CBF) rapidly and repeatedly. Method. Based on the ultrasound technique a device was developed to measure flow volume per unit of time in the internal carotid artery. The system utilizes dual beam, angle-independent Doppler technology, and employs simultaneous sampling and full spectrum determination. The aim of this study was to evaluate this device in comparison with cerebral blood flow measurements using the well established Xenon¹³³ clearence technique. Findings. 10 patients suffering from SAH were included. 20 measurements were performed. CBF was measured employing the Xenon¹³³ clearence technique. Velocity profiles across the ICA were obtained with the high-resolution FlowGuard Doppler ultrasound flow system (Cardiosonix Ltd., Israel). According to the statistical analysis the ICA flow correlated significantly to the mean rCBF15 index of the hemisphere (p<0.0001). Conclusions. This new device seems to be promising for monitoring cerebral blood flow in critically ill neurological and neurosurgical patients.Published online September 18, 2003     

Mannitol causes compensatory cerebral vasoconstriction and vasodilation in response to blood viscosity changes

There is no proof that osmotic agents such as mannitol lower intracranial pressure (ICP) by decreasing brain water content. An alternative mechanism might be a reduction in cerebral blood volume through vasoconstriction. Mannitol, by decreasing blood viscosity, would tend to enhance cerebral blood flow (CBF), but the cerebral vessels would constrict to keep CBF relatively constant, analogous to pressure autoregulation. The cranial window technique was used in this study to measure the pial arteriolar diameter in cats, together with blood viscosity and ICP changes after an intravenous bolus of 1 gm/kg of mannitol. Blood viscosity decreased immediately; the greatest decrease (23%) occurred at 10 minutes, and at 75 minutes there was a "rebound" increase of 10%. Vessel diameters decreased concomitantly, the largest decrease being 12% at 10 minutes, which is exactly the same as the 12% decrease in diameter associated with pronounced hyperventilation (PaCO2 30 to 19 mm Hg) in the same vessels; at 75 minutes vessel diameter increased by 12%. With hyperventilation, ICP was decreased by 26%; 10 minutes after mannitol was given, ICP decreased by 28%, and at 75 minutes it showed a rebound increase of 40%. The correlation between blood viscosity and vessel diameter and between vessel diameter and ICP was very high. An alternative explanation is offered for the effect of mannitol on ICP, the time course of ICP changes, "rebound effect," and the absence of influence on CBF, all with one mechanism.     

Pressure autoregulation and positron emission tomography-derived cerebral blood flow acetazolamide reactivity in patients with carotid artery stenosis

OBJECTIVE: Testing autoregulation is of importance in predicting risk of stroke and managing patients with occlusive carotid arterial disease. The use of small spontaneous changes in arterial blood pressure and transcranial Doppler (TCD) flow velocity can be used to assess autoregulation noninvasively without the need for a cerebrovascular challenge. We have previously described an index (called "Mx") that achieves this. Negative or low positive values (<0.4) indicate intact pressure autoregulation, whereas an Mx greater than 0.4 indicates diminished autoregulation. The objective of this study was to compare acetazolamide reactivity of positron emission tomography (PET)-derived cerebral blood flow (CBF) with Mx in patients with carotid arterial disease. METHODS: In 40 patients with carotid arterial disease, we used bilateral TCD recordings of the middle cerebral artery to derive Mx and compared this with PET-derived CBF measurements of acetazolamide reactivity. RESULTS: Mx correlated inversely with baseline PET CBF (P = 0.042, R = -0.349) but not with postacetazolamide CBF or cerebrovascular reactivity to acetazolamide. This may reflect discordance between pressure autoregulation and acetazolamide reactivity. Mx correlated significantly with degree of internal carotid artery stenosis (P = 0.022, R = 0.38), whereas CBF reactivity to acetazolamide did not correlate with Mx (P = 0.22). After the administration of acetazolamide, slow-wave activity in blood pressure and TCD flow velocity recordings was seen to diminish, rendering the calculation of Mx unreliable after acetazolamide. CONCLUSION: The measurement of Mx offers a noninvasive, safe technique for assessing abnormalities of pressure autoregulation in patients with carotid arterial disease.     

Leflunomide prevents vasospasm secondary to subarachnoid haemorrhage

Summary Background. Though cerebral vasospasm is one of the most serious complications of subarachnoid haemorrhage (SAH), its complex pathogenesis is poorly understood and available clinical treatment options are unsatisfactory. This study was designed to examine the efficacy of leflunomide, an immunomodulatory agent with inhibitory properties, on vascular smooth muscle cell proliferation and inflammation in a rabbit cerebral vasospasm model. Methods. Twenty-two adult New-Zealand rabbits were assigned to 4 groups: control, SAH, SAH plus vehicle, SAH plus leflunomide. Subarachnoid haemorrhage was induced by administration of 1 ml of fresh unheparinised autologous arterial blood into the cisterna magna. Oral leflunomide (2 mg/kg) or vehicle treatment was started 12 h after the induction of subarachnoid haemorrhage and administered once a day. Three days later, the animals were sacrificed and the basilar artery was examined histologically for the lumen area and the thickness of the vessel wall. Inflammatory reaction was also examined by counting white blood cells within the vessel wall by means of light microscopic examination using haematoxylin and eosin staining. Findings. Severe and moderate vasospasms were detected in the basilar artery of the SAH and SAH plus vehicle treated groups, respectively. Leflunomide effectively reduced the vasospasm of the basilar artery. Compared to the vehicle treated group, leflunomide significantly reduced the lumen area (p < 0.01) and hyperplasia of the vessel wall (p < 0.01). Although inflammatory response within the vessel wall was reduced in the leflunomide treated group, no statistical significance was found between groups (p = 0.07). Conclusion. This study demonstrates for the first time that leflunomide treatment attenuates cerebral vasospasm in a rabbit SAH model while inflammatory reaction in the vessel wall is not affected. Although further studies are needed to reveal its molecular mechanisms in relieving vasospasm, leflunomide may provide a therapeutic potential for human cerebral vasospasm induced by SAH.     

Is postischaemic water accumulation related to delayed postischaemic hypoperfusion in rat brain?

Summary The effect of reversible cerebral ischaemia on brain oedema development was studied with a gravimetric method. Cerebral blood flow changes after ischaemia were correlated with alterations in brain specific gravity. Forebrain ischaemia (15 min) was induced in rats by reversible bilateral ligation of both carotid arteries plus induction of controlled hypotension to 50 mm Hg. The specific gravity of different brain structures was determined in a Percoll^® column up to 24 h after ischaemia. In addition, regional cerebral blood flow was measured by¹⁴C-iodoantipyrine autoradiography.Cerebral ischaemia resulted in reduction of cerebral blood flow to less than 1% of normal in cortical structures and the caudatoputamen. One hour after the end of ischaemia blood flows were still reduced to 30–50% of the control level indicative of delayed postischaemic hypoperfusion. Specific gravity in cortex and hypothalamus reached a maximal decrease 10 min after the end of the ischaemia, and was still significantly reduced at 1 h, while it was normal again 6 hrs later.Regression analysis between regional cerebral blood flows and the corresponding specific gravities were made at various time points, but no significant correlations could be established.Other mechanisms, like vasoconstriction, rheologic or metabolic factors may be causative for the delayed postischaemic hypoperfusion.     

The attenuation of vasospasm by using a sod mimetic after experimental subarachnoidal haemorrhage in rats

Background. Delayed cerebral vasoconstriction and brain ischemia, are critical problems in the management of a patient affected by rupture of an intracranial aneurysm. Overexpression of Cu–Zn superoxide dismutase (Cu–Zn SOD) can reduce the extent of cerebral vasospasm. We, therefore investigated if vasospasm, can be prevented by a novel, stable, and cell permeable SOD mimetic, MnTBAP [Mn(III) tetrakis (4-benzoic acid) porphyrin] which permeates the biological membranes and scavenges superoxide anions and peroxynitrite. Methods. 28 rats (225–250g) were divided equally into four groups: group 1: control; group 2: SAH only; group 3: SAH plus placebo; and group 4: SAH plus MnTBAP. We used a double haemorrhage method to produce SAH. Starting six hours after SAH, 5mg/kg MnTBAP (Calbiochem, Darmstadt-Germany; Cat. No 475870)) or an equal volume of 0.9% saline (37°C) was administered by intraperitoneal injection twice daily for 5 days to groups 4 and 3 respectively. MnTBAP or 0.9% saline injections were continued up to fifth day after SAH and rats were sacrificied on the fifth day. Brain sections at the level of the pons were examined by light microscopy. Planimetric measurements were made for the cross-sectional areas of the lumen and the vessel wall (intima plus media) of the basilar artery by a micrometer. Finding. Administration of MnTBAP significantly attenuated the vasoconstriction of the basilar artery in group 4 compared with the groups 2 and 3 (p<0.001). Interpretation. These results suggest that this SOD mimetic (MnTBAP) attenuates delayed cerebral vasoconstriction following experimental SAH and that superoxide anions have a role in the pathogenesis of vasospasm after SAH.Published online July 25, 2003