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Fatima A. Sehba, Rowena Flores, Artur Muller, Victor Friedrich, Jiang-Fan Chen, Gavin W. Britz, H. Richard Winn, and Joshua B. Bederson

Object

The role of adenosine A2A receptors in the early vascular response after subarachnoid hemorrhage (SAH) is unknown. In other forms of cerebral ischemia both activation and inhibition of A2A receptors is reported to be beneficial. However, these studies mainly used pharmacological receptor modulation, and most of the agents available exhibit low specificity. The authors used adenosine A2A receptor knockout mice to study the role of A2A receptors in the early vascular response to SAH.

Methods

Subarachnoid hemorrhage was induced in wild-type mice (C57BL/6) and A2A receptor knockout mice by endovascular puncture. Cerebral blood flow, intracranial pressure, and blood pressure were recorded, and cerebral perfusion pressure was deduced. Animals were sacrificed at 1, 3, or 6 hours after SAH or sham surgery. Coronal brain sections were immunostained for Type IV collagen, the major protein of the basal lamina. The internal diameter of major cerebral arteries and the area fraction of Type IV collagen–positive microvessels (< 100 μm) were determined.

Results

The initial increase in intracranial pressure and decrease in cerebral perfusion pressure at SAH induction was similar in both types of mice, but cerebral blood flow decline was significantly smaller in A2A receptor knockout mice as compared with wild-type cohorts. The internal diameter of major cerebral vessels decreased progressively after SAH. The extent of diameter reduction was significantly less in A2A receptor knockout mice than in wild-type mice. Type IV collagen immunostaining decreased progressively after SAH. This decrease was significantly less in A2A receptor knockout mice than in wild-type mice.

Conclusions

These results demonstrate that global inactivation of A2A receptors decreases the intensity of the early vascular response to SAH. Early inhibition of A2A receptors after SAH might reduce cerebral injury.

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Suresh N. Magge, H. Isaac Chen, Rohan Ramakrishna, Liyi Cen, Zhen Chen, J. Paul Elliott, H. Richard Winn, and Peter D. Le Roux

Object

Vasospasm is a leading cause of morbidity and death following aneurysmal subarachnoid hemorrhage (SAH). It is important to predict which patients are at risk for vasospasm so that interventions can be made. There are several potential risk factors for vasospasm, one of which is age. However, the effect of age on vasospasm, particularly symptomatic vasospasm, remains controversial.

Methods

Three hundred ninety-one patients were retrospectively identified from a prospective observational database of patients with SAH who had been admitted to a single center. Demographic and clinical data were recorded, and cerebral angiograms obtained at admission and between 5 and 10 days later were compared. The relationship between age and angiographic and symptomatic vasospasms was examined using logistic regression techniques.

Results

Mild (86 patients), moderate (69 patients), severe (56 patients), and no angiographic vasospasms (180 patients) were documented by comparing admission and follow-up angiograms in each patient. Symptomatic vasospasm was identified in 69 patients (17.6%). Angiographic vasospasm was more frequent as age decreased. Except in patients < 30 years old, the frequency of symptomatic vasospasm also increased with decreasing age (p = 0.0001). After adjusting for variables known to be associated with vasospasm, an advanced age was associated with a reduced incidence of any angiographic vasospasm (OR 0.96, 95% CI 0.94–0.97), severe angiographic vasospasm (OR 0.96, 95% CI 0.95–0.98), and symptomatic vasospasm (OR 0.98, 95% CI 0.96–0.99).

Conclusions

Results in this study show that a younger age is associated with an increased incidence of angiographic and symptomatic vasospasm.

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Ik-Seong Park, Joseph R. Meno, Cordelie E. Witt, Abhineet Chowdhary, Thien-Son Nguyen, H. Richard Winn, Al C. Ngai, and Gavin W. Britz

Object

Cerebrovascular dysfunction after subarachnoid hemorrhage (SAH) may contribute to ischemia, but little is known about the contribution of intracerebral arterioles. In this study, the authors tested the hypothesis that SAH inhibits the vascular reactivity of intracerebral arterioles and documented the time course of this dysfunction.

Methods

Subarachnoid hemorrhage was induced using an endovascular filament model in halothane-anesthetized male Sprague-Dawley rats. Penetrating intracerebral arterioles were harvested 2, 4, 7, or 14 days postinsult, cannulated using a micropipette system that allowed luminal perfusion and control of luminal pressure, and evaluated for reactivity to vasodilator agents.

Results

Spontaneous tone developed in all pressurized (60 mm Hg) intracerebral arterioles harvested in this study (from 66 rats), with similar results in the sham and SAH groups. Subarachnoid hemorrhage did not affect dilation responses to acidic pH (6.8) but led to a persistent impairment of endothelium-dependent dilation responses to adenosine triphosphate (p < 0.01), as well as a transient attenuation (p < 0.05) of vascular smooth muscle–dependent dilation responses to adenosine, sodium nitroprusside, and 8-Br-cyclic guanosine monophosphate (cGMP). Impairment of NO-mediated dilation was more sustained than adenosine- and 8-Br-cGMP–induced responses (up to 7 days postinsult compared with 2 days). All smooth muscle–dependent responses returned to sham levels by 14 days after SAH.

Conclusions

Subarachnoid hemorrhage led to a persistent impairment of endothelium-dependent dilation and a transient attenuation of vascular smooth muscle–dependent dilation responses to adenosine. Impairment of NOmediated dilation occurred when the response to cGMP was intact, suggesting a change in cGMP levels rather than an alteration in intracellular mechanisms downstream from cGMP.

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Grzegorz Miekisiak, Kristen Yoo, Adam L. Sandler, Tobias B. Kulik, Jiang-Fan Chen, and H. Richard Winn

Object

The authors tested the hypothesis that adenosine, acting through the A2A receptor, is not involved in hypercarbic hyperemia by assessing the effects of increased PaCO2 on cerebral blood flow (CBF) in vivo in wild-type and A2A receptor knockout mice. In addition, they evaluated the effect of abluminal pH changes in vitro on the diameter of isolated perfused penetrating arterioles harvested from wild-type and A2A receptor knockout mice.

Methods

The authors evaluated in a blinded fashion the CBF response during transient (60-second) hypercapnic (7% CO2) hypercarbia in anesthetized, ventilated C57Bl/6 wild-type and adenosine A2A receptor knockout mice. They also evaluated the hypercarbic response in the absence and presence of the nonselective and selective adenosine antagonists.

Results

Cerebral blood flow was measured using laser Doppler flowmetry. There were no differences between the CBF responses to hypercarbia in the wild-type and the knockout mice. Moreover, the hypercarbic hyperemia response was not affected by the adenosine receptor antagonists. The authors also tested the response to alteration in abluminal pH in isolated perfused, pressurized, penetrating arterioles (average diameter 63.3 ± 3.6 μm) harvested from wild-type (6 mice) and knockout (5 mice) animals. Arteriolar dilation in response to a decrease in abluminal pH, simulating the change in vivo during hypercarbia, was similar in wild-type (15.9 ± 2.6%) and A2A receptor knockout (17.7 ± 1.3%) mice. With abluminal application of CGS 21680 (10−6 M), an A2A receptor agonist, wild-type arterioles dilated in an expected manner (9.8 ± 0.7%), whereas A2A receptor knockout vessels had minimal response.

Conclusions

The results of the in vivo and in vitro studies in wild-type and A2A receptor knockout mice support the authors' hypothesis that hypercarbic vasodilation does not involve an adenosine A2A receptor–related mechanism.

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Michael M. Haglund, Joseph R. Meno, Daryl W. Hochman, Al C. Ngai, and H. Richard Winn

Object

This study was undertaken to test the hypothesis that cerebral blood flow (CBF) and the intrinsic optical signal could be dissociated by altering adenosine receptor activity and to uncover the origin of the optic signal using a cranial window in the anesthetized rat.

Methods

In anesthetized, ventilated, and temperature-controlled rats with closed cranial windows, the authors evaluated simultaneously the alterations in pial arteriolar diameter, intrinsic optical signals (690 nm), and somatosensory evoked potentials during cortical activation evoked by contralateral sciatic nerve stimulation (SNS). To dissociate the vascular and intrinsic signal, they topically applied the adenosine receptors antagonists theophylline (5 μM), which affects A1 and A2A receptors, and 8-cyclopentyl-1,3-dipropylxanthine (CPX, 1 μM), which blocks the A1 receptor. The former interacts primarily with the vasculature whereas the latter influences the parenchyma exclusively.

Results

During 20 seconds of contralateral SNS, pial arterioles in the hindlimb somatosensory cortex dilated in a characteristic peak and shoulder pattern. As compared with mock cerebrospinal fluid alone, theophylline significantly (p < 0.05) attenuated SNS-induced vasodilation (mean ± standard deviation 8.1 ± 2.5% vs 21.7 ± 1.9%; 4 rats in each group). In contrast, CPX potentiated vasodilation significantly (p < 0.05) during SNS (54.7 ± 15.8% for the CPX group vs 20.1 ± 1.9% for the controls; 5 rats in each group).

The change in optical signal persisted after cessation of SNS in all the animals. Thus, the pattern of change of the optical signal was distinctly different from the pattern of changes in arteriolar diameter (which returned rapidly to baseline). Moreover, the optical signal during SNS was increased by 50% by theophylline and by almost 5-fold by CPX (p < 0.05). The area of change of the intrinsic signal was also increased by the topical application of theophylline and CPX.

The somatosensory evoked potential recordings revealed no significant changes after theophylline application, but CPX caused a small diminution of the N1 wave (p < 0.01).

Conclusions

The noncongruent temporal profiles of the changes in pial arteriolar diameter and optical signal, imaged at 690 nm, indicate that the optical signal at 690 nm is not related to CBF. Alteration of adenosine receptor activity independently changed cortical activity, as measured by the optical signal, and CBF, as determined by pial arteriolar diameter. Manipulation of the adenosine receptor activity during increased cortical activity confirmed the temporal dissociation of optical signal and CBF and provided further evidence for the role of adenosine in regulating CBF.

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Gavin Britz and H. Richard Winn

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Introduction

Natural history of unruptured intracranial aneurysms

H. Richard Winn

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H. Richard Winn and Gavin W. Britz

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Gregory G. Heuer, Michelle J. Smith, J. Paul Elliott, H. Richard Winn, and Peter D. Leroux

Object. Increased intracranial pressure (ICP) is well known to affect adversely patients with head injury. In contrast, the variables associated with ICP following aneurysmal subarachnoid hemorrhage (SAH) and their impact on outcome have been less intensely studied.

Methods. In this retrospective study the authors reviewed a prospective observational database cataloging the treatment details in 433 patients with SAH who had undergone surgical occlusion of an aneurysm as well as ICP monitoring. All 433 patients underwent postoperative ICP monitoring, whereas only 146 (33.7%) underwent both pre- and postoperative ICP monitoring.

The mean maximal ICP was 24.9 ± 17.3 mm Hg (mean ± standard deviation). During their hospital stay, 234 patients (54%) had elevated ICP (> 20 mm Hg), including 136 of those (48.7%) with a good clinical grade (Hunt and Hess Grades I–III) and 98 (63.6%) of the 154 patients with a poor grade (Hunt and Hess Grades IV and V) on admission. An increased mean maximal ICP was associated with several admission variables: worse Hunt and Hess clinical grade (p < 0.0001), a lower Glasgow Coma Scale (GSC) motor score (p < 0.0001); worse SAH grade based on results of computerized tomography studies (p < 0.0001); intracerebral hemorrhage (p = 0.024); severity of intraventricular hemorrhage (p < 0.0001); and rebleeding (p = 0.0048). Both intraoperative cerebral swelling (p = 0.0017) and postoperative GCS score (p < 0.0001) were significantly associated with a raised ICP. Variables such as patient age, aneurysm size, symptomatic vasospasm, intraoperative aneurysm rupture, and secondary cerebral insults such as hypoxia were not associated with raised ICP. Increased ICP adversely affected outcome: 71.9% of patients with normal ICP demonstrated favorable 6-month outcomes postoperatively, whereas 63.5% of patients with ICP between 20 and 50 mm Hg and 33.3% with ICP greater than 50 mm Hg demonstrated favorable outcomes. Among 21 patients whose raised ICP did not respond to mannitol therapy, all experienced a poor outcome and 95.2% died. Among 145 patients whose elevated ICP responded to mannitol, 66.9% had a favorable outcome and only 20.7% were dead 6 months after surgery (p < 0.0001). According to results of multivariate analysis, however, ICP was not an independent outcome predictor (odds ratio 1.26, 95% confidence interval 0.28–5.68).

Conclusions. Increased ICP is common after SAH, even in patients with a good clinical grade. Elevated ICP post-SAH is associated with a worse patient outcome, particularly if ICP does not respond to treatment. This association, however, may depend more on the overall severity of the SAH than on ICP alone.

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Michelle J. Smith, Peter D. Le Roux, J. Paul Elliott, and H. Richard Winn

Object. Nitric oxide (NO) metabolism may influence vasospasm after subarachnoid hemorrhage (SAH). It has been demonstrated in recent studies that erythrocytes carry NO for release in vessels, whereas transfused erythrocytes may lack stored NO. Several converging lines of evidence also indicate that blood transfusion may exacerbate poor outcomes in some critically ill patients. In this study the authors hypothesized that patients with SAH who received red blood cell (RBC) transfusions were at greater risk for vasospasm and poor outcome.

Methods. The authors retrospectively reviewed a prospective observational database, including hospital records, computerized tomography (CT) scans, and pre- and postoperative four-vessel angiograms, in which the management methods used in 441 patients undergoing surgery for ruptured cerebral aneurysms were described. Two hundred seventy patients (61.2%) received an RBC transfusion during their hospital stay. After adjustment for Hunt and Hess grade, SAH grade on CT scans, delay between rupture and surgery, smoking status, and intraoperative aneurysm rupture, a worse outcome was more likely in patients who received intraoperative blood (odds ratio [OR] 2.44, confidence interval [CI] 1.32–4.52; 120 patients). Intraoperative RBC transfusion did not influence subsequent angiographically confirmed vasospasm (OR 0.92, CI 0.6–1.4). Worse outcome was observed in patients who received blood postoperatively (OR 1.81, CI 1.21–2.7), but not after adjustments were made for confounding variables (OR 1.48, CI 0.83–2.63). Angiographic vasospasm was observed in 217 patients and, after adjusting for confounding variables, was more frequent among patients who received postoperative RBC transfusion (OR 1.68, CI 1.02–2.75). Among patients in whom angiographically confirmed vasospasm developed there was a tendency to have received more blood than in those with no vasospasm; however, a clear dose-dependent response was not observed.

Conclusions. Development of angiographically confirmed vasospasm after SAH is associated with postoperative RBC transfusion and worse outcome is associated with intraoperative RBC transfusion. Before blood is transfused, patients with SAH should be carefully assessed to determine if they are symptomatic because of anemia.