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ACTAUNIVERSITATISUPSALIENSISUPPSALA2006
Digital Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Medicine 151
Carotid Artery Stenosis
Surgical Aspects
BJÖRN KRAGSTERMAN
ISSN 1651-6206ISBN 91-554-6564-1urn:nbn:se:uu:diva-6834
List of papers
I Kragsterman B, Logason K, Ahari A, Troëng T, Pärsson H, Bergqvist D. Risk factors for complications after carotid endarterectomy – a population-based study. Eur J Vasc Endovasc Surg 2004; 28: 98-103.
II Kragsterman B, Pärsson H, Lindbäck J, Bergqvist D, Björck M. Outcomes of Carotid Endarterectomy for Asymptomatic Stenosis in Sweden are Improving– results from a population based registry. J Vasc Surg 2006 (in press).
III Kragsterman B, Björck M, Lindbäck J, Bergqvist D, Pärsson H. Long-term survival after carotid endarterectomy for asymptomatic stenosis. Submitted.
IV Kragsterman B, Pärsson H, Bergqvist D. Local haemody-namic changes during carotid endarterectomy – the influence on cerebral oxygenation. Eur J Vasc Endovasc Surg 2004; 27: 398-402.
V Kragsterman B, Pärsson H, Siegbahn A, Bergqvist D. Cere-bral ischemia during carotid endarterectomy – analyses of markers for activation of inflammation, coagulation and fibrinolysis. Submitted.
Reprints were made with the permission of the publishers.
Cover picture: MRA of a caroid artery stenosis. The picture kindly provided by Johan Wikström, Depatment of Radiology, Uppsala University Hospital.
Contents
Contents ..........................................................................................................5
Introduction.....................................................................................................9Background ................................................................................................9Definitions of neurological events ...........................................................10Symptomatic versus asymptomatic carotid artery stenosis ......................12Imaging ....................................................................................................12
CEA of symptomatic carotid artery stenosis .......................................14CEA of asymptomatic carotid artery stenosis......................................15Technical considerations of CEA ........................................................15
Tolerance of carotid clamping..................................................................16Cerebral ischaemia and reperfusion during CEA ................................16Inflammation .......................................................................................17Coagulation and fibrinolysis................................................................17
Swedvasc..................................................................................................19
Aims..............................................................................................................20
Subjects and methodology ............................................................................21Papers I-III: ..............................................................................................21
Swedvasc validation ............................................................................21Swedvasc definitions ...........................................................................22Definitions in the papers......................................................................23Statistics...............................................................................................23
Papers IV-V..............................................................................................24CEA .....................................................................................................24Measurements ......................................................................................24Statistics...............................................................................................25
Results...........................................................................................................27Paper I-III .................................................................................................27Paper I ......................................................................................................27
Case-control study ...............................................................................28Paper II .....................................................................................................29Paper III....................................................................................................31
Validation results (papers I-III) ...........................................................34
Comments to papers I-III .........................................................................35Papers IV-V..............................................................................................35Paper IV ...................................................................................................36
Transit time volume blood flow ..........................................................36Cerebral oximetry ................................................................................37Measurement associations ...................................................................37Comments to paper IV.........................................................................38
Paper V.....................................................................................................39Levels of biomarkers ...........................................................................39Comments to paper V ..........................................................................41
General discussion ........................................................................................42CEA for symptomatic stenosis .................................................................42
Timing of CEA ....................................................................................43CEA for asymptomatic stenosis ...............................................................44
Plaque morphology..............................................................................46Registry data.............................................................................................46Risk factors...............................................................................................47
Gender .................................................................................................47Age.......................................................................................................48Contralateral carotid artery occlusion..................................................49
Carotid shunt indications..........................................................................50Cerebral ischemia ................................................................................51
Conclusions...................................................................................................53
Summary in Swedish (svensk sammanfattning) ...........................................54Bakgrund .............................................................................................54Syfte.....................................................................................................54Delarbeten 1-5 .....................................................................................55Sammanfattning...................................................................................57
Acknowledgements.......................................................................................58
References.....................................................................................................60
Abbreviations
ACAS Asymptomatic carotid atherosclerosis study ACST Asymptomatic carotid surgery trial ARR Absolute risk reduction CEA Carotid endarterectomy CI Confidence interval CCA Common carotid artery DSA Digital subtraction angiography ECA External carotid artery ECST European carotid surgical trial EEG Electroencephalography GSM Grey scale media ICA Internal carotid artery MCA Middle cerebral artery NASCET North American symptomatic carotid endarterectomy trial NIRS Near-infrared spectrometry RCT Randomised controlled trial SBI Silent brain infarction SEP Somatosensory evoked potentials SP Stump pressure TIA Transitory ischaemic attack TCD Transcranial Doppler
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Introduction
BackgroundStroke is the abrupt onset of focal neurological symptoms of a presumed vascular aetiology. These symptoms are the result of sudden death of brain tissue due to ischaemia subsequent to compromised blood flow. The cerebral blood flow may be impaired due to occlusion or rupture of the intra- and extracranial vessels. In the western world stroke is one of the leading causes of morbidity and mortality.
In Sweden stroke is one of the most common causes of hospitalisation and every year approximately 25-30 000 patients suffer from a stroke and an additional 5-6 000 suffer from a transitory ischaemic attack (TIA) [1, 2]. In the population approximately 20 000 patients are disabled by their neuro-logical deficits and another 80 000 have non-disabling symptoms [3]. Hence, it is the most common cause of disability and the third leading cause of death in Sweden.
The aetiology of stroke includes both cerebral haemorrhage and cerebral infarction, and the majority of these strokes (~85%) are of ischaemic origin [1]. Approximately 15-25% of ischaemic strokes are due to lesions in the extracranial or major intracranial arteries[3-5]. Atherosclerotic plaques are predominantly located at arterial bifurcations, and if situated in the internal carotid arteries the circulation to the brain may be compromised. If a carotid atherosclerotic plaque ulcerates it may dislodge emboli, or stimulate to for-mation of thrombosis with subsequent embolism, most frequently into the area of distribution of the middle cerebral artery (MCA).
Stroke prevention is primarily based on medical treatment, but in some situations surgical treatment is the method of choice. Medical treatment to reduce the overall cardiovascular risk includes antiplatelet medications, stat-ins (with several beneficial effects in addition to lowering lipids), anticoagu-lation for atrial fibrillation, smoking cessation, control of hypertension and metabolic control in the diabetic patients.
The role for surgical treatment of severe carotid artery stenosis in stroke prevention, both primary and secondary, has been established in large ran-domised controlled trials (RCT) [6-11]. However, the outcome both in short- (perioperative results) and long-term (durability and survival) must be opti-mised to achieve most overall benefit from the procedure. In Sweden 600-700 carotid endarterectomies (CEA) has been performed annually over the
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last ten years. Approximately 90% of these have been for symptomatic le-sions. During the last 2-3 years the numbers of patients undergoing CEA, especially for severe stenosis without recent neurological symptoms, has increased [12].
It seems very important to analyse the results of CEA, when implemented as a widespread treatment modality in the general population, for both symp-tomatic and asymptomatic indication.
Definitions of neurological events Stroke is by the World Health Organisation (WHO) defined as clinical symptoms of focal and/or global disturbance of cerebral function lasting more than 24 hours or leading to death, with no apparent cause other than vascular.
Transitory ischemic attack (TIA) is defined as a reversible event with symptoms lasting up to 24 hours.
Stroke can be classified into different subgroups, with regard to duration or severity of functional impairment, but there are great inconsistencies in the terms used.
In Swedvasc stroke duration is divided into transient stroke with symp-toms from 24 hours to 30-days, and permanent stroke with neurological deficits still persistent at 30-days.
After CEA the term perioperative stroke is frequently used, but can vary both regarding type and duration of the event. However, it mostly includes ipsilateral neurological deficits persisting for more than 24 hours and pre-senting during the period from surgery to 30-day follow-up.
Regarding the functional impairment after stroke, many different scales and definitions have been suggested. Classification into non-disabling or disabling stroke is one commonly practised. Non-disabling stroke may be defined as minimal focal neurological deficit, persisting for more than 24 hours but not leading to disability or significant impairment in activities of daily living. Disabling stroke may be defined as a neurological deficit lasting for more than 30 days and inducing a change of lifestyle. In the often cited modified Rankin scale non-disabling stroke represents grade 2 and dis-abling stroke grade 3 [13, 14].
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Table 1. The modified Rankin scale
The modified Rankin scaleGrade Disability
Stroke definition used in the thesis
0 No symptoms at all 1 No significant disability despite symptoms;
able to carry out all usual duties and activi-ties.
2 Slight disability; unable to carry out all pre-vious activities but able to look after own affairs without assistance.
Non-disabling stroke
3 Moderate disability requiring some help, but able to walk without assistance
4 Moderate severe disability; unable to walk without assistance and unable to attend to won bodily needs without assistance.
5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention.
Disabling stroke
Another stroke classification is based on the origin or possible source of embolism, usually divided into four different categories; cardiac (eg atrial fibrillation), large artery strokes (lesions in the aortic arch, extracranial ves-sels or the major intracranial branches), small vessel disease / lacunar infarc-tions (occlusion of minor intracranial branches) and others (eg carotid dis-section or sinus thrombosis).
Among the large artery strokes, which may represent 15-25% of all is-chemic strokes, carotid artery lesions are the dominant source of origin [4]. Some confusion may exist with regard to the definition of relevant vessel and affected side. The relevant vessel is selected based on the location of atherosclerotic lesions, the clinical features of the neurological deficit and/or imaging of the ischaemic lesion. Neurological deficits due to carotid artery stenosis (carotid territory events) are mainly embolisations in the distribution of the (middle) cerebral artery, whereas vertebrobasilary events are those localised in the posterior circulation. An ipsilateral event refers to an ischemic lesion on the same side as the relevant vessel, and is to be distin-guished from the side affected with neurological deficits.
Ocular symptoms such as amaurosis fugax or retinal embolism are attrib-uted to the ipsilateral carotid artery stenosis due to direct embolisation to the ophthalmic artery.
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Symptomatic versus asymptomatic carotid artery stenosisA patient classified as having a symptomatic carotid artery stenosis has re-cently, in most definitions suffered a central neurological event with symp-toms within the last 6 months (and often imaging of cerebral ischemia), cor-responding to the relevant vessel [7-9, 11].
Patients with an asymptomatic carotid artery stenosis have either never had any symptoms or had symptoms at least 6 months previously, corre-sponding to the side of the carotid artery stenosis [6, 10]. There is a group of patients often referred to as having non-hemispheric symptoms and this may include vertebrobasilary events (ie posterior circulation events) and non-specific symptoms (eg dizziness or vertigo). In the literature the classifica-tion of these patients varies widely, and they may be included in the symp-tomatic or asymptomatic cohort with or without specific definitions.
Imaging
Internal carotid artery (ICA) stenosis can be measured using different imag-ing modalities. The “golden standard” used in the majority of the large ran-domised trials is (selective) digital subtraction angiography (DSA). How-ever, different measurement methods have been used for grading the degree of stenosis. The two most referred methods are the ones used in the ECST and NASCET, which have different measuring points of the stenosis and are therefore not directly comparable. In Figure1 the two methods are demon-strated and correlated.
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Degree of internal carotid artery stenosis with different
measuring methods
NASCET (%) ECST (%)
40 70
50 75
60 80
70 85
80 91 A C B
NASCET(%) =(1-B)/A x100 ECST(%) =(1-B)/C x100
90 97
Figure 1. Carotid stenosis defined according to NASCET or ECST methodology, the differences in measurement technique and comparisons of grading.
Since angiography is an invasive technique with a periprocedural risk for neurological events of up to 1.2% (ACAS) [6], other non-invasive modalities have been established such as magnetic-resonance-tomography angiography (MRA), computed-tomography (CT) angiography and duplex ultrasonogra-phy. With MRA and CT angiography the stenosis is measured with similar morphological criteria as DSA, whereas duplex classification of the degree of stenosis is based upon measuring blood flow velocities (as shown in Fig-ure 2), which is then related to defined stenosis criteria [15]. Duplex has been established as an easy accessible and reliable [16] method that in addi-tion to stenosis grading also may define plaque morphology (further dis-cussed below) [17-19].
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Figure 2. Duplex investigation of ICA stenosis.
CEA of symptomatic carotid artery stenosis Patients with carotid territory neurological events within the last 6 months, who have a severe internal carotid artery stenosis, should be considered for CEA given that they are medically fit for surgery and have functional bene-fit. RCTs have demonstrated an overall benefit for CEA compared to the best medical treatment for this group of patients.
The absolute risk reduction (ARR) of stroke or death in the two largest and most influential trials was in the European Carotid Surgery Trial 8.5% at 5 years and 19.4% at 3 years in the North American Symptomatic Carotid Endarterectomy Trial (in both trials 70-99 % stenosis) [7-9, 11].
However, as the trials differed in measurement of the degree of stenosis as well as the outcome, the results are not possible to directly compare. In a re-analysis of these trials together with the Veterans Affairs trial (VA309) [20], with reassessments of original angiograms and using the same criteria for stenosis (NASCET-method) and for outcome, the overall effect of CEA was investigated. In these pooled data the 5-year ARR of ipsilateral ischemic stroke and/or operative stroke or death was 5.9 % (60-69% stenosis), 15.8% (70-79% stenosis), 17.7% (80-89% stenosis) and 32.4% (90-99% stenosis, not including near-occlusion) [21]. The “number needed to treat” (NNT) to prevent one event at 5 years is 6 for a stenosis 70%. The perioperative stroke or death rate was 7.1% in pooled data.
It is essential in routine clinical practise to assess complication rates and to continually evaluate patient selection, in order to guarantee that the results
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of CEA are at least as good when performed outside strictly controlled clini-cal trials.
CEA of asymptomatic carotid artery stenosis Patients with a stenosis of the internal carotid artery, but without any medi-cal history of neurological events from the artery’s distribution area within the last 6 months, have also been the subject for large RCTs. In these trials a net benefit for CEA over the best medical treatment has been demonstrated, but the risk reduction was less compared to trials on symptomatic stenoses [6, 10, 22-24].
The estimated ARR at 5 years for ipsilateral stroke (including operative stroke or mortality) was in the Asymptomatic Carotid Artheriosclerosis Study (ACAS) 5.9% (5.1% vs 11.0%) and in the Asymptomatic Carotid Surgery Trial (ACST) 5.4% (6.4% vs 11.8%), or a little more than 1% per year [6, 10]. The NNT to prevent one event at 5 years were 17 in ACAS and 19 in ACST.
One parameter that has a pronounced impact on the net benefit for these patients is the perioperative combined stroke or death rate, which was 2.3% in ACAS and 2.8% in ACST, with the same caveats as for CEA of sympto-matic stenosis about the generalisation of these results in routine clinical practice.
Technical considerations of CEA Patch angioplasty is one of the technical aspects of CEA that has often been debated and studied during the last decade. In a Cochrane review [25] it was shown that routine patching conferred a reduction in perioperative stroke/thrombosis and late stroke/restenosis compared to routine primary closure. However, many surgeons use patch angioplasty selectively, the ra-tionale for this based on their own experience and peroperative judgements (which are difficult to standardise in an RCT).
The technique of eversion endarterectomy (EEA) has also been the focus in several trials. In a recent Cochrane review a possible decrease in resteno-sis was found but no association with early or late stroke or mortality risks could be identified [26].
An important issue is the possible impact of anaesthesia techniques on the outcomes from the procedure. A Cochrane meta-analysis of non-randomised trials showed a benefit for CEA under local anaesthesia (LA) vs general
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anaesthesia, but this was not demonstrated when analysing the previous ran-domised trials [27]. Thus, this uncertainty has motivated a large ongoing randomised trial (GALA).
One of the obvious advantages with LA is the direct possibility to assess tolerance of carotid clamping and the need for shunting. If the procedure is done under general anaesthesia with selective shunting, other methods for determining shunt indication are used depending upon availability and pref-erences of surgical centres and individual surgeons.
Tolerance of carotid clamping The intolerance of carotid clamping during CEA may result in reversible or irreversible cerebral ischaemia depending on the degree and the duration of inadequate cerebral perfusion. Factors which can contribute to the extent of impairment caused by the clamping are the collateral blood circulation (egcircle of Willis) and various other compensatory mechanisms (ie blood pres-sure and oxygenation). As mentioned above, when CEA is performed under general anaesthesia and with the use of selective shunting, an indirect method to assess an adequate cerebral perfusion is essential.
Well established methods for neuromonitoring include transcranial Dop-pler (TCD) with blood velocity measurements in the middle cerebral artery and detection of (micro)embolisation [28, 29], electroencephalography (EEG) measuring cerebral activity [30], somatosensory evoked potentials (SEP) with measurement of cerebral responsiveness [31] and cerebral oxi-metry with near-infrared spectroscopy (NIRS) which monitors changes in cerebral oxygenation [32, 33].
Another method used for deciding on shunt indication is carotid artery stump pressure, which indirectly assesses the capacity of the collateral circu-lation [34]. A method less well documented is transit time flowmetry, which measures volume blood flow in the carotid arteries with readings evaluating the ICA flow before clamping and after reperfusion [35, 36]. This method also offers a possible quality assessment of the CEA.
Cerebral ischaemia and reperfusion during CEACerebral ischaemia induced by carotid clamping during CEA may induce an activation of inflammatory mediators and alterations in haemostasis [37-39].Although the patient clinically may tolerate clamping well, a relative re-
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gional ischaemia might develop due to inadequate perfusion and/or embo-lism, with resulting reversible or irreversible cerebral injury [40-42].
The patients with symptomatic carotid artery stenosis may also demon-strate altered levels of markers for the inflammatory and haemostatic sys-tems after their cerebral insult [43-45]. What is less investigated is how the regional relative ischaemia during surgical clamping affects inflammatory and haemostatic markers, when measured in the local venous outflow from the intracranial structures.
InflammationInflammation is the tissue response to injury which is mediated by a variety of factors. It may be characterised by an acute and a chronic phase. In both phases of inflammation a group of secreted polypeptides known as cytokines are key modulators in a complex network of interactions.
Among the cytokines, interleukin-6 (IL-6) is involved in both the acute phase (pro-inflammatory cytokine) and in mediating humoral response in chronic inflammation. IL-6 is a pleiotropic glycoprotein that in experimental and clinical studies has been a predictor of cerebral ischaemia/reperfusion injuries. Elevated levels have also been found in patients with acute stroke [46-48].
Another pro-inflammatory pathway is the CD40-CD40 ligand system. CD40 is an important activation receptor on many cells (eg lymphocytes, monocytes, macrophages, fibroblasts, dendritic-, smooth muscle- and endo-thelial cells) whose engagement via the ligand (CD40L or CD154) induces or upregulates inflammation, releases pro-inflammatory cytokines or con-nective tissue-degrading enzymes and procoagulant activity [49-51].
Increasing evidence also support the role for CD40-CD40L in athero-genesis and plaque instability [52-55]. Furthermore, the transmembrane pro-tein CD40L is upregulated during acute stroke which persists for at least 3 months [56].
Coagulation and fibrinolysis Coagulation is rapidly initiated when tissue factor (TF) is exposed to factor VII. The activated TF/VII complex activates factors IX and X. Factor Xa converts prothrombin to thrombin and prothrombin fragment 1+2 (F1+2),
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which is greatly facilitated by the presence of coenzyme Va. F 1+2 with a t½ of 90 min is a stable marker of coagulation (factor Xa activity) and altered levels has been demonstrated for patients with carotid atherosclerosis and stroke [57-59]. Thrombin acts on fibrinogen to form soluble complexes (soluble fibrin). In Figure 3 the final steps of the coagulation pathway are shown (schematic presentation).
Figure 3. Schematic presentation of the coagulation pathway
Fibrinolysis (Figure 4) is initiated through the release of tissue plasminogen activator and urokinase from endothelial cells following injury and in re-sponse to thrombin. They cleave plasmin from plasminogen bound to fibrin within the clot. The control pathway is primarily set in motion by plasmino-gen activator inhibitor – 1 (PAI-1) which prevents tPA from activating circu-lating plasminogen to plasmin. PAI-1 is a marker of the fibrinolytic process and has a t½ of approximately 2 hours [60]. Plasmin degrades fibrin into D-dimers and fibrin degradation products (FDP). D-dimer acts as a marker of both fibrin generation (coagulation), degradation (fibrinolysis) and is also linked to the acute phase response.
X
Xa(Va, Ca)
TF / VII a (Ca)
Prothrombin Thrombin
F 1+2 AT III
TAT
Fibrinogen
Soluble fibrin
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Figure 4. . Schematic presentation of the final steps of the fibrinolytic pathway.
Swedvasc
The Swedish Vascular Registry (Swedvasc) started as a regional registry in 1987 and has national coverage since 1994, thus the registry includes all surgical centres performing CEA in the country.
Prospective data on basic demography and risk factors, together with de-tails of surgical techniques and postoperative outcome are registered. Fol-low-up includes perioperative (30-day) complications and outcome, as well as overall outcome and patency at one year (neurological events are not reg-istered specifically after 30 days).
The registry has been validated both internally and externally on several occasions [61]. A validated vascular registry with national coverage can provide population based data on outcome and alterations over time for vas-cular interventions, eg CEA.
tPA
Plasmin Plasminogen
Fibrin D-dimer
Antiplasmin
PAI-1
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Aims
In patients undergoing carotid endarterectomy; to demonstrate population-based results on perioperative morbidity and mortality after CEA (paper I-II.)to analyse risk factors for complications after CEA in a population (paper I-II).to evaluate alterations over time in outcome after CEA for asymp-tomatic stenosis (paper II).to assess the long-term survival for patients undergoing CEA for asymptomatic stenosis (paper III)to evaluate different methods for predicting the need for shunt dur-ing carotid clamping in patient undergoing CEA under general an-aesthesia (paper IV).to characterise the effects of carotid clamping on regional cerebral perfusion and reperfusion, with regard to markers of the inflamma-tory, coagulation and fibrinolytic systems (paper V).
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Subjects and methodology
Papers I-III: Swedvasc has coverage of all centres performing CEA in Sweden since 1994. In retrospective reviews data on all registered CEAs were retrieved for two time periods. From January 1994 until December 1996 for a combined cohort and case-control study of perioperative outcome and risk factors (pa-per I). From January 1994 until December 2003 for studies with special fo-cus on patients operated on for asymptomatic carotid artery stenosis con-cerning perioperative outcome (paper II) and long-term survival (paper III).
The studies were ethically approved by the registry review board, which according to Swedish law has the authority concerning registry data.
Swedvasc validation Validation of the registry with regard to CEA registrations was performed with different methods;
1. a case-control review of neurological complications by independ-ent observers (paper I)
2. a random sample of ~ 10 % of all procedures for asymptomatic stenosis (paper II)
3. a target validation of unclear complication registrations among the patients operated on for an asymptomatic stenosis (paper II)
4. a cross-match with the National Population-registry for accurate data on mortality and date of death (papers II-III)
5. an external validation by cross-match with the In-Patient Registry (IPR) for registrations of CEA during the year 2003 (papers II-III).
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Schematic figure of the validation processes are shown in Figure 5.
Figure 5. The five different validation procedures of the Swedvasc registrations for CEA during 1994-2003.
Swedvasc definitions Risk factors in Swedvasc have had the same definitions throughout the study-period:
Cerebrovascular disease; all present or previous neurological events (stroke, TIA or AF). Diabetes mellitus; treatment with insulin, oral medication or diet. Hypertension; medication or a diastolic blood-pressure 110. Cardiac disease; previous myocardial infarction, atrial fibrillation, heart-failure, angina pectoris, coronary artery by-pass, operation for valvular disease or signs of ischemia on ECG. Previous vascular surgery; open or endovascular procedure or am-putation for vascular disease. Renal insufficiency; a serum creatinine > 150 mol/l. Smoking; regular smoking within five years.
Postoperative neurological deficits are classified as either:
CEA for asymptomatic stenosis N=671 II) Cross-match with National Population-registry:
all perioperative deaths reported (papers II-III)
IPR 4%
IV) Random sample: N obtained 65/requested 71
(paper II)
III) Target validation: Unclear 30-days complica-
tion registrations N obtained 15/requested 21
(paper II)
I) Case-control study: 65 cases /130 controls (paper I)
V) Cross-match with the In-Patient Registry 2003: 4.1% unregistered in Swedvasc (papers
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A) Ipsilateral carotid territory events: Transitory ischemic attack (TIA) including amaurosis fugax (AF) Transient stroke (deficit >24 hours and < 30 days) Permanent stroke (deficit > 30 days)
B) Other perioperative neurological events Cerebrovascular event (all perioperative neurological events not classified as an ipsilateral carotid territory event, for example con-tralateral carotid territory events or posterior circulation events)
Definitions in the papers In these papers the definition of asymptomatic stenosis excluded all ipsilat-eral carotid artery events and non-hemispheric symptoms within 6 months (non-hemispheric symptoms including posterior circulation events and non-specific symptoms).
In paper III the patients operated on bilaterally were identified and one of the CEAs was selected, as the index procedure, for analysis. As the focus of the study was the patients operated on for an asymptomatic lesion, these were primarily selected as index procedures. In case of one asymptomatic and one symptomatic carotid lesion, the CEA of the asymptomatic artery was defined as the index procedure. If both arteries were asymptomatic or symptomatic, the first operated vessel was defined as the index procedure.
StatisticsStatistical analyses were performed using the SPSS for Windows program package and R [62]. Continuous variables were summarized by the median (range or quartiles) while categorical variables were summarized by percent-ages. Continuous variables were compared with the Student´s t-test or Wil-coxon-Mann-Whitney test and categorical variables with the Pearson ²-test or Fisher´s exact test depending on the distribution of the variable.
Preoperative variables that were positively associated with postoperative outcome at p<0.1 were selected for multivariate analysis using logistic re-gression. Relative risks (RR) for the cohort part of the study and odds ratio (OR) for the case-control part was calculated when possible (paper I).
Analyzes of risk factors for the different combined outcomes were per-formed using logistic regression with the presented model designed based on the number of (adverse event) AE, the completeness of the variables in the data-base and on the clinical relevance. As the numbers of AE were small, the numbers of variables that may be included in the model were limited (recommended to be 1 variable per 10 events) (paper II).
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Logistic regression models were fitted to estimate the relative odds (OR) of 5 year mortality for different risk factors, as well as for asymptomatic vs symptomatic patients adjusted for each of these risk factors one at a time. Kaplan-Meier curves were used to illustrate crude cumulative survival. Sur-vival curve comparisons were done using logrank test and hazard ratios, but non-proportionality of the hazards limits the ability of analysis (paper III).
The odd ratios (OR) and relative risks (RR) are presented with 95% con-fidence intervals (CI). A statement of statistical significance implies a p-value < 0.05.
Papers IV-V Prospective studies on patients undergoing CEA, assessing different effects of carotid clamping. Inclusion criteria were symptomatic stenotic lesions of the ICA of 70% as measured by Duplex ultrasonography.
All patients had given informed consent to participate and the medical ethics committee for Uppsala University had approved the study (Uppsala 99080).
CEAAll procedures were performed under normotensive, normocarbic general
anaesthesia. An arterial line was inserted via the contralateral radial artery. The CEA was performed with standard surgical technique by a longitudi-
nal arteriotomy. A fabric patch was used selectively. Intravenous unfractionated heparin (5000 IU) was given before clamping
in all patients. Dextran 70 (50 ml/h, 10h) was started after arrival in recov-ery unit.
A postoperative duplex ultrasonography of the operated ICA was per-formed before the patients left the hospital. After 30 days the patient was examined by a neurologist.
MeasurementsStump pressure was measured, via a cannula in CCA connected to a cali-
brated pressure transducer, before and after clamping of CCA and ECA. A Javid shunt was inserted if the (mean) stump pressure was less than 40 mmHg (papers IV-V).
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Volume blood flow was measured using a calibrated transit time ultra-sonographic perivascular probe, positioned on the proximal part of the pre-pared CCA (CardioMed flowmeter CM1005, Medistim A/S, Oslo, Norway). Measurements were recorded before clamping with separate readings of CCA, ICA and ECA. Following reperfusion, the probe was positioned at the same site and flow was separately measured in CCA, ECA and ICA, 5 and 10 minutes after declamping (paper IV).
Two cerebral oximeters (model Invos 4100A, Somanetics, MI, USA) were used for simultaneous bilateral rSO2 monitoring. Sensors from the dual-channel system were applied on the forehead bilaterally. The system monitored changes in cerebral saturation referred to as an rSO2 index, the absolute values being considered too relative within a given patient. The numerical rSO2 readings recorded at 1-min intervals were stored on com-puter discs. Percent change was calculated according to the formula (paperIV):
mean RSO2 preclamp - min RSO2% change= --------------------------------------- x 100 mean RSO2 preclamp
Blood samples were drawn via a catheter inserted into the ipsilateral supe-rior jugular bulb (via the common facial vein and affixed by suture ligature) and simultaneously from the contralateral radial artery; before clamping, during clamping (5, 15, 30 min) and after reperfusion (5 min). Baseline sam-ples were taken the day before surgery from the cubital vein. The plasma was separated and snap-frozen (-70 C). All samples were analysed for frag-ment 1+2 (F1+2), plasminogen activator inhibitor -1 (PAI-1), fibrin degrada-tion product (D-dimer), interleukin-6 (IL-6) and soluble CD40 ligand (CD40L)
Baseline median (and quartile) values were compared to a reference group of 50 healthy patients (paper V).
StatisticsStatistical analyses were performed using SPSS for Windows statistical package (SPSS Inc, USA). Results are presented with median and range or interquartil range (IQR)
Non-parametric rank tests were used to compare rSO2 and flow values be-fore, during clamping and after reperfusion. For analyses of associations Spearman´s correlation and linear regression were used (paper IV).
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Comparison of data within groups were analysed with Wilcoxon signed rank test (two-tailed) (paper V).
Box plots with logarithmic scale were used to demonstrate the different measurements semi-graphically. Outliers are defined by SPSS as observa-tions > 1½ box lengths from upper/lower quartile and extreme values if > 3 lengths.
Baseline parameters with skewed distribution were presented as plots of study patients together with median and quartiles for study and reference values.
A p-value of 0.05 was considered as statistically significant.
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Results
Paper I-III The preoperatively registered baseline characteristics for the patients in-cluded in papers I-III are listed in Table 2
Table 2.Preoperative registered risk factors and indications for CEA. Comparison between the groups with symptomatic vs asymptomatic stenosis in papers II-III.
Baseline characteristics Paper I (%) All
indica-tions
Papers II-III (%)
Sympto-matic
Papers II-III (%)
Asympto-matic
p-value
Gender (male) 66 67 64 0.16 Cardiac disease 45 45 47 0.18 Hypertension 52 60 65 0.02 Previous vascular surgery 19 16 39 <0.01 Diabetes mellitus 14 19 19 0.86 Pulmonary disease 6 9 9 0.93 Renal insufficiency 3 4 6 <0.01 Smoking 38 42 41 0.77 Indication for CEA Minor stroke 34 40 NA TIA 34 37 NA Amaurosis fugax 18 20 NA Asymptomatic 11 NA 11 Others (eg non-hemispheric)
3 2 NA
Paper I A total of 1518 CEAs on 1411 patients were reported during a three year period (Jan 1994-Dec 1996). The mean patient age was 68.8 (range 53-90) years. Patch angioplasty was used in 29.1%. Baseline characteristics are presented in Table 2.
28
Registered 30-days complications were stroke (permanent and transient) in 4.9%, TIA/amaurosis fugax in 1.2% and the combined perioperative stroke or death rate in 5.9%. Causes of the 22 deaths were 13 cardiac, 7 strokes, 1 pneumonia and 1 ruptured aortic aneurysm.
In the analysis of predictors for different outcomes, the independent fac-tors for combined permanent stroke and death (4.3%) are shown in Table 3, and were the indication for surgery (minor stroke vs. other indications) (RR=1.4), diabetes mellitus (RR=1.4), cardiac disease (RR=1.4) and opera-tion at a university hospital (RR=1.4).
Table 3. Risk factors for combined permanent stroke or death N=65/1518 (4.3%.*=X2, †Mann-Whitney-U test, ‡ Fisher’s exact test
Univariate analysis Multivariate analysisRisk factor p RR
(95% CI) p RR
(95% CI) Indication (stroke vs others) 0.02† 1.41 (1.06-1.87) 0.02 1.38 (1.04-1.83) Age >75 years 0.09* 1.56 (0.93-2.63) 0.14 Gender (male) 0.51* 1.18 (0.71-1.99) Diabetes mellitus 0.09* 2.05 (1.19-3.53) 0.02 1.41 (1.04-1.89) Hypertension 0.03* 1.69 (1.03-2.78) 0.08 Cardiac disease <0.01* 1.98 (1.22-2.73) <0.01 1.43 (1.11-1.86) Previous vascular surgery 0.13 1.51 (0.88-2.59) Pulmonary disease 0.79‡ Renal insufficiency 1.0‡ Current smoker 0.05* 0.58 (0.31-1.00) 0.09
There was no significant correlation between the annual caseload of the cen-tres and complication rates (p=0.17). Patch angioplasty did not influence the complication rate (p=0.70).
Case-control study The 65 cases of permanent stroke or death were compared with 130 controls (without serious complications but matched for operating centre, indication and age).
Results of comparison for the chosen variables are presented in Table 4. Contralateral occlusion, present in 15/65 cases and 7/130 controls, was the only statistically significant factor (OR=5.3) and remained as a risk factor also after correction for the use of shunt.
29
Table 4. The impact of different variables on perioperative permanent stroke ordeath risk. *=Students-test, **Fisher’s exact test, ***=X2, ****=Mann-Whitney-U test
Variables p-value/OR
Stenosis degree, mean 84.5±11.8 (SD) range 35-100
0.61*
Contralateral occlusion N=22 (15 case vs 7 controls)
<0.001* OR=5.3 (2.0-13.1)
Infarct on CT preoperatively N=83 (30 cases vs 53 controls)
0.47***
Bleeding; ml (case; median=200 (0-1600), controls; median=150 (0-700))
0.16****
Shunt N=79 (28 cases vs 51 controls)
0.61***
Occlusion time; min (case; mean=29.7 (SD 25.6) controls; mean=26.6 (SD 21.4)
0.41*
Operation time; min (case; median 128 (60-314) controls; median 120 (59-200))
0.18****
Tacking suture N=67 (24 case vs 43 controls)
0.59***
Local anaesthesia vs general anaesthesia (cases; 16 vs 49, controls; 39 vs 91)
0.43***
Paper IIA total of 6182 carotid endarterectomies were registered during this ten-year period (1994-2003), among these 10.9% had indication asymptomatic steno-sis. Bilateral CEAs were performed on 6% of the patients.
Mean age was 70 years (quartiles 64; 75) for both the symptomatic and asymptomatic group. Baseline characteristics are presented in Table 2.
Patch closure was performed in 34% for asymptomatic vs 32% for symp-tomatic lesions (p=0.20).
The perioperative morbidity and mortality rates are shown in Table 5, with a combined stroke (permanent and transient) or death rate of 2.1% for asymptomatic vs 4.3% for the symptomatic group (p<0.01) over the whole time period. There were two fatal strokes (of 3 deaths) among the proce-dures for asymptomatic and 17 (of 74 deaths) among those for symptomatic stenosis.
30
Table 5. Perioperative complications after CEA for the whole time period (sympto-matic vs asymptomatic stenosis) and the two 5-year periods (asymptomatic stenosis 1994-1998 vs asymptomatic stenosis 1999-2003).
Complication Sympt 1994-2003
N=5511
Asympt 1994-2003
N=671
P
X2
Asympt 1994-1998
N=330
Asympt1999-2003
N=341
p
X2
Permanent stroke 2.1% 0.9% 0.04 1.5% 0.3% 0.09 Transient stroke 1.3% 1.0% 0.54 1.5% 0.6% 0.24 TIA 1.3% 0.3% 0.02 0.3% 0.3% 0.98 Cerebrovascular event 2.0% 1.7% 0.54 1.8% 1.5% 0.72 Cardiovascular event 2.5% 4.2% 0.01 4.6% 3.8% 0.64 Death 1.4% 0.4% 0.05 0.9% 0.0% 0.08 Stroke or death 4.3% 2.1% <0.01 3.3% 0.9% 0.03
Data from the asymptomatic cohort was divided into two 5-year periods (1994-1998 and 1999-2003). During the first period 330 operations were performed (12.6% of the total number of CEAs during that time period), compared to 341 procedures (11.7%) during the second.
Baseline characteristics were comparable between the two periods except that hyperlipidaemia (p< 0.01) and hypertension (p=0.02) were more fre-quent in the second period.
Patch closure was more frequently used during the second period (28 % vs 40 %, p=0.01). The frequency of eversion endarterectomy increased over time (0.3% vs 5.9%, p< 0.01).
Perioperative morbidity and mortality rates are shown in Table 5. There was no mortality and only one permanent (non-disabling) stroke during the second period.
Logistic regression analysis was performed on the asymptomatic group testing the factors age, gender and patch for different combinations of out-come. When all stroke, TIA, cardiovascular complications and death were used as outcome in the model, the only significant variable identified was age with an OR=2.8 (1.4-5.6) for those older than 75 years. In the same model, women had an OR=1.4 (0.7-2.8) and patch OR=0.8 (0.4-1.6).
31
Paper IIIDuring the ten-year period 1994-2003 a total of 5808 patients were regis-tered in Swedvasc for a primary carotid endarterectomy. In 10.8% of the patients the index CEA was for asymptomatic stenosis. The total proportion of patients operated on bilaterally with CEA was 6%, and among patients with an asymptomatic stenosis 24% (bilateral asymptomatic lesions in 6%).
Median age was 70 years (quartiles 64; 75), equal for the symptomatic and asymptomatic cohort. Baseline characteristics are presented in Table 2.
Patch closure was performed in 34% of patients with asymptomatic vs 32% with symptomatic lesions (p= 0.15). Eversion CEA was used in 3.3% for asymptomatic vs 1.9% for symptomatic stenosis (p=0.01).
The median (range) time at risk was 5.1 (0.1-11.8) years. The Kaplan-Meier curves in Figure 6 display the crude cumulative survival rate with respect to indication for CEA.
The median survival for the asymptomatic cohort was estimated to 10.2 (9.0-*) years and for the symptomatic 10.8 (10.5-11.6) years (* the upper limit of the 95% confidence interval for the curve has not yet crossed the 0.5 level). The average hazard did not differ significantly between the sympto-matic and asymptomatic groups (p=0.12; HR=0.89 (0.76-1.03)).
32
0 2 4 6 8 10 12
0.0
0.2
0.4
0.6
0.8
1.0
Follow-up years
Cum
ulat
ive
surv
ival
asymptsympt
6305164
5564652
3733294
2502116
1511182
45460
00
Figure 6. Kaplan-Meier curve for crude cumulative survival of the asymptomatic (solid line) and symptomatic (dotted line) cohort. Numbers of patients at risk listed for every second year of follow-up.
The analyzed data on all patients with a completed 5-year follow-up, with respect to the risk factors registered at baseline, are presented in Figure 7. Previous vascular surgery (OR=1.8), cardiac disease (OR=1.7), diabetes (OR=2.3) and age (OR=1.5) were predictors of decreased 5-year survival.
33
0.3 0.5 1.0 2.0 5.0
Age (per 10 yrs)
Gender(Male)
Cerebrovascular disease
Diabetes mellitus
Hyperlipidaemia
Hypertension
Cardiac disease
Previous vascular surgery
Pulmonary disease
Renal insufficiency
Smoking
Patch
Bilateral CEA
1.52
1.17
1.45
2.28
0.93
1.21
1.70
1.80
1.02
2.18
0.83
1.60
1.00
(1.08, 2.1)
(0.71, 1.9)
(0.87, 2.4)
(1.28, 4.1)
(0.47, 1.8)
(0.73, 2.0)
(1.03, 2.8)
(1.10, 3.0)
(0.44, 2.4)
(0.75, 6.3)
(0.50, 1.4)
(0.95, 2.7)
(0.60, 1.7)
OR
Figure 7. Risk factors for 5-year mortality in asymptomatic patients. The circles and lines represent crude relative odds and 95 % confidence intervals.
34
Validation results (papers I-III) Paper I In the process of reviewing patient reports in the control group an independ-ent observer found one patient (1/130) with a transient stroke not registered and one patient (1/130) with a permanent stroke misjudged as a local neuro-logical complication (a central, not peripheral, facial paresis with mild symp-toms persisting 30 days).
Paper IIComplete medical records were obtained for 84/92 (91%) of the random sample and target validation. In reviewing the records we found; a) two per-manent strokes and three transient strokes incorrectly registered, b) one tran-sient stroke and one TIA not registered (Table 6).
The two incorrectly registered permanent strokes were non-disabling.
Table 6. Validation of perioperative neurological complication registration after CEA with indication asymptomatic stenosis. Results from a random sample as well as target validation of unclear perioperative complication registrations. NA = not applicable. * Contralateral carotid territory symptoms but with contralateral occlusions, ac-cording to the (new) Swedvasc definition should these have been registered as tran-sient strokes.
Valida-tion
Npatient-records
obtained / requested
Nincorrectregistra-
tions
Neurological deficit Classification in registry
Classifica-tion in validation
1)Minor contralateral finger dysfunction (IV-V)
Transientstroke
Permanent stroke
Random sample
65/71 (93%) 2
2)Contralateral facial paresis (corner of mouth)
Local neurol-ogy
Permanent stroke
1) Thrombosis or occlusion; 2/3
1Contralateral arm dys-function (minutes dura-tion)
Not registered TIA
2) Peripheral embolization; 2/2
0NA NA NA
1-2) Ipsilateral (worsen-ing) arm dysfunction (3 and 7 days duration)
Cerebrovascu-lar event
Transientstroke *
3) Cerebro-vascular event; 8/9
3
3) Contralateral hand/arm dysfunction (<7 days duration)
Cerebrovascu-lar event
Transientstroke
Target Validation
4) Missing 30-day registration; 7/7
1 Contralateral hand dys-function and aphasia (<5 days duration)
Not registered Transient stroke
Total 84/92 (91%) 5
35
Papers II-III In the cross-match with the National Population-registry all perioperative deaths had been reported to the Swedvasc.
During 2003, 771 CEAs were registered in Swedvasc and 782 patients in the IPR. Three hospitals had exactly the same number of procedures in both registries; ten had more in Swedvasc and eight more in the IPR. In those latter eight hospitals a surplus of 32 operations were registered in the IPR. A total of 4.1% (32/782) of those in the IPR were unregistered in Swedvasc.
Comments to papers I-III In analysing registry data the reliability of the results may be discussed, one potential weakness is the completeness of registrations and another is self-auditing. The completeness of the registrations for CEA has been evaluated previously with good validity [61].
Concerning the problem of self-reported data [63] Swedvasc strongly rec-ommends independent neurological evaluation. Another factor that may contribute to the validity is that the results of the individual surgeons are confidential and that much of the data are registered prospectively.
To overcome some of these inherent problems with register data we per-formed several different validation procedures, and the results demonstrate good accuracy with few missed and incorrect registrations. Furthermore, none of these missed or incorrectly registered events were disabling strokes and there was no death unreported.
Papers IV-V Patient demographics and indication for CEA are demonstrated in Table 7.
36
Table 7. Preoperative registered risk factors and indications for CEA.
Baseline characteristics Paper IV (%)
Paper V (%)
Age (range) 71 (51-84) 69 (58-75) Gender (male) 70 83 Cardiac disease 45 17 Hypertension 52 67 Previous vascular surgery 19 11 Diabetes mellitus 14 17 Pulmonary disease 6 6 Renal insufficiency 3 6 Current smoker 38 39 Indication for CEA Minor stroke 30 39 TIA 60 17 Amaurosis fugax 10 33 Others (eg non-hemispheric) 11
Paper IV Sixty-two patients were included. The median clamping time was 42 (32-57) minutes. Eight patients (13%) were operated upon using a Javid shunt (based on stump pressure <40mm Hg). Patch angioplasty was used for arteriotomy closure in 82% of the patients.
One patient developed an intraoperative stroke but no other neurological deficits developed perioperatively, resulting in a stroke or death rate of 1.6%. Duplex follow up within 30 days revealed no major pathology of the ICA
Transit time volume blood flow Transit time volume flow measurements increased after the CEA in CCA (p<0.05) and ICA (p<0.001) as demonstrated in Table 8. Patients with con-tralateral ICA occlusion had higher ipsilateral ICA flow before clamping (p=0.04).
37
Table 8. Results of median flow (ml/min) before clamping and after reperfusion in the CEA. CCA and ICA flow increased significantly after the procedure. ** p<0.05
CCA ECA ICA
Before clamping 164 (102-412) 102 (38-190) 78 (39-222) 5 min after reperfusion 238 (141-460) 79 (55-116) 122 (90-194) 10 min after reperfusion 297 (174-430)** 81 (40-148) 162 (80-436)**
Cerebral oximetry Cerebral oximetry decreased (rSO2) after clamping in patients requiring a shunt (based on stump pressure < 40 mmHg), after shunt placement the rSO2was reversed (49% vs 58%), shown in Table 9. No significant changes were registered in the contralateral hemisphere.
Table 9. Results of cerebral oximetry (rSO2) during CEA. Correlation between decreases in rSO2 and need for shunt (stump pressure < 40mmHg), reversed by shunt placement. * p<0.01.
Beforeclamping
At clamping 5 min after reperfusion
10 min after reperfusion
No Shunt 63 (59-65) 62 (57-67) 66 (63-73) 65 (63-71) Shunt 65 (62-71) 49 (42-54)* 61 (57-70) 62 (61-70) After shunt 58 (57-61)*
Measurement associations The associations between the different measurements are demonstrated in Figure 8.
Associations were found between: A high ICA volume flow before clamping and low stump pressure (r= -0.45, p= 0.03). A high ICA volume flow before clamping and decreasing rSO2 dur-ing clamping (r=-0.41 p=0.01). A low stump pressure and decreasing rSO2 during clamping (r=-0.61 p=0.002), the rSO2 changes was reversed by shunt inser-tion.
38
Figure 8. Scatter plots and curve estimations for associations between stump pressure, transit time volume flow and cerebral oximetry.
Comments to paper IV The results in this paper are based on the preset shunt indication of stump pressure < 40mmHg, and as the only complication occurred in a patient op-erated on with a shunt, other means of comparisons were not possible. How-ever, there was reasonable number of patient included and the measurement association was relatively strong (eg stump pressure vs cerebral oximetry) which strengthen the results.
39
Paper VTwenty-two patients scheduled for elective CEA for symptomatic internal carotid artery (ICA) stenosis were prospectively included in the study. Four patients needed a perioperative shunt (based on stump-pressure <40 mmHg) and were excluded before the analysis, leaving eighteen patients completing the study.
The contralateral ICAs were occluded in two patients, one had a stenosis of > 70% and the remaining fifteen had stenosis < 70% on duplex ultrasono-graphy.
Seventeen patients received aspirin and of these four had additional treatment with dipyridamole. The remaining patient was on clopidogrel. Five patients were on warfarin, but all had INR < 1.5 on the day of the CEA.
Median (range) clamping time was 56 (29-87) min. Patch angioplasties were used in 89%.
No patient suffered any perioperative central neurological event.
Levels of biomarkers The patterns for the jugular bulb (JB) levels during the procedure in relation to radial artery (RA), baseline (BL) and to the previous value are shown in Table 10.
Interleukin-6 IL-6 was elevated compared to baseline levels throughout the CEA. The jugular bulb values increased prominently directly after clamping and then again after reperfusion. Throughout the procedure the jugular bulb levels were higher than in the radial artery.
Soluble CD40L During CEA the levels of soluble CD40L did not change from baseline or between the measurement intervals. All samples, both jugular bulb and ra-dial artery, showed a similar pattern.
Fragment 1+2 The jugular bulb levels of F1+2 increased from baseline during the initial part of the CEA, until clamping with heparinisation when it rapidly de-creased (5 min after clamping) and then levelled out. There were no differ-ences between jugular bulb and radial artery levels.
Plasminogen activator inhibitor-1 PAI-1 levels did not change from baseline until after reperfusion when it increased, but not in relation to the previous (30min after clamping) levels.
40
The jugular bulb levels were lower than in the radial artery during the proce-dure until after reperfusion.
Cross-linked fibrin degradation product (D-dimer) Jugular bulb D-dimer levels were increased throughout the procedure in comparison with peripheral and baseline levels, with a significant increase at clamping.
Table 10. Comparisons between the cerebral (jugular bulb (JB)), peripheral (radial artery (RA)) and baseline (BL) levels at the different moments of the procedure. Arrows indicating the cerebral (JB) samples in regard to increased or decreased level as compared to the RA, BL or previous JB samples. Test used Wilcoxon Signed Rank Test.
Comparisons between cerebral (JB), peripheral (RA) and baseline (BL) mean levels
Analysis
Beforeclamping
5min after clamping
15min after clamping
30min after clamping
Afterreperfusion
IL-6JB vs RA p=0.019 p=0.036 p=0.011 p=0.016 p=0.001 JB vs BL p=0.036 p=0.004 p=0.008 p=0.001 p<0.001 JB vs JB p=0.050 p=0.088 p=0.001 p<0.001
CD40L JB vs RA p=0.551 p=0.586 p=0.469 p=0.279 p=0.056 JB vs BL p=0.245 p=0.407 p=0.737 p=0.244 p=0.272 JB vs JB p=0.712 p=0.426 p=0.865 p=1.000
F 1+2 JB vs RA p=0.127 p=0.602 p=0.099 p=0.125 p=0.205 JB vs BL p=0.003 p=0.959 p=0.299 p=0.378 p=0.910 JB vs JB p=0.002 p=0.234 p=0.938 p=0.589
PAI-1JB vs RA p=0.009 p=0.004 p=0.001 p=0.004 p=0.155 JB vs BL p=0.205 p=0.394 p=0.469 p=0.326 p=0.046 JB vs JB p=0.315 p=0.629 p=0.315 p=0.875
D-dimerJB vs RA p=0.011 p=0.003 p=0.003 p=0.006 p=0.005 JB vs BL p=0.006 p=0.001 p=0.001 p=0.001 p<0.001 JB vs JB p=0.004 p=0.307 p=0.495 p=0.642
41
Comments to paper V Although a small number of patients, the activation of inflammation and fibrinolysis in the jugular bulb samples demonstrated a consistent pattern. The regional pattern of biomarkers after carotid clamping was suggestive of cerebral ischaemia. This effect was clear despite the fact that all patients received unfractionated heparin, however, with regard to coagulation (and possibly also fibrinolysis) the alterations of marker for thrombin generation (eg F1+2) would probably have been increased.
42
General discussion
After the publication of the large randomised trials on CEA of carotid artery stenosis, this treatment modality was implemented and is now one of the most common vascular procedures which are performed in Sweden [12].However, some concerns have been raised about the results in routine clini-cal practice.
A validated registry, with coverage of all centres performing CEA in the country can provide population-based data on the national outcome of the procedure. In analysing the overall benefit of the procedure both the short- and long-term outcomes are important.
The perioperative results are influenced by intra- and postoperative com-plications, and as the aim of the surgery is to decrease the future stroke risk, the combined stroke or death rate is an important and commonly reported outcome measure. Most perioperative strokes occur within the first days after the procedure, so tolerance of carotid clamping and surgical technique among other factors have impact on outcome [64].
Long-term outcome of CEA is dependent both on the durability of the procedure and the late mortality, especially for the patients with asympto-matic stenosis. Some patients with certain risk factors may benefit less from CEA than others, and these factors may differ between short- or long-term outcomes.
CEA for symptomatic stenosis The two most influential trials of CEA for recent symptomatic severe carotid stenosis are ECST and NASCET, a third (Veteran Affairs VA309) was stopped early when the results from the first two studies were published [7-9, 11, 20].
Although differences in the definition of complications and the degree of stenosis make comparison difficult, the rate for perioperative stroke or death were in ECST 7.0% and in NASCET 6.7%. When analysing these studies
43
pooled (including also VA309) and with the data reassessed for degree of stenosis and outcome, the stroke or death rate was 7.1 % for stenosis 70% (NASCET-method) [21].
In a systematic review of all studies on perioperative results after CEA the pooled estimate of stroke or death risk was 5.1% (for studies published after 1994, including 18885 CEAs) [65].
The corresponding risk of perioperative stroke (permanent and transient) or death was 5.9% in Swedvasc during 1994-1996 (paper I) and 4.3% during 1994-2003 (paper II).
Comparisons between the results from randomised trials and vascular reg-istries (or single centres) should be interpreted with caution, although exten-sive register validations can make such comparisons more reliable. Follow-ing the present analysis, it seems reasonable to suggest that the population-based perioperative results for CEA of symptomatic stenosis in Sweden compares well with the results from the RCTs.
Timing of CEA Timing of CEA after the qualifying event is an important factor to con-
sider since the net benefit decreases over time due to an initially high stroke recurrence rate [7, 9, 66].
In patients with large artery atherosclerosis the risk of recurrent stroke in population based studies was 4.0% at 7 days, 12.6% at one month and 19.2% at 3 months [4]. With TIA as the presenting symptom there was a high risk of recurrent TIA or stroke in a population based study with 2.5% (TIA) vs 1.4% (stroke) at 2 days, 6.2% vs 6.7% at 1 month and 7.9% vs 9.5% at 3 months, respectively [2]. Approximately 15-26% of patients with an ische-mic stroke have had a preceding TIA and 43% had the event within 7 days prior to the stroke (92% in the same vascular territory) [67].
However, there are some concerns about the risk for reperfusion compli-cations (ie hemorrhagic transformation) in early CEA after cerebral infarc-tions. This is not well investigated in controlled trials but it has been a com-mon practice to defer the surgery 4-8 weeks after a larger infarction [68, 69]. In a recent prospective study of CEA within 15 days of preceding symptom, the authors concluded that there was no association with increased pe-rioperative risk related to CT/MR cerebral infarctions [70]. The size of the cerebral infarction was not evaluated in this study but relatively large infarc-tion volumes on imaging in combination with residual neurological disability are suggested as factors to consider when deciding on the timing for CEA [71, 72]. Large volume infarctions may constitute a group where special considerations should be taken into account, the choice being either to defer
44
the procedure or to perform early revascularisation with intense postopera-tive blood pressure regulation.
In a systematic review of the literature on stroke or death risk after CEA the pooled estimates for “urgent” surgical indication (ie stroke in evolution, crescendo TIA) demonstrated an OR=4.9 (3.4-7.1) vs nonurgent surgery. However, when comparing neurological stable patients there was no differ-ence between early (<3-6 weeks) and late (>3-6 weeks) CEA (OR=1.1 (0.8-1.6) early vs late CEA) [65].
In summary, it seems reasonably that the majority of patients with TIA or minor stroke should benefit most if the CEA can be performed as soon as possible after the event (hence, the logistics for such an organisation being an issue by itself).
CEA for asymptomatic stenosis In the two largest trials on CEA for asymptomatic stenosis the combined
perioperative stroke or death rate were 2.3% in ACAS and 2.8% in ACST, as compared with 2.1% in the Swedvasc registry (1994-2003) [6, 10].
When analysing this registry data for the two 5-year periods, the pe-rioperative stroke or death rate decreased in the later time period (1999-2003) to 0.9%. This is consistent with other series of CEA for asymptomatic stenosis [73, 74] and also with a recently published meta-analysis where the pooled estimate of the absolute risk of stroke or death decreased for the as-ymptomatic indication in the later time period [65]. Many different factors may have contributed to this improvement in outcome including patient se-lection, surgical technique, pre- and postoperative medical treatment. No major single factor was possible to identify in the present papers (further discussed later).
Although the perioperative results are promising, the net benefit of the procedure is not statistically evident in the RCTs until 2-3 years after the CEA, and this makes the long-term outcome an important issue. The long-term follow-up of ACST is still ongoing (~2 years) and other series on late outcome (> 5 years) of CEA for asymptomatic stenosis are from a few single centres reporting 10-year survival of approximately 60%. In Table 11 some series on long-term survival are listed for patients with asymptomatic carotid stenosis, both for natural history and after CEA (with asymptomatic indica-tion ranging from 33% to 100%).
45
Table 11. Studies on long-term survival for patients with severe asymptomatic ca-rotid artery stenosis, both for surgically and medically treated patients.
Ref Patient group studied N Pat
%Asympt
Mean / median
age
5-year survival
%
10-year survival
%
PaperIII
CEA asymptomatic stenosis
631 100 70 78.2 45.5
[75] CEA asymptomatic stenosis (+ combined and non-hemispheric)
312 100 69 74.6 (SD 5.3)
59.4 (SD8.6)
[76] CEA asymptomatic stenosis (with/without silent brain infarction)
103 198
100 67 78.3 (SD 4.6)
86.0 (SD 2.8)
60.6 (SD7.4)
69.3 (SD6.9)
[77] CEA 1000 33 72 92.8 87.2
[78] CEA 1897 64 70 72.4 44.7
[79] CEA 540 47 68 92(SD 1)
89(SD 2)
[80] Asymptomatic carotid stenosis (>60%) and contralateral occlusion
82 100 66 83(SD 5.6)
67(SD 16)
[81] Asymptomatic carotid stenosis (>60%)
216 100 66 79
[82] Asymptomatic carotid stenosis (50-79%)
426 100 74 77
The median survival time was 10.2 years for the asymptomatic patient in the present paper (paper III). The survival time is thus reduced compared to the life expectancy of an average 70-year old person in Sweden (12.3 years for men vs 15.4 years for women (1995) and 13.7 years for men vs 15.5 years for women (2004)). However, it is important to bear in mind that these pa-tients represent a selected group and one should therefore not make any gen-eral conclusions for all patients with asymptomatic stenosis based on these results.
In summary, this extensively validated Swedvasc data for CEA of the as-ymptomatic cohort demonstrates perioperative complication rates well com-parable with those from the randomised trials. Concerning the long-term outcome it seems reasonable to select patients based on risk-benefit consid-erations in regard to risk factors (discussed in the following) and the pa-tients’ own preferences.
46
Plaque morphology Patient selection for CEA is primarily based on the degree of ICA stenosis derived from the results of the RCTs. However, although the degree of stenosis correlated well with the stroke rate in patients with asymptomatic stenosis, 34% of all ipsilateral neurological events and 35% of the ipsilateral strokes occurred in patients with a stenosis <60% (NASCET-method) [83].
Several other factors are involved in the development of an unstable ca-rotid artery plaque [84]. Morphological characteristics of vulnerable plaques can be demonstrated by different imaging modalities, such as duplex classi-fication by computed grey scale media (GSM), pixel distribution analysis and fibrous cap thickness. [17-19, 85]. Another developing technique is high resolution MRA with characterisation of lipid content and fibrous cap [86, 87].
However promising the studies of carotid plaque imaging may seem they are not yet fully assessed for implementation in routine clinical practice [84, 88].
Registry dataRegistry data have several inherent limitations but Swedvasc has been vali-dated on several occasions with >90% report rate and reproducibility con-cerning CEA [61, 89]. During 2003 (the last year in this series), a cross-match for all patients who had an operation code for CEA, was compared to the in-hospital registry of the National Board of Health and Welfare with a 96% accuracy.
Four different validations; a case-control study (1994-1996), a cross-match of death dates with the National board of Health and Welfares popula-tion registry (1994-2003), a random sample of asymptomatic patients and a review of all unclear complications registered in the asymptomatic patients (1994-2003) were performed in the present studies. During this validation process we did not find any disabling stroke or death unreported.
Baseline risk factors are prospectively registered in Swedvasc but the reli-ability depends on the accuracy of the responsible surgeon while completing the protocol. When analysing the registrations of these risk factor for CEA during the time period 1994-2003, the percentage of missing fields (includ-ing “unknown” registrations) are shown in Table 12.
47
Most of the risk factors have more than a 95% registration rate and the accuracy of these registrations has previously been validated with a 60% reproducibility (probably mainly due to the poor registration of hyperlipi-daemia) [61].
Table 12. Baseline risk factors among patients registered for CEA during 1994-2003 in Swedvasc. Percentage of registrations marked as unknown or missing fields.
Baseline risk factor Registration; unknown or missing
Diabetes mellitus 5.1% Hyperlipidaemia 39% Hypertension 3.9% Cardiac disease 4.5% Previous vascular surgery 4.2% Pulmonary disease 5.3% Renal insufficiency 6.3% Current smoking 9.8%
Risk factors It is essential to evaluate the individual patient when deciding upon CEA, as it is a prophylactic procedure in which all different risk-benefit considera-tions have to be taken into account. Several risk factors have been identified in the literature and some have also been demonstrated in the present papers (I-III) as potential predictors of negative outcome from the procedure. Many of the publications on risk factors are subgroup analyses (sometimes small subgroups), single centre series or register based studies with low level of evidence. However, reports on pooled data from the RCTs, meta-analyses and systematically reviews may better contribute to the management deci-sions. Some important factors to consider in the clinical situation are dis-cussed below.
GenderIn the RCTs females had less benefit from the CEA compared to men, this due to a higher operative risk and a lower risk for stroke on medical treat-ment [6-11].
In a pooled analysis (remeasured stenosis with NASCET-method) of the large symptomatic trials, CEA was clearly beneficial in women with >70%
48
stenosis (ARR 9.9% (1.8-18.0)) but not in those with < 70% stenosis (ARR -2.7% (-8.8-3.5)) [66].
A meta-analysis of the asymptomatic trials (ACAS/ACST) demonstrated a considerable uncertainty with regard to the benefit of CEA for women, the OR for stroke or death being 0.96 (0.63-1.45), based on events during a mean follow-up of 2-3 years [90]. The long-term net benefits might be un-derestimated but this should be disclosed with the stroke incidence in the coming years of follow-up.
In the Swedvasc data analysed (paper I-III), gender did not influence ei-ther perioperative stroke/death risk (all indications) or 5-year mortality (as-ymptomatic indication). Long-term survival was 10.2 years in all patients but due to the small numbers with this follow-up specific gender analysis was not meaningful, however the expected survival was longer for women than for men. This may be interpreted either as a possible increased long-term benefit due to longer survival or as a reduced late survival after CEA with perhaps a reduced stroke risk on medical treatment alone.
In summary, it seems clear that the majority of women benefit from CEA for symptomatic carotid artery stenosis 70%. A dilemma is concerning women with asymptomatic stenosis where (level 1) evidence has not yet clearly demonstrated a benefit of CEA. However, it seems reasonable not to exclude all women with asymptomatic stenosis but to perform CEA with appropriate selection and continuous focus/follow-up on the perioperative results.
AgeA subgroup analysis of the RCTs demonstrated an increased benefit of CEA for symptomatic stenosis ( 70%) in patients older than 75 years, with a 5-years ARR=37.2%, this mainly due to the relatively high stroke risk on medical treatment [66]. Noteworthy is that the trials included approximately only 10% of patients 75 years of age (and very few patients 80 years) and that the elderly patients in the trials might represent a selection of generally fit individuals [91].
In a systematic review of all publications reporting data on association be-tween age and procedural risk of stroke or death following CEA, the pooled results showed an OR=1.2 (1.0-1.4) for patients 75 years and an OR=1.2 (0.9-1.5) for those 80 years of age [92].
In the present paper (I) age > 75 years was an independent predictor for perioperative mortality (RR=1.6 (1.0-2.4)) but not for permanent/fatal stroke or the combined (stroke or death) outcome.
For patients with asymptomatic stenosis CEA is more of a long-term in-vestment, as it will take 2-3 years to statistically compensate for the pe-rioperative risk and even 2-3 more years to gain the absolute stroke risk re-duction from the procedure. In ACAS and ACST the projected aggregated 5-
49
year ARR of stroke or procedural morbidity was 5.5% (6.0 vs 11.5) [10]. In subgroup analysis of those older than 75 years no significant benefit after successful CEA was demonstrated (ACST: ARR 3.3% (-1.9-8.4)) but due to the small number of patients these results are less conclusive [10].
In the present studies of CEA for asymptomatic stenosis (paper II-III) age was a predictor of combined perioperative morbidity and mortality with an OR=2.8 (1.4-5.6) for age >75 years and also for decreased 5-year survival with an OR=1.5 (1.1-2.1) per 10 years.
In summary, it seems reasonable not to withhold CEA for symptomatic stenosis in patients older than 75 years, although consideration must be taken with regard to other risk factors/comorbidity. This is supported by the sub-stantial early stroke risk on medical treatment alone and consequently less influenced by the late outcome/expected survival after the procedure. On the contrast, patient with asymptomatic stenosis who are older than 75 years do not generally seem to be good candidates for a prophylactic CEA, as the net benefit may be of limited duration.
Contralateral carotid artery occlusion In the analyses of the RCTs, occluded contralateral internal carotid arteries have had conflicting impact on the outcome, this mainly due to different medical and surgical risks.
In the pooled data of the trials on symptomatic lesions the surgical (stroke or death) risk after CEA for the patient with a contralateral occlusion was 18.0% (8.4-27.7) vs 7.0% (5.6-8.3) for those with a patent contralateral ar-tery. The medical (ipsilateral stroke) risk of a contralateral occlusion was 25.8% (15.5-36.0) vs 20.9% (18.4-23.3) at 5 years. Although the wide CIs indicates that there were limited numbers of patients studied within this group, the CI for surgical risk with contralateral occlusion was separated from the overall surgical risk ((8.4-27.7) vs (6.1-8.8)) predicting increased stroke or death risk after CEA for this group [66].
However, when performing a subgroup analysis of the patients with con-tralateral occlusion in NASCET, it was demonstrated that despite a higher surgical risk, CEA conferred a significant reduction in the 2-year risk of ipsilateral stroke (ARR=43.3% (22.1% surgical vs 69.4% medical risk) [93].
In a systematic review of CEA with risk factor analyses, a trend towards increased perioperative stroke or death risk with contralateral occlusion was found with an OR=1.9 (1.3-2.7). In this review the prevalence was low (4.7%) and only two studies reached significance [94].
In the present case-control study (paper I) contralateral occlusion was the only identified factor predicting increased perioperative stroke or death risk with an OR=5.3 (2.0-13.1). In the control group 5.4% (7/130) had contralat-eral occlusion.
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In the randomised trials of CEA for asymptomatic stenosis the impact of contralateral occlusion is difficult to analyse because of the considerable difference in the risk-benefit calculations. In ACAS there was a 5-year ARR= -2.0% (5.5% surgical vs 3.5% medical risk) for contralateral occlu-sion, which was a result of the benign course of medically treated subjects [95]. In contrast the findings in ACST demonstrated a 5-year ARR=8.6% (1.5% surgical vs 10.1% medical risk) [10].
In summary, patients that have severe symptomatic disease and contralat-eral occlusion seem to benefit from CEA in spite of a higher perioperative risk. However, for the patients with an asymptomatic stenosis and a contra-lateral occlusion, the level of evidence seems too uncertain for general man-agement guidelines.
Carotid shunt indications Tolerance of carotid clamping during CEA is obviously best tested in an awake patient, however not all vascular centres practice local anaesthesia, and so far no level 1 evidence on perioperative outcome clearly favouring either local or general anaesthesia has been demonstrated [27].
CEA under general anaesthesia confers the problem with assessing the pa-tients´ tolerance to clamping and if selective shunting is practiced, some indirect method for deciding on the need for shunting is necessary [96, 97]. Various methods are available, including intracerebral circulation monitor-ing (eg TCD) [28], activity (eg SEPS or EEG) [98, 99] or oxygenation (NIRS) [100, 101] with intermittent or continuous measurements during the clamping.
Other methods predict the need for shunt on measurements before the ar-teriotomy, such as carotid stump pressure and transit time volume flow measurement. Carotid stump pressure (SP) is the “back pressure” in the clamped ICA and measuring SP indirectly assesses the capacity of the cere-bral collateral blood flow [34]. Recently SP was investigated in patients un-dergoing CEA under local anaesthesia and the threshold of 40mmHg was considered reliable (false-negative rate 1.0%) [102].
Transit time volume flow measurements might be used for different pur-poses during CEA, first in combination with SP to decide on shunt indica-tion, as low SP in combination with a high volume flow decreases the cere-bral oxygenation during clamping (paper IV). Secondly, measuring the vol-ume flow and wave form during reperfusion offers completion control (abso-lute flow and/or decreasing flow). Furthermore, the differences between the volume flow before and after the CEA may indicate of possible risk of hy-perperfusion [103, 104]. Hyperperfusion syndrome is a rare but potentially serious complication after CEA that confers a high risk for neurological morbidity and mortality [105].
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Considering that none of the methods used to predict the patients´ toler-ance to clamping during CEA under general anaesthesia is in all aspects superior to the others, decisions on which method to use will be based on availability, technical issues, local experience or expertise with the methods and the interpretation of the measurements.
Cerebral ischemia Carotid clamping during CEA impairs the cerebral perfusion to various de-grees, and although the patient clinically tolerates clamping a relative is-chaemia may result in subclinical reversible or irreversible damage. In re-sponse to the clamped induced regional hypoperfusion other investigators have identified different markers for cerebral ischaemia such as inflamma-tory mediators [38], metabolites or anti-oxidants [39, 106, 107] and markers for cellular brain damage [40-42]. These markers of cerebral ischaemia is detected in mixed venous blood samples collected from the ipsilateral jugu-lar bulb, which has been demonstrated to be of predominantly intracerebral origin [108].
In the present paper (V) a pattern suggestive of regional ischaemic re-sponse after carotis clamping during CEA were demonstrated by the jugular bulb levels of IL-6, D-dimer and PAI-1. These markers for the inflammatory and fibrinolytic systems were most prominently altered directly after clamp-ing and reperfusion, although almost all of the jugular bulb (cerebral) levels differed from the radial artery (peripheral) levels throughout the procedure. The marker for the coagulation system or more specific the thrombin genera-tion, F1+2, rapidly decreased after systemic heparinisation which was ad-ministered at the time of clamping. Unfractionated heparin has t½ of ap-proximately 2 hours and since it was not reversed the effect on antithrombin III persisted during the procedure. This heparin effect is in agreement with a previous report on haemostasis during CEA [109].
Several investigators have identified altered levels of inflammatory and haemostatic markers in stroke patients, both in the acute face and during follow up [44, 46, 47, 56, 58, 110-116]. Furthermore, in association with carotis plaques various markers of these systems have been demonstrated [52, 57, 59, 117-122].
With the advances in stroke research regarding plaque instability and is-chaemia/reperfusion injury, there may be a potential for therapeutic modula-tions during CEA [48, 123-125].
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53
Conclusions
We conclude that; the population-based perioperative complication rates for CEA in Swedvasc compares well with the large randomised trials (paper I-II). the risk factors in Swedvasc for preoperative complications after CEA were the indication for surgery (minor stroke vs. other indica-tions), age, diabetes, cardiac disease and contralateral occlusion (paper I-II).the perioperative outcome after CEA for patients with asympto-matic severe carotid artery stenosis improved over time (paper II).the long-term survival was reduced for the patients undergoing CEA for asymptomatic stenosis. Predictors of decreased late sur-vival were age, diabetes, cardiac disease and previous vascular sur-gery (paper III)the shunt indication during carotid clamping may be evaluated by a combination of stump pressure and transit time volume flow meas-urements (paper IV).the altered levels of markers for the inflammatory and fibrinolytic systems induced by carotid clamping during CEA suggested devel-opment of regional cerebral ischemia (paper V).
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Summary in Swedish (svensk sammanfattning)
BakgrundSlaganfall (stroke) är en av de vanligaste orsakerna till sjukhusvård, handi-kapp och mortalitet i Sverige. Åderförkalkning med förträngning av hals-pulsådern, karotisstenos, beräknas orsaka ~ 15 % av alla stroke. Patienterna med karotisstenoser delas in olika kategorier, asymtomatiska respektive symtomatiska. En patient med en symtomatisk stenos har inom de senaste 6 månaderna haft en TIA/stroke som härrört från denna kärlförträngning.
Stora randomiserade studier har visat att operation av karotisstenoser, ka-rotis endartärektomi (CEA), minskar risken för att insjukna i ett nytt stroke jämfört med bästa medicinska behandling. Den totala riskreduktionen av detta profylaktiska ingrepp är dock direkt avhängig komplikationsfrekven-sen, ffa avseende bestående stroke och/eller mortalitet. Operationsresultaten i allmän klinisk praxis får inte vara sämre än i de randomiserade studierna för att den sammantagna vinsten av ingreppet skall kvarstå.
Vid CEA stängs ena halspulsådern av, vilket påverkar hjärnans cirkula-tion och syresättningen i varierande grad. Olika metoder för att bedöma på-verkan av kärlavstängningen används, för att avgöra behovet av att under operationen använda en shunt för att säkerställa cirkulationen.
Om hjärncirkulationen lokalt får otillräckligt med syresatt blod leder detta till olika grad och omfattning av hjärncellsskada, sk cerebral ischemi. Cere-bral ischemi leder också till aktivering av inflammation, koagulation och fibrinolys, vilket kan ytterligare påverka omfattningen av den ev skadan.
SyfteMålsättningarna med avhandlingen var att undersöka de populationsbaserade resultaten för patienter som opererats med CEA i Sverige, och hur de har utvecklats över tiden, även avseende långtidsöverlevnad; att utvärdera olika metoder för att bedöma när shunt bör användas under karotis operationen; att undersöka hjärnans aktivering av inflammation, koagulation och fibrinolys vid kärlavstängning under CEA.
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Delarbeten 1-5
Riskfaktorer för komplikationer efter CEA – en populationsbaserad studie.
Material/metod Data från Svenska kärlregistret (Swedvasc) för alla registrerade CEA
(n=1518) under 1994-1996 insamlades. En kombinerad kohort- och fall-kontrollstudie genomfördes. Totalt 43 patienter med permanent stroke och 22 dödsfall (65/1518) var registrerade och jämfördes med två slumpmässigt valda kontroller per fall. Registret validerades.
Resultat Komplikationsfrekvensen för permanent stroke och/eller död var 4.3 %. Oberoende riskfaktorer var operationsindikation minor stroke, diabetes och hjärtsjukdom. Kontralateral ocklusion var enda riskfaktorn i fall-kontrollstudien. Registrets validitet var god.
Resultaten av karotisendartärektomi för asymtomatiska stenoser i Sverige förbättras – analys från ett populationsbaserat register.
Material/metod Alla i Swedvasc registrerade CEA mellan 1994-2003 insamlades och analy-serades. Registret validerades på fyra sätt; mot befolknings- och patientad-ministrativa registret samt i ett slumpmässigt och ett riktat urval av CEA (asymtomatiska).
Resultat6182 CEA var registrerade, varav 671 för asymtomatisk stenos. Inga oregi-strerade dödsfall eller major stroke upptäcktes vid valideringen. Analyserat på hela tidsperioden var risken för stroke och/eller död efter CEA av asym-tomatisk stenos 2.1%. Resultaten förbättrades över tiden med risken för stro-ke och/eller död sjunkande från 3.3% 1994-1998 till 0.9% 1999-2003. Under den andra tidsperioden rapporterades inget perioperativt invalidiserande stroke eller dödsfall.
Långtidsöverlevnad efter karotisendartärektomi för asymtomatisk stenos
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Material/metod Alla i Swedvasc registrerade CEA mellan 1994-2003 insamlades och analy-serades med överlevnadsanalyser. Samkörning med befolkningsregistret genomfördes för korrekta dödsdatum.
ResultatTotalt 5808 patienter var opererade för CEA under tidsperioden, av dessa var 10.8% opererade för en asymtomatisk stenos. Medianuppföljningen var 5.1 år. För gruppen opererade för asymtomatisk karotisstenos var medianöver-levnaden 10.2 år. Riskfaktorer för sämre 5-årsöverlevnad var ålder, tidigare kärlkirugi, hjärtsjukdom, diabetes mellitus.
Lokala hemodynamiska förändringar vid karotisendartärektomi – hur påverkas den cerebrala syresättningen.
Material/metod Prospektiv studie av 62 patienter med symtomgivande täta förträngning av A carotis interna (ICA) opererade i generell narkos. Mätningar av stumptryck, volymflöde samt cerebral oxygenering (rSO2).
ResultatLågt stumptryck var associerat med både högt ICA-flödet före, samt med en sänkning av rSO2 under kärlavstängning, det senare reverserades vid shunt-insättning. Ett högt ICA-flödet före kärlavstängning var också associerat med en sänkning av rSO2 under kärlavstängning.
Cerebral ischemi vid karotisendartärektomi – analys an markörer för aktivering av inflammation, koagulation samt fibrinolys
Material/metod Prospektiv studie av 18 patienter opererade med CEA i generell anestesi. Via kateter i vena jugularis interna i skallbashöjd (jugularis bulben (JB)) togs blodprover på bestämda tidpunkter under ingreppet. Vid samma tidpunkter togs även motsvarande prover från radialiskaterer (RA). Utgångsprover togs dagen före operation och dessa jämfördes med referensprover från 50 friska 20-65 åringar. Provanalyser: CD40L, IL-6, F1+2, PAI-1 och D-Dimer.
ResultatD-dimer,IL-6 och PAI-1 visade signifikanta skillnader mellan jugularis (JB) och radialis (RA) proverna, med en markant jugularisaktivering vid kärlav-stängningen/påsläpp som tecken på cerebral ischemi.
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SammanfattningDe nationella resultaten för perioperativa komplikationer efter CEA var väl jämförbara med de randomiserade studiernas. Resultaten för operation av asymtomatisk karotisstenos förbättrades över tiden, dock var långtidsöver-levnaden minskad.
Vid bedömningen av patientens tolerans för kärlavstängning under CEA kan kombination av stumptryck och volymsflödesmätning var användbart.
Karotisavstängning leder till förändrade nivåer av markörer för regional inflammations- och fibrinolysaktivering som tecken på cerebral ischemi.
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Acknowledgements
I wish to express my sincere gratitude to all those who have contributed to make this thesis possible:
Håkan Pärsson, my tutor and friend, for guiding me into this field of scien-tific work with encouragement and never failing enthusiasm. Always giving me good spirits and in a very positive way influenced my scientific and “non-scientific” training. Furthermore for sharing your knowledge in vascu-lar surgery.
David Bergqvist, my co-tutor, for your profound scientific and clinical knowledge together with your personal qualities.
Ola Forsberg, my first tutor in the field of vascular surgery, for your excep-tionally inspiring personality and knowledge.
Christer Ljungman, head of the section of vascular surgery, for your lead-ership and clinical skills. Martin Björck, enthusiastic co-writer, for your support both in the scientific and clinical work. Annika Boström-Ardin, Lasse Karlsson, Anders Wanhainen, Håkan Rudström and Johnny Steuer, past and present colleagues at the vascular team in Uppsala, for cre-ating a good atmosphere and backing me both in my absent and at work. Kerry Filler, colleague, for linguistic revision.
Claes Forsell, for teaching refined vascular surgical technique. Stig Rein-holdson, for your guidance and general support. Claes Rudberg and col-legues at the Department of Surgery in Västerås, for sharing their operative skills.
Agneta Siegbahn, professor in clinical chemistry, for advice and support in laboratory issues.
Johan Lindbäck, for valuable statistical discussions and assistance.
Members of Swedvasc, for helping me out with data collection.
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Professor Ulf Haglund, former head of the Department Surgery in Uppsala, professor Lars Wiklund, head of the Department of Surgical Science and associate professor Ewa Lundgren, present head of the Department Surgery for providing facilities for scientific and clinical work.
My parents Ulla and Arne, together with my parents-in-law Gunnel and Henry, for all help and encouragements during these years.
My family, Eva, Ellen, Erik and Axel, for all being fantastic and the most important part of my life.
This work has been supported by grants from Uppsala University, Tornspi-rans Foundation, the Swedish Research Concil, the Swedish Stroke Associa-tion, the Swedish Vascular Registry and Gorthon Foundation.
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Acta Universitatis UpsaliensisDigital Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Medicine 151
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A doctoral dissertation from the Faculty of Medicine, UppsalaUniversity, is usually a summary of a number of papers. A fewcopies of the complete dissertation are kept at major Swedishresearch libraries, while the summary alone is distributedinternationally through the series Digital ComprehensiveSummaries of Uppsala Dissertations from the Faculty ofMedicine. (Prior to January, 2005, the series was publishedunder the title “Comprehensive Summaries of UppsalaDissertations from the Faculty of Medicine”.)
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