Howard Yonas

Guidelines for the Early Management of Patients With Acute Ischemic Stroke A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

Background and Purpose— The authors present an overview of the current evidence and management recommendations for evaluation and treatment of adults with acute ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators responsible for the care of acute ischemic stroke patients within the first 48 hours from stroke onset. These guidelines supersede the prior 2007 guidelines and 2009 updates. Methods— Members of the writing committee were appointed by the American Stroke Association Stroke Council’s Scientific Statement Oversight Committee, representing various areas of medical expertise. Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Panel members were assigned topics relevant to their areas of expertise, reviewed the stroke literature with emphasis on publications since the prior guidelines, and drafted recommendations in accordance with the American Heart Association Stroke Council’s Level of Evidence grading algorithm. Results— The goal of these guidelines is to limit the morbidity and mortality associated with stroke. The guidelines support the overarching concept of stroke systems of care and detail aspects of stroke care from patient recognition; emergency medical services activation, transport, and triage; through the initial hours in the emergency department and stroke unit. The guideline discusses early stroke evaluation and general medical care, as well as ischemic stroke, specific interventions such as reperfusion strategies, and general physiological optimization for cerebral resuscitation. Conclusions— Because many of the recommendations are based on limited data, additional research on treatment of acute ischemic stroke remains urgently needed.

Comparative Overview of Brain Perfusion Imaging Techniques

Background and Purpose— Numerous imaging techniques have been developed and applied to evaluate brain hemodynamics. Among these are positron emission tomography, single photon emission computed tomography, Xenon-enhanced computed tomography, dynamic perfusion computed tomography, MRI dynamic susceptibility contrast, arterial spin labeling, and Doppler ultrasound. These techniques give similar information about brain hemodynamics in the form of parameters such as cerebral blood flow or cerebral blood volume. All of them are used to characterize the same types of pathological conditions. However, each technique has its own advantages and drawbacks. Summary of Review— This article addresses the main imaging techniques dedicated to brain hemodynamics. It represents a comparative overview established by consensus among specialists of the various techniques. Conclusions— For clinicians, this article should offer a clearer picture of the pros and cons of currently available brain perfusion imaging techniques and assist them in choosing the proper method for every specific clinical setting.

Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group

Background and Purpose— In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. Methods— An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. Results— It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. Conclusion— The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial

BACKGROUND The inconsistent effect of hypothermia treatment on severe brain injury in previous trials might be because hypothermia was induced too late after injury. We aimed to assess whether very early induction of hypothermia improves outcome in patients with severe brain injury. METHODS The National Acute Brain Injury Study: Hypothermia II (NABIS: H II) was a randomised, multicentre clinical trial of patients with severe brain injury who were enrolled within 2·5 h of injury at six sites in the USA and Canada. Patients with non-penetrating brain injury who were 16-45 years old and were not responsive to instructions were randomly assigned (1:1) by a random number generator to hypothermia or normothermia. Patients randomly assigned to hypothermia were cooled to 35°C until their trauma assessment was completed. Patients who had none of a second set of exclusion criteria were either cooled to 33°C for 48 h and then gradually rewarmed or treated at normothermia, depending upon their initial treatment assignment. Investigators who assessed the outcome measures were masked to treatment allocation. The primary outcome was the Glasgow outcome scale score at 6 months. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, NCT00178711. FINDINGS Enrolment occurred from December, 2005, to June, 2009, when the trial was terminated for futility. Follow-up was from June, 2006, to December, 2009. 232 patients were initially randomised a mean of 1·6 h (SD 0·5) after injury: 119 to hypothermia and 113 to normothermia. 97 patients (52 in the hypothermia group and 45 in the normothermia group) did not meet any of the second set of exclusion criteria. The mean time to 35°C for the 52 patients in the hypothermia group was 2·6 h (SD 1·2) and to 33°C was 4·4 h (1·5). Outcome was poor (severe disability, vegetative state, or death) in 31 of 52 patients in the hypothermia group and 25 of 56 in the normothermia group (relative risk [RR] 1·08, 95% CI 0·76-1·53; p=0·67). 12 patients in the hypothermia group died compared with eight in the normothermia group (RR 1·30, 95% CI 0·58-2·52; p=0·52). INTERPRETATION This trial did not confirm the utility of hypothermia as a primary neuroprotective strategy in patients with severe traumatic brain injury.

Guidelines and Recommendations for Perfusion Imaging in Cerebral Ischemia A Scientific Statement for Healthcare Professionals by the Writing Group on Perfusion Imaging, From the Council on Cardiovascular Radiology of the American Heart Association

A number of techniques have been developed during the past four decades to evaluate cerebral perfusion. The oldest used 133Xe, a lipophilic radioactive tracer that easily diffuses through the blood-brain barrier (BBB). It was either injected or inhaled, and probes placed over the scalp were used to measure perfusion to the cerebral cortex.1,2 In the mid-1970s, the development of a scanner to detect the emission of positrons led to positron emission tomography (PET) in humans.3 Using a number of radioisotopes, this technology can measure cerebral blood flow (CBF) and various metabolic processes, but until recently it has been primarily used as a research tool. Stable (“cold”) xenon was found to attenuate x-rays in a manner similar to iodine, and there were a number of projects in the 1970s to use this gas as a contrast agent for the rapidly emerging technology of computed tomography (CT), particularly as a perfusion tracer.4 This resulted in the development of the xenon-enhanced CT (XeCT) technique to calculate CBF in patients.5 With improvements in single photon emission CT (SPECT) during the 1980s, a number of compounds that are metabolized in the central nervous system (CNS) were found to be appropriate for perfusion imaging.6,7 Perfusion-weighted and diffusion-weighted magnetic resonance (MR) imaging (PWI and DWI) were developed in the late 1980s,8,9 and that technology has continued to improve. Finally, with the evolution of helical and spiral multislice CT technology, CT perfusion (CTP) imaging is becoming a potentially important clinical technique.10 Although the development of these technologies has been fascinating, their role in evaluating a variety of diseases of the CNS is controversial. It might seem obvious that a disorder of blood flow, such as acute stroke or chronic vascular occlusive disease, should be studied with a perfusion imaging technique. …

Compromised cerebral blood flow reactivity is a predictor of stroke in patients with symptomatic carotid artery occlusive disease

PURPOSE The purpose of this study was to determine whether the hemodynamic consequences of extracranial carotid disease correlate with the risk of subsequent cerebral infarction. METHODS In 95 patients with symptoms who had greater than or equal to 70% stenosis (31 patients) or who had occlusion (64 patients) of the ipsilateral carotid artery, cerebral blood flow was measured by the stable xenon/computed tomography technique both at baseline and after vasodilatory challenge with intravenous acetazolamide. Patients were stratified into group 1, 43 patients with no more than a 5% decrease in flow in any vascular territory, and group 2, 52 patients with greater than a 5% decrease in one or more vascular territories after an acetazolamide challenge. RESULTS In group 2, 15 (28.9%) of 52 patients had a new stroke, but only one (2.3%) of 43 patients in group 1 did (p = 0.0005). Of patients with total carotid occlusion 10 (26%) of 38 in group 2 and none (0%) of 26 in group 1 had a new stroke (p = 0.003). Of patients with greater than or equal to 70% stenosis, five (36%) of 14 in group 2 and only one (6%) of 17 in group 1 had a stroke (p = 0.067). CONCLUSION The loss of cerebral reactivity in patients with symptoms who had greater than or equal to 70% carotid stenosis or occlusion is an important predictor of impending cerebral infarction.

Determination of irreversible ischemia by xenon-enhanced computed tomographic monitoring of cerebral blood flow in patients with symptomatic vasospasm.

In patients with subarachnoid hemorrhage, delayed neurological deficits, often followed by infarction, are believed to result from ischemia caused by vasospasm. Cerebral blood flow (CBF) data have been useful in predicting the risk of vasospasm in these patients and in distinguishing those deficits caused by vasospasm. Although CBF thresholds for infarction have been established in animals, few clinical studies have correlated CBF values with neurological symptoms and infarction. To assess the sensitivity to ischemia provided by xenon-enhanced computed tomography (Xe/CT) of CBF and to define the clinical significance of specific values that it measures, we compared the clinical, CT, and Xe/CT findings on CBF in 51 patients with subarachnoid hemorrhage caused by ruptured aneurysms. Each patient had 1 to 6 Xe/CT studies. Fourteen patients had symptomatic vasospasm. In all 14, the first post deficit Xe/CT study found abruptly reduced CBF, either regionally or globally. In 9 of these 14 patients, flow values fell below 15 ml/100 g/min in 2 or more adjacent 2-cm cortical regions of interest, and in all 9, concurrent follow-up CT scans showed infarction in these regions. Eight of the 9 had paralysis and a severe sensory deficit. No patient whose CBF remained above 18 ml/100 g/min developed infarction. The blood flow studies caused neither significant complications nor neurological deterioration. The Xe/CT CBF method appears very sensitive to the early detection of symptomatic vasospasm. In most patients with subarachnoid hemorrhage, this noninvasive technique can replace angiography to delineate the location and severity of vasospasm, and may be useful in predicting the development of infarction.

Operative exposure and management of the petrous and upper cervical internal carotid artery.

The exposure and operative management of the petrous and upper cervical internal carotid artery (ICA) in 29 patients is detailed. Twenty-seven of these patients had extensive cranial base neoplasms (benign or malignant), 1 had an inflammatory cholesteatoma, and 1 had an aneurysm of the upper cervical ICA immediately proximal to the carotid canal. Preoperative studies useful in the evaluation of these patients included computed tomography, magnetic resonance imaging, cerebral and cervical angiography, and a balloon occlusion test of the ICA with evaluation of neurological status and of cerebral blood flow. The exposure of the upper cervical and petrous ICA was useful to obtain proximal control of the cavernous ICA, aided in the operative approach to extensive petroclival, intracavernous, and parapharyngeal neoplasms, and enabled the total resection of 23 of 27 such tumors. A subtemporal and preauricular infratemporal fossa approach was most commonly used for the exposure of the artery. Intraoperative arterial management consisted of exposure and decompression only, dissection from encasing neoplasm, resection of the invaded arterial segment and vein graft reconstruction, or intentional arterial occlusion. Vascular complications included 1 stroke due to delayed arterial occlusion, 1 stroke and death due to infection spreading from the nasopharynx with bilateral ICA rupture, and 1 pseudoaneurysm formation secondary to wound infection necessitating postoperative balloon occlusion of the ICA. Nonvascular complications included facial nerve paralysis in 10 patients (usually temporary), glossopharyngeal and vagal paralysis in 13 patients requiring Teflon injection of the vocal cord in 9, temporary difficulties with mastication in 9 patients, and wound infection in 3. The surgical exposure and management of the upper cervical and petrous ICA may permit a total operative resection of extensive cranial base neoplasms and is also an alternative for the management of vascular lesions involving these segments of the artery. With malignant neoplasms extending from the nasopharynx, postoperative infection remains a problem and may best be resolved by the use of a vascularized rectus abdominis muscle flap to reconstruct defects of the nasopharynx. Bilateral ICA encasement by neoplasms is also a major problem to be solved. The value of such an aggressive approach to the management of malignant neoplasms remains to be proven.

The Cortical Ischemic Core and Not the Consistently Present Penumbra Is a Determinant of Clinical Outcome in Acute Middle Cerebral Artery Occlusion

Background and Purpose— Patient selection for acute stroke therapy based on physiology rather than on time may lead to expansion of the therapeutic window, improved outcomes, and fewer side effects than currently achieved. This approach requires early determination of both irreversible (core) and reversible (penumbra) ischemia in acute stroke. Methods— Using established perfusion thresholds, we characterized the relationship among core, penumbra, and brain tissue perfused above penumbral thresholds (non-core/non-penumbra [NC/NP]) in 36 patients with middle cerebral artery (MCA) stem occlusion who underwent quantitative cerebral blood flow (CBF) assessment with xenon-enhanced CT within 6 hours of symptom onset. Results were expressed as percentage of core, percentage of penumbra, or percentage of NC/NP relative to the ipsilateral cortical MCA territory and were correlated with clinical and radiological variables and with clinical outcomes. Results— While great variability in the mean±SD percentage of core (37.6±18.7) and NC/NP (30.3±16.6) was observed, the percentage of penumbra was relatively constant from individual to individual, constituting approximately one third of the cortical MCA territory (32.1±7). In univariable and multivariable analyses, percent core and not percent penumbra was significantly associated with outcome. Conclusions— In acute MCA occlusion, penumbra is consistently present within a relatively narrow range, despite great variability in the size of core. This may explain why the core and not the penumbra is the main determinant of outcome in our group of patients. Recanalization therapy in acute MCA occlusion should ideally be guided by diagnostic methods capable of rapidly and reliably identifying irreversible ischemia.

Factors affecting survival rates for acute vertebrobasilar artery occlusions treated with intra-arterial thrombolytic therapy: a meta-analytical approach.

OBJECTIVE To determine whether recanalization, coma at presentation, or clot location in the basilar artery influences the relative mortality risk after intra-arterial thrombolytic therapy for acute vertebrobasilar artery occlusions. METHODS Studies were identified using the MEDLINE database for January 1987 to November 1997. Series were included if they involved 10 or more patients with basilar or vertebrobasilar artery occlusions, used urokinase and/or recombinant tissue plasminogen activator, and were written in English. A fixed-effect meta-analysis approach was used to estimate the risk of death with the aforementioned risk factors. Each study was weighted according to sample size. Relative risks were calculated with 95% confidence intervals. RESULTS As calculated from peer-reviewed published data, the relative mortality risk for patients for whom recanalization was attempted but not achieved was 2.34 (95% confidence interval, 1.48-3.71; n = 126). Coma at presentation was associated with a relative mortality risk of 1.95 (95% confidence interval, 1.26-2.99; n = 145). Clot locations in the distal one-third of the basilar artery were shown to favor survival, compared with clots located in the proximal and/or middle portions of the basilar artery (relative risk, 0.52; 95% confidence interval, 0.31-0.86; n = 126). CONCLUSION The combined data suggest that coma at presentation has an independent and adverse effect on survival rates. Complete recanalization, distal clot location, and responsiveness at the time of presentation are statistically significant factors for increased patient survival rates.