Doppler Monitoring Research Articles

Cerebral microembolization during antegrade selective cerebral perfusion

Background. This study quantified the number of intraoperative microemboli in patients undergoing aortic arch surgery using selective cerebral perfusion (SCP) in comparison with those in patients undergoing ascending aortic replacement without circulatory arrest and SCP. Methods. A transcranial Doppler monitoring of the medial cerebral artery was performed in 15 patients undergoing proximal arch replacement with SCP (SCP group) and 15 patients undergoing replacement of the ascending aorta (control group). Results. There was no significant difference in the high-intensity transient signal counts between the SCP group and the control group at any phase. In the SCP group, 4.8% of microemboli occurred during cross-clamping, and only 0.6% occurred during SCP. In the control group, 4.6% occurred during cross-clamping. Most microemboli occurred after removing the cross-clamps in both groups; 92.2% in the SCP group and 92.1% in the control group. Conclusions. The present study demonstrated that outbreak frequency of microemboli during SCP was very low, and thus implies that the risk of embolic event that may be caused by SCP is very low.

CON: Fluid Restriction for Cardiac Patients During Major Noncardiac Surgery Should be Replaced by Goal-Directed Intravascular Fluid Administration

CON: Fluid Restriction for Cardiac Patients During Major Noncardiac Surgery Should be Replaced by Goal-Directed Intravascular Fluid Administration

Cerebral Microembolization During Antegrade Selective Cerebral Perfusion

This study quantified the number of intraoperative microemboli in patients undergoing aortic arch surgery using selective cerebral perfusion (SCP) in comparison with those in patients undergoing ascending aortic replacement without circulatory arrest and SCP. A transcranial Doppler monitoring of the medial cerebral artery was performed in 15 patients undergoing proximal arch replacement with SCP (SCP group) and 15 patients undergoing replacement of the ascending aorta (control group). There was no significant difference in the high-intensity transient signal counts between the SCP group and the control group at any phase. In the SCP group, 4.8% of microemboli occurred during cross-clamping, and only 0.6% occurred during SCP. In the control group, 4.6% occurred during cross-clamping. Most microemboli occurred after removing the cross-clamps in both groups; 92.2% in the SCP group and 92.1% in the control group. The present study demonstrated that outbreak frequency of microemboli during SCP was very low, and thus implies that the risk of embolic event that may be caused by SCP is very low.

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In order to investigate whether combined measurement of the systemic vascular resistance index (SVRI) by Swan-Ganz catheter examination and transcranial Doppler (TCD) monitoring of cerebral blood flow velocity is more useful than TCD monitoring alone for detection of vasospasm after subarachnoid hemorrhage (SAH), we performed both examinations serially on 20 patients with SAH and compared the results with those of serial cerebral angiographic examinations for diagnosis of vasospasm. The TCD and SVRI criteria for vasospasm were > 120cm/s and > 1200, respectively. Cerebral angiography detected vasospasm in seven of the patients. TCD monitoring demonstrated an accuracy of 70% for diagnosis of vasospasm, while a combination of SVRI and TCD monitoring demonstrated an accuracy of 90%. Thus SVRI measurement in addition to TCD monitoring appears to allow accurate evaluation of vasospasm.

Comparison of Cardiac Outputs of Major Burn Patients Undergoing Extensive Early Escharectomy: Esophageal Doppler Monitor Versus Ther-modilution Pulmonary Artery Catheter

Comparison of Cardiac Outputs of Major Burn Patients Undergoing Extensive Early Escharectomy: Esophageal Doppler Monitor Versus Ther-modilution Pulmonary Artery Catheter

Microbubble Administration Accelerates Clot Lysis During Continuous 2-MHz Ultrasound Monitoring in Stroke Patients Treated With Intravenous Tissue Plasminogen Activator

We sought to evaluate the effects of administration of microbubbles (MBs) on the beginning, speed, and degree of middle cerebral artery (MCA) recanalization during systemic thrombolysis and continuous 2-MHz pulsed-wave transcranial Doppler (TCD) monitoring. We evaluated 111 patients with acute stroke attributable to MCA occlusion treated with intravenous tissue plasminogen activator (tPA). Thirty-eight patients were treated with tPA plus continuous 2-hour TCD monitoring plus 3 doses of 2.5 g (400 mg/mL) of galactose-based MBs given at 2, 20, and 40 minutes after tPA bolus (MB group). These patients were compared with 73 patients who were allocated to receive tPA plus continuous 2-hour TCD ultrasound (US) monitoring (tPA/US group) or tPA plus placebo monitoring (tPA group), most of whom were enrolled in a previous study of US-enhanced thrombolysis. The beginning, degree, and time to maximum completeness of recanalization during the first 2 hours of tPA bolus were recorded. Median prebolus National Institutes of Health Stroke Scale (NIHSS) score was 18. Eighty patients (72%) had a proximal and 31 (28%) a distal MCA occlusion on TCD. Thirty-seven patients (33%) received tPA/US, 38 (34%) received tPA/US/MB, and 36 (32%) were treated with tPA alone. Stroke severity, time to treatment, location of MCA occlusion, and presence of carotid artery disease were similar among groups. Two-hour recanalization was seen in 14 (39%), 25 (68%), and 27 patients (71%) in the tPA, tPA/US, and tPA/US/MB groups, respectively (P=0.004). Two-hour complete recanalization rate was significantly (P=0.038) higher in the tPA/US/MB group (54.5%) compared with tPA/US (40.8%) and tPA (23.9%) groups. The time to beginning of recanalization after tPA bolus was 26+/-18 minutes in the tPA/US group and 19+/-12 minutes in the tPA/US/MB group (P=0.12). Four patients (3.6%) experienced symptomatic intracranial hemorrhage: 2 (5.5%), 1 (2.7%), and 1 patient (2.6%) who received tPA only, tPA/US, and tPA/US/MB, respectively, experienced symptomatic intracranial hemorrhage. At 24 hours, 31%, 41%, and 55% of tPA, tPA/US, and tPA/US/MB improved >4 points in the NIHSS score. Administration of MBs induces further acceleration of US-enhanced thrombolysis in acute stroke, leading to a more complete recanalization and to a trend toward better short- and long-term outcome.

Transcranial Doppler monitoring during carotid endarterectomy

Transcranial Doppler monitoring of the middle cerebral artery blood flow velocity was used as an adjunct to routine methods of cerebral monitoring in a prospective study of 30 consecutive patients undergoing carotid endarterectomy to investigate whether transcranial Doppler monitoring provided information influencing operative technique. Application of carotid clamps caused a significant fall in middle cerebral artery velocity and there was a linear relationship between middle cerebral artery velocity and internal carotid artery stump pressure. Assuming a stump pressure of less than 50 mmHg to be an indication for shunting, this would correspond to a systolic middle cerebral artery velocity of less than 42 cm/s and a mean velocity of less than 30 cm/s. Transcranial Doppler monitoring immediately identified problems with shunt function and demonstrated a higher frequency of intraoperative embolization than had been anticipated, particularly after shunt insertion and final restoration of flow. With revision of operative technique this phenomenon is rarely encountered now. Two of the 30 patients exhibited a minor neurological deficit on recovery of consciousness, and transcranial Doppler monitoring was able to identify the probable underlying cause in both cases. Unnecessary and potentially hazardous re-exploration was avoided. In the absence of transcranial Doppler monitoring the neurological deficit in one of the patients might have been much worse.

Hemodynamic Measurements After Cardiac Surgery: Transesophageal Doppler Versus Pulmonary Artery Catheter

The purpose of this study was to compare hemodynamic data derived from the transesophageal Doppler monitor (Medicina TECO, Berkshire, United Kingdom) against those obtained from a pulmonary artery catheter after coronary artery bypass grafting (CABG). Prospective, nonrandomized, clinical study. Single, tertiary referral center. Thirty-five adult patients. Cardiac output and hemodynamic variables were measured and compared at 4 predefined time points in patients undergoing elective off-pump CABG surgery from January 2003 through June 2003. A total of 140 pairs for cardiac output (CO) data were obtained. Transesophageal cardiac output (TECO) values ranged from 1.9 to 8.7 L/min. Thermodilution cardiac output (TDCO) values ranged from 2.7 to 7.6 L/min. Matched measurements were made with each patient at intervals of 30 minutes. Bland-Altman analysis revealed a mean bias of 1.18 +/- 1.36 L/min, with a correlation (r) of 0.593 (p < 0.000) between TECO and TDCO. Similarly poor correlation was observed among cardiac index (r = 0.523), stroke volume (r = 0.615), systemic vascular resistance (r = 0.595), left ventricular stroke work index (r = 0.594), and right ventricular stroke work index (r = 0.590) measured by an esophageal Doppler monitor against a pulmonary artery catheter. A transesophageal Doppler device (Medicina TECO) cannot be relied on as a sole method for monitoring cardiac output and derived hemodynamic variables in patients after CABG surgery.

Comparison of conventional extracorporeal circulation and minimal extracorporeal circulation with respect to microbubbles and microembolic signals

The intention of minimal extracorporeal circulation (MECC) is to reduce priming volume and minimize contact of blood with polymers and air in a closed system. In contrast to conventional extracorporeal circulation (ECC), a venous reservoir is missing. Thus, air trapping is limited and avoidance of bubble embolism is a major concern. This study investigates microbubbles (MBB) number and size in the venous and arterial lines of ECC and MECC compared to the number of microembolic signals (MES) in the right and left middle cerebral artery (MCA). Twenty patients undergoing coronary surgery were operated either with conventional ECC (cardiotomy reservoir, Rotaflow pump, Quadrox oxygenator, Quart filter) or MECC (Quart filter, Rotaflow pump, Quadrox oxygenator). Number and size of MBB were monitored in the venous and arterial lines with an ultrasound Doppler system. MES in right and left MCAs were measured by transcranial Doppler (TCD) monitoring. Patients undergoing MECC had additional sealing of the venous cannula by a ligature at the site of its insertion into the right atrium. There were no significant differences between groups with respect to age, X-clamping, bypass time and number of distal anastomoses. The number of MES and MBB in the arterial line was comparable between the groups. On the venous side, MECC-perfusion shows a significantly lower number of MBB. This could be explained with the additional sealing of the venous cannula. Furthermore, our data indicate that the MBB-volume reaching the pump will also appear in the arterial outflow and into the patient's MCA. For this reason, the avoidance of air contamination is a major concern for surgeons, anaesthesiologists and perfusionists.

Esophageal Doppler Monitoring during Organ Donor Resuscitation: New Benefits of Existing Technology

Esophageal Doppler Monitoring during Organ Donor Resuscitation: New Benefits of Existing Technology

Intravenous TPA for Very Old Stroke Patients

Background: Although thrombolysis in patients with advanced age is considered more risky, some may benefit from TPA treatment. We studied safety and recanalization/recovery in patients older than 80 years treated with TPA and compared them with younger stroke patients. Methods: We studied patients treated with intravenous TPA and divided them into younger (<80 years) and older (≧80 years) groups for comparison. Diagnostic transcranial Doppler was completed before bolus, and patients were consequently monitored for up to 2 h when feasible. Clinical data included NIH Stroke Scale score, symptomatic intracranial hemorrhage (ICH) and discharge disposition. Results: We studied 127 younger (mean 63 years, range 31–79) and 56 older patients (mean 84 years, range 80–93). Median baseline NIH Stroke Scale score was higher in the older group (18 vs. 14 points, NS). Occlusion locations, onset to needle time (median 130 vs. 120 min) as well as improvement at 24 h (median 5 vs. 4 points) were similar in both groups. Transcranial Doppler monitoring showed similar partial or complete recanalization rates (66 vs. 66%), onset to recanalization time (median 160 vs. 158 min) and reocclusion rates (26 vs. 25%). Symptomatic and fatal ICH was not higher in the older group (7.1 and 3.5% vs. 6.3 and 3.9%, NS). There was higher mortality among older patients (20 vs. 11%, NS). At discharge, 23% of older patients went home, 41% underwent rehabilitation and 16% were transferred to skilled nursing facilities, compared with 31, 43 and 15% respectively, in the younger group. Conclusion: After intravenous TPA treatment, patients over 80 years of age have similar recanalization, short-term improvement and symptomatic ICH rates compared with younger patients. However, older patients tend to have higher in-hospital mortality.

Extracranial Arterial Dissection

Carotid artery dissection (CAD) was first recognized as a cause of ischemic stroke in the mid-1950s,1 although there were pathological reports on the condition dating from 1872.2 The incidence of extracranial internal CAD is ≈2 to 3 per 100 000 per year.3 For extracranial vertebral artery dissection (VAD), community-based epidemiological data are not available. Data from hospital-based case series show the extracranial VAD incidence to be estimated ≈1 to 1.5 per 100 000 per year.3 The recurrence rate of stroke in CAD is estimated to be <1% per year.4 The pathogenesis of ischemic strokes in CAD is still a matter of debate. Former studies showed a high frequency of angiographic findings suggesting embolism with cerebral arterial branch occlusions in ≈15%,5 and cases with free-floating intraarterial thrombi were occasionally reported. Recently, transcranial doppler monitoring studies revealed microembolic signals downstream of the dissected arteries.6 In extracranial internal CAD, …

Usefulness of a New Grading System Based on Coronary Flow Velocity Pattern in Predicting Outcome in Patients With Acute Myocardial Infarction Having Percutaneous Coronary Intervention

In acute myocardial infarction, the coronary blood flow velocity waveform changes with the damage in the infarcted myocardium. We developed a grading system using the shorter diastolic deceleration time (DDT), appearance of systolic flow reversal (SFR), and disappearance of systolic anterograde flow. We studied 72 patients with a first anterior acute myocardial infarction. Doppler guidewire monitoring and myocardial contrast echocardiography were performed 10 and 15 minutes after percutaneous coronary intervention, and left ventriculography was performed at discharge (24 +/- 2 days) to measure regional wall motion (SD/chord). Patients were classified into 4 groups according to the coronary blood flow velocity pattern: group I (n = 39), DDT >or=600 ms; group II (n = 10), DDT <600 ms; group III (n = 17), DDT <600 ms with SFR; and group IV (n = 14), DDT <600 ms with SFR and without systolic anterograde flow. The no-reflow phenomenon was observed in no patients in group I, in 3 in group II, in 11 in group III, and all 14 patients in group IV. Regional wall motion was highest in group I and decreased with increasing group number (groups I, II, III, and IV, -1.45 +/- 0.80, -2.36 +/- 0.60, -2.90 +/- 0.50, and -3.20 +/- 0.52 SD/chord, respectively). With the progression of damage in the infarcted myocardium, the DDT shortened first, followed by the appearance of SFR, and then the disappearance of systolic anterograde flow. In conclusion, analysis of the coronary blood flow velocity pattern allows assessment of the severity of microvascular dysfunction and prediction of left ventricular functional outcomes.

Leukocyte Count Predicts Microembolic Doppler Signals During Carotid Stenting

Protected stenting has emerged as a safe and effective alternative to endarterectomy for the treatment of carotid stenosis in patients at high operative risk. Distal microembolization occurs invariably during carotid stenting. Little is known about the relationship between systemic inflammation and embolization during carotid stenting. We examined 43 consecutive patients who underwent carotid stenting with simultaneous transcranial Doppler (TCD) monitoring of the ipsilateral middle cerebral artery. Embolization was quantified by measuring microembolic signals (MES) on TCD. Preprocedure leukocyte counts were related to MES. In unadjusted analyses, preprocedure leukocyte count was positively correlated with total procedural MES (r2= 0.16; P=0.008). After considering age, gender, comorbidities, concomitant medical therapies, and the use of emboli prevention devices, increasing leukocyte count (beta=35 for each 1000/microL increment; P=0.018) remained a significant and independent predictor of embolization (model-adjusted r2=0.365; P=0.0005). Increasing preprocedure leukocyte count independently predicted more frequent MES during carotid stenting. These data suggest that systemic inflammation may influence the degree of procedural embolization.

Prediction of Early Cerebral Outcome by Transcranial Doppler Monitoring in Carotid Bifurcation Angioplasty and Stenting

The symbiotic diazotrophs comprise with a very diverse group of Gram negative soil bacteria, collectively called as rhizobia found in nodule of legume plant. Rhizobia adopt themselves in different environment including soil, rhizosphere and grown within legume roots, where they fix nitrogen. The establishment of symbiosis is a very complicated process involving a coordinated exchange of signal between legume plants and the symbionts. The nodule development requires synthesis of signal molecules such as Nod factors that are important for induction of nodule development. There are different types of surface polysaccharides such as lipopolysaccharides, capsular polysaccharides, neutral and acidic polysaccharides found in rhizobia. The production of symbiotically active polysaccharides may allow rhizobial strains to adapt themselves to changing environmental conditions and interact efficiently with legume plants. Despite extensive research, the actual molecular function of the surface polysaccharides of rhizobia in symbiosis remains unclear. This review emphasized on the structural composition of extracellular polysaccharide of different rhizobia isolated from different legume plants. The compositions of extracellular polysaccharides are different in different rhizobia. The various compositions of extracellular polysaccharides produced by the symbionts are considered as the signaling molecules essential for determining host plant specificity. The present status of the biological functions of the exo-polysaccharide in symbiosis such as host specificity, successful invasion, formation of infection thread and induction of nodule formation in legume plants is also summarized here.

LETTERS TO THE EDITOR

In a recent issue of the Journal of Trauma, Kim et al. described their experience with the esophageal Doppler monitor (EDM) in major burn patients. Other authors have reported the historical development of the EDM, reviewed the technical and scientific aspects of this modality, and compared the EDM with the pulmonary arterial catheter (PAC). However, most studies exclude the bedside, practical aspects of EDM placement and use. We retrospectively reviewed our EDM utilization over the past 27 months, with emphasis on the practical aspects of its use, potential indications, and contraindications. The purpose of this paper is to share our EDM experience with the reader.

Impaired Clearance of Microemboli and Cerebrovascular Symptoms During Carotid Stenting Procedures

Transcranial Doppler monitoring shows a high prevalence of microemboli during carotid artery stenting (CAS); however, the occurrence of cerebrovascular symptoms (CVSs) does not seem to be related to the microembolic load. To evaluate embolic and hemodynamic transcranial Doppler monitoring findings and their relationships with the occurrence of procedural CVSs. Patients Fifty-four patients who had carotid stenosis of more than 70% underwent a total of 57 CAS procedures during transcranial Doppler monitoring of mean blood flow velocity and microembolic signals in the middle cerebral artery. The occurrence of transient ischemic attack, transient monocular blindness, and stroke during the CAS procedure was considered CVSs. Nine (15.8%) of the 57 patients had CVSs during the procedure (ie, 6 patients with transient ischemic attack, 1 with transient monocular blindness, 1 with a minor stroke, and 1 with a major stroke). The mean blood flow velocity median values were statistically significantly lower (P < .001) in the group of 9 patients with CVSs (36 cm/s; interquartile range, 32.3-38.5) compared with the 48 without CVSs (48 cm/s; interquartile range, 41.5-52). The median number of isolated microembolic signals was similar in the 2 groups (72; interquartile range, 66-81 vs 75; interquartile range, 67-83.5). The median number of microembolic signal showers (clusters of too many signals to be counted separately in one cardiac cycle) presented a nonsignificant prevalence in the patients with CVSs (9; interquartile range, 7.5-11.2) compared with the ones without CVSs (8.2; interquartile range, 7-9). The low flow velocity in the middle cerebral artery may impair the clearance of the microembolic load and should be considered a precursor of CVSs during the CAS procedure.

Esophageal Doppler monitoring predicts fluid responsiveness in critically ill ventilated patients

To test whether fluid responsiveness can be predicted by the respiratory variation in aortic blood flow and/or the flow time corrected for heart rate monitored with esophageal Doppler. Prospective study in a 24-bed medical intensive care unit of a university hospital. 38 mechanically ventilated patients with sinus rhythm and without spontaneous breathing activity in whom volume expansion was planned. The aortic blood flow was measured using an esophageal Doppler monitoring device before and after fluid infusion (500 ml NaCl 0.9% over 10 min). The variation in aortic blood flow over a respiratory cycle between its minimal and maximal values was calculated. The flow time was also measured. Aortic blood flow increased by at least 15% after volume expansion in 20 patients (defined as responders). Before fluid infusion the respiratory variation in aortic flow was higher in responders than in nonresponders (28+/-12% vs. 12+/-5%). It significantly decreased after volume expansion (18+/-11%) in responders only. A respiratory variation in aortic flow before volume expansion of at least 18% predicted fluid responsiveness with a sensitivity of 90% and a specificity of 94%. Flow time increased with fluid infusion in responders and nonresponders. A flow time corrected for heart rate below 277 ms predicted fluid responsiveness with a sensitivity of 55% and a specificity of 94%. The area under the ROC curve generated for variation in aortic blood flow ABF was greater than that generated for flow time. The respiratory variation in aortic blood flow reliably predicts fluid responsiveness in patients with sinus rhythm and without breathing activity.

Acute Hyperglycemia State Is Associated With Lower tPA-Induced Recanalization Rates in Stroke Patients

Hyperglycemia (HG) has a deleterious effect in stroke patients by accelerating ischemic brain damage; moreover, its antifibrinolytic effect may also influence reperfusion. We aimed to study the effect of acute/chronic HG on tissue-type plasminogen activator (tPA)-induced recanalization. We studied 139 consecutive stroke patients with documented intracranial artery occlusion treated with intravenous tissue-type plasminogen activator (tPA). Admission glucose levels were recorded (in mg/dL). The existence of previous chronic HG was determined by plasma levels of glycosylated hemoglobin (HbA1c, %) and fructosamine (in micromol/L). Transcranial Doppler monitoring assessed complete recanalization 2 hours after tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 48 hours. On admission, the median NIHSS score was 18 and mean glucose value was 140+/-63 mg/dL. At 2 hours, 32% of patients(n=44) achieved complete recanalization. Patients who recanalized showed lower admission glucose levels (127 vs 146 mg/dL; P=0.039) but no differences in HbA1c (6.3% vs 6.3%; P=0.896) or fructosamine (292 vs 293 micromol/L; P=0.957) were observed. Other variables associated with recanalization were initial distal middle cerebral artery occlusion (P=0.011) and platelet count (P=0.015). Patients with an admission glucose level >158 mg/dL had lower recanalization rates (16% vs 36.1%; P=0.035) and a higher NIHSS score at 48 hours (7 vs 14.5; P=0.04). After adjustment for stroke etiology, age, and risk factors, the only independent predictors on admission of no recanalization were glucose value >158 mg/dL (odds ratio [OR], 7.3; 95% confidence interval [CI], 1.3 to 42.3; P=0.027), proximal middle cerebral artery occlusion (OR, 2.6; 95% CI, 1.1 to 6.5; P=0.034), and platelet count <219,000/mL (OR, 2.6; 95% CI, 1.1 to 6.1; P=0.029). In tPA-treated patients, the acute but not chronic HG state may hamper the fibrinolytic process, delaying reperfusion of the ischemic penumbra. Early measures to reduce HG may favor early recanalization.

Carotid Endarterectomy in Nonagenarians

The North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial demonstrated that a greater benefit from carotid endarterectomy (CEA) was seen in elderly compared with younger patients. However, no patients older than 89 years were included in either study. We hypothesized that CEA is safe and effective in patients 89 years and older. This is a retrospective review of 3 neurosurgeons' CEA experience with nonagenarian patients. Of our 1800 patients who underwent CEA, 26 were 89 years or older. Twenty-three patients had had cerebral ischemic symptoms (unilateral hemispheric symptoms in 21 and 2 dizzy spells associated with bilateral high-grade stenosis). Cerebral angiography was performed in 3 patients. Twenty-three patients underwent noninvasive imaging. Four patients had bilateral high-grade stenosis and underwent staged bilateral CEA. All procedures were performed after the induction of general anesthesia with electroencephalographic (and, more recently, transcranial Doppler) monitoring and etomidate-induced burst suppression for cerebral protection during cross-clamping. Unusual technical difficulties were frequently noted, including high bifurcations, looping rotated internal carotid arteries, and marked adherence of surrounding soft tissues. In 3 of the 30 procedures, a shunt was used. There were no perioperative cerebral ischemic or cardiac events. The mean hospital stay was 2 days. One patient had a transient vocal cord paresis. Twenty-two patients were alive and well 24 months following the procedure. Four patients died of non-stroke-related causes. Carotid endarterectomy was successfully performed without perioperative cerebral or cardiac complications in our series of 26 patients 89 years and older undergoing 30 CEAs. Extrapolating from reported results from the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial, we believe CEA should be considered in nonagenarian patients with high-grade symptomatic carotid stenosis who are otherwise well medically. Our recommendations are less certain in the case of asymptomatic disease.