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R. Loch Macdonald

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R. Loch Macdonald

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Shigeki Ono, Taro Komuro and R. Loch Macdonald

Object. Hemoglobin causes contraction of cerebral arteries and is also believed to cause vasospasm after subarachnoid hemorrhage (SAH). The goal in this study was to determine if overexpression of heme oxygenase-1 (HO-1), the principal enzyme involved in the metabolism of hemoglobin, would reduce contractions of cerebral arteries brought on by hemoglobin and decrease vasospasm after experimental SAH.

Methods. Injection of adenovirus expressing HO-1 (Ad5HO-1) into the cisterna magna of rats produced a significant increase in expression of HO-1 messenger RNA, and protein and HO-1 activity in the basilar artery ([BA]; p < 0.05 for each measure compared with vehicle and/or control virus, according to analysis of variance or unpaired t-test). Injection of adenovirus expressing β-galactosidase (Ad-βGal) produced only mild, statistically nonsignificant increases. The HO-1 immunoreactivity was localized to the BA adventitia after injection of Ad5HO-1 or Ad-βGal. Injection of Ad5HO-1 and Ad-βGal increased the baseline diameter of the BA (measured directly via a transclival window) and brainstem cerebral blood flow (CBF), measured by laser Doppler flowmetry, compared with vehicle. Contraction of the BA after addition of hemoglobin was significantly inhibited, reduction in brainstem CBF was significantly prevented, and carboxyhemoglobin concentration was significantly increased in rats injected with Ad5HO-1 compared with Ad-βGal and vehicle. Vasospasm was significantly ameliorated in rats in which Ad5HO-1 was injected into the cisterna magna at the time of SAH in a double-hemorrhage model.

Conclusions. These results show that overexpression of HO-1 inhibits arterial contractions induced by hemoglobin and can reduce vasospasm after experimental SAH.

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Daipayan Guha, Shona Coyne and R. Loch Macdonald


Antithrombosis (AT), defined here as either antiplatelets or anticoagulants, is a significant risk factor for the development of chronic subdural hematomas (cSDHs). Resuming AT following the evacuation of cSDH is a highly variable practice, with scant evidence in the literature for guidance. Here, a retrospective analysis of a cohort of patients from a single institution undergoing surgical drainage of cSDH was performed to evaluate postoperative complications and determine the optimal timing of the resumption of common antithrombotic agents.


This retrospective analysis was performed on 479 patients undergoing surgical evacuation of cSDH at St. Michael’s Hospital over a 5-year period (2007–2012). The collected variables included the type of AT agent, indications for AT, timing and type of postoperative complications, and the restart intervals for the AT agents, when available. Postoperative complications were classified as major hemorrhages, minor hemorrhages, orthromboembolic events.


Among all 479 study patients, 71 experienced major hemorrhage (14.8%), 110 experienced minor hemorrhage (23.0%), and 8 experienced thromboembolism (1.67%) postoperatively. Patients on any type of preoperative AT regimen were at a higher risk of major hemorrhage (19.0% vs 10.9%; OR 1.93; 95% CI 1.15–2.71; p = 0.014). The type of AT agent did not affect the frequency of any postoperative complications. Patients on any preoperative AT regimen experienced earlier postoperative major hemorrhages (mean 16.2 vs 26.5 days; p = 0.052) and thromboembolic events (mean 2.7 vs 51.5 days; p = 0.036) than those patients without a history of AT; the type of AT agent did not affect timing of complications. Patients who were restarted on any AT therapy postoperatively were at decreased risk of major rebleeding following resumption than those patients who were not restarted (OR 0.06; 95% CI 0.02–0.2; p < 0.01).


Patients with a history of preoperative AT experienced thromboembolic complications significantly earlier than those patients without AT, which peaked at 3 days postoperatively with no increase in hemorrhage risk when AT was restarted. Cursory evidence is presented that shows resuming AT early following the surgical evacuation of cSDH at 3 days postoperatively may be safe. However, much larger prospective studies are required prior to providing any definitive recommendations regarding the optimal timing and method of resumption of individual agents.

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R. Loch Macdonald

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R. Loch Macdonald

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Colum P. Nolan and R. Loch Macdonald

✓ The authors tested the null hypothesis that published literature with a high level of evidence does not support the assertion that subarachnoid hemorrhage (SAH) causes cerebral vasospasm, which in turn causes cerebral infarction and poor outcome after aneurysmal SAH. The medical literature on SAH was searched in MEDLINE. The author's personal files of all published literature on SAH were reviewed. References cited in Cochrane reviews as well as the published papers that were reviewed were also retrieved.

There is no question that SAH causes what the authors have chosen to call “angiographic vasospasm.” However, the incidence and severity of vasospasm in recent series of patients is not well defined. There is reasonable evidence that vasospasm causes infarction, but again, accurate data on how severe and how diffuse vasospasm has to be to cause infarction and how often vasospasm is the primary cause of infarction are not available. There are good data on the incidence of cerebral infarction after SAH, and these data indicate that it is highly associated with poor outcome. The link between angiographic vasospasm and poor outcome is particularly poorly described in terms of what would be considered data of a high level of evidence.

The question as to whether there is a clear pathway from SAH to vasospasm to cerebral infarction to poor outcome seems so obvious to neurosurgeons as to make it one not worth asking. Nevertheless, the obvious is not always true or accurate, so it is important to note that published literature only weakly supports the causative association of vasospasm with infarction and poor outcome after SAH. It behooves neurosurgeons to document this seemingly straightforward pathway with high-quality evidence acceptable to the proponents of evidence-based medicine.

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Nir Lipsman, Jocelyn Tolentino and R. Loch Macdonald


Prognostic factors for outcome after aneurysmal subarachnoid hemorrhage (SAH) include the clinical and pathological characteristics of the patient and hemorrhage as well as some aspects of treatment. Because treatment can vary between countries and continents, the authors used a large database of patients with SAH to determine the effect of the geographic location of treatment on outcome.


Data obtained in 3567 patients who were entered into randomized trials of tirilazad between 1991 and 1997 were analyzed. Patients underwent treatment in 162 neurosurgical centers in 21 countries in North America, Europe, Africa, and Australia. The dependent variable was clinical outcome assessed 3 months after SAH with the Glasgow Outcome Scale, which was analyzed as a 5-point variable and dichotomized into favorable (good recovery or moderate disability) and unfavorable (severe disability, vegetative state, or death) outcomes. The effect of country or continent of treatment on outcome was assessed using univariate and multivariate logistic regression and proportional odds modeling before and after adjusting for numerous other factors significantly associated with outcome.


The authors constructed several multivariate analysis models and demonstrated that for almost every model, country was not a significant predictor of outcome (p > 0.05). There was variation in outcome between countries, but this was mostly due to differences in other admission characteristics that influence outcome such as age, clinical grade, and subarachnoid clot thickness. Because the number of patients entered from some countries was small, countries were grouped, and the data were analyzed by continent. This grouping gave more stable estimates and created an appropriate model for both logistic and proportional odds models and again showed that continent had no significant effect on outcome.


Despite the variations in treatment that undoubtedly exist between countries and continents, the location of treatment had minimal effect on outcome. Outcome was influenced mostly by clinical characteristics on admission such as neurological grade, patient age, and amount of SAH.

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R. Loch Macdonald, M. Christopher Wallace and John R. W. Kestle

✓ The postoperative angiograms in 66 patients who underwent craniotomy for clipping of 78 cerebral aneurysms were reviewed. Indications for urgent postoperative angiography included neurological deficit or repeat subarachnoid hemorrhage. Routine postoperative angiograms were carried out in the remaining patients. Postoperative angiograms were reviewed to determine the incidence of unexpected findings such as unclipped aneurysms, residual aneurysms, and unforeseen major vessel occlusions. Logistic regression analysis was used to test if the following were factors that predicted an unexpected finding on postoperative angiography: aneurysm site or size; the intraoperative impression that residual aneurysm was left or a major vessel was occluded; intraoperative aneurysm rupture; opening or needle aspiration of the aneurysm after clipping; or development of a new neurological deficit after surgery. Kappa values were calculated to assess the agreement between some of these clinical factors and unexpected angiographic findings.

Unexpected residual aneurysms were seen in three (4%) of the 78 occlusions. In addition, three aneurysms were completely unclipped (4%); these three patients were returned to the operating room and had their aneurysms successfully obliterated. There were nine unexpected major vessel occlusions (12%); six of these resulted in disabling stroke and two patients died. Of six major arteries considered to be occluded intraoperatively and shown to be occluded by postoperative angiography, two were associated with cerebral infarction. Logistic regression analysis showed that a new postoperative neurological deficit predicted an unforeseen vessel occlusion on postoperative angiography. Factors could not be identified that predicted unexpected residual aneurysm or unclipped aneurysm.

The inability to predict accurately the presence of residual or unclipped aneurysm suggests that all patients should undergo postoperative angiography. Since a new postoperative neurological deficit is one factor predicting unexpected arterial occlusion, intraoperative angiography may be necessary to help reduce the incidence of stroke after aneurysm surgery. With study of more patients or of factors not examined in this series, it may be possible to select cases more accurately for intraoperative or postoperative angiography.

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R. Loch Macdonald, Axel Rosengart, Dezheng Huo and Theodore Karrison

Object. The goal of this study was to determine factors associated with the development of symptomatic vasospasm among patients with aneurysmal subarachnoid hemorrhage (SAH) who participated in the randomized, double-blind, placebo-controlled trials of tirilazad between 1991 and 1997.

Methods. Data obtained from 3567 patients entered into trials of tirilazad were analyzed using uni- and multivariate logistic regression to determine factors that predict the development of symptomatic vasospasm. Symptomatic vasospasm was defined by clinical criteria accompanied by laboratory- and radiologically determined exclusion of other causes of neurological deterioration. Transcranial Doppler ultrasonographic and/or angiographic confirmation was not required. In these patients, the aneurysms were scheduled to be treated surgically, and no patient undergoing endovascular treatment was included. A multivariate analysis showed that factors significantly associated with vasospasm were age 40 to 59 years, history of hypertension, worse neurological grade, thicker blood clot on the cranial computerized tomography (CT) scan obtained on hospital admission, larger aneurysm size, presence of intraventricular hemorrhage (IVH), prophylactic use of induced hypertension, and not participating in the first European tirilazad study.

Conclusions. Symptomatic vasospasm was associated with the amount of SAH on the CT scan, the presence of IVH, and the patient's neurological grade. The association with patient age may reflect alterations in vessel reactivity associated with age. A history of hypertension may render the brain more susceptible to symptoms from vasospasm. The explanation for the relationships with aneurysm size, use of prophylactic induced hypertension, and the particular study is unclear.