Lancet Neurology 2010 Kumar

7/27/2019 Lancet Neurology 2010 Kumar

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Medical complications after stroke

Sandeep Kumar, Magdy H Selim, Louis R Caplan

Patients who have had a stroke are susceptible to many complications. These individuals commonly have comorbiditiessuch as hypertension, diabetes, heart disease, or other ailments that increase the risks of systemic medicalcomplications during stroke recovery. However, several complications can arise as a direct consequence of the braininjury itself, from the ensuing disabilities or immobility, or from stroke-related treatments. These events have asubstantial effect on the final outcome of patients with stroke and often impede neurological recovery. Cardiaccomplications, pneumonias, venous thromboembolism, fever, pain, dysphagia, incontinence, and depression areparticularly common after a stroke and usually require specific interventions for their prevention and treatment.However, there are few data to guide the management of these complications. Systematic investigations are thereforeneeded to further study the effects of medical complications on stroke recovery and to improve interventions for theprevention and treatment of these events.

Introduction

Stroke is a leading cause of death and disability worldwide.Medical complications are frequent among individualswho have had a stroke, increasing the length of hospitalisation as well as the costs of care. Thesecomplications are a major cause of death in the acuteand subacute stroke phases.1–3 Pre-existing medicalconditions, advanced age, and pre-stroke disability canaffect an individual’s risk for developing theseevents. Patients with severe, disabling strokes areparticularly vulnerable.1,4–7 Medical complications canhinder functional recovery and are associated with poorerfunctional outcome after adjusting for stroke severity andage.1 The explanation for this association is unclear butthese events probably interfere with rehabilitative

therapies. Furthermore, fever, hyperglycaemia, systemicinflammatory response, hypoxia, or medications used totreat some of these complications might have a directlydamaging physiological effect on an injured brain ormight compromise its capability for plastic change.

Most medical complications develop within the firstfew weeks of stroke.1,6,8 Some events, such as cardiacabnormalities, dysphagia, and pneumonia, are oftenapparent early after stroke onset whereas others, such asbed sores, venous thrombosis, and falls, can occur afterseveral days. Many complications are preventable or,when this is not possible, early recognition and treatmentcan be effective in ameliorating these events early in theircourse. Therapeutic dilemmas can arise when treatment

of a systemic complication poses a potentially harmfuleffect on the stroke-injured brain. These situations requireappropriate tailoring of management strategies afterconsidering the risks and benefits of different treatmentapproaches. For example, an acute myocardial infarctionafter an acute stroke might require withholding of thrombolytic therapies and even modification of other coronary revascularisation procedures. Additionalconsiderations could involve the choice of antiplateletdrug, whether to use β blockers, or which blood pressuregoals to pursue. Other situations when standardmanagement practices might need to be altered in thecontext of a new stroke could include the use of

anticoagulants for treating deep vein thrombosis (DVT)

or pulmonary embolism in patients with intracerebralhaemorrhage or antithrombotic treatment in patientswith ischaemic stroke and gastrointestinal haemorrhage.

Several investigators have systematically collected andanalysed data on medical complications after stroke andothers have focused on specific medical events afterstroke. The reported frequency of such complicationshas varied (table) owing to differences in study designsand inception cohorts. Most studies have involved thecollection of data from an inpatient cohort either in ahospital setting or at a rehabilitation facility, enrollingpatients at different time points during their strokerecovery. Time to enrolment might have affected whichcomplications were observed; studies that were done

during rehabilitation are more likely to have omittedpatients who died from either medical or neurologicalcomplications during hospitalisation. However, patientsat rehabilitation facilities probably had more disablingstrokes than patients who were discharged from hospitalearlier, and patients with less severe deficits are likely tohave been discharged earlier. Some investigators haverelied on participants enrolled in a randomised controlledtrial for analysis; in general, these individuals mighthave been healthier than patients who have beenexcluded from trial participation owing to substantialcomorbidities. The criteria used for identifying com-plications have also varied across these studies—somehave used a retrospective case ascertainment method

from medical records whereas others were prospectivebut used different criteria. Despite these shortcomings,these reports provide useful insights into systemicmedical complications in patients with stroke.

In this Review, we discuss some of the importantmedical complications after a stroke and highlight therelevant preventive and treatment aspects of care basedon published data. We focus on non-neurological medicalcomplications of stroke with an emphasis on those thatoccur in the acute and subacute phases of stroke recovery.Only major systemic medical complications arediscussed; neurological complications such as seizures,encephalopathy, recurrent strokes, and some systemic

Lancet Neurol 2010; 9: 105–18

See In Context page 36

Department of Neurology,

Stroke Division, Beth Israel

Deaconess Medical Center and

Harvard Medical School,

Boston, MA, USA (S Kumar MD,

M H Selim MD, L R Caplan MD)

Correspondence to:

Sandeep Kumar, Department of

Neurology, Stroke Division, Beth

Israel Deaconess Medical Center

and Harvard Medical School,

330 Brookline Avenue,

Palmer 127 West Boston,

MA 02215, USA

[email protected]


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complications such as hypertension and hyperglycaemiaare beyond the scope of this paper and have not beenincluded.

Cardiac complicationsStroke and ischaemic heart disease share several riskfactors. Underlying cardiac diseases such as atrialfibrillation, valvular heart disease, or congestive heartfailure increase the risk of stroke, and stroke can provokedisturbances in autonomic control and predisposepatients to cardiac complications.10–15 The occurrence of serious cardiac events and non-stroke vascular death inpatients with stroke is therefore high.16 Data from theVirtual International Stroke Trials Archive (VISTA)reveals that most serious cardiac complications occurearly after stroke.17 Patients with congestive heart failure,diabetes, severe strokes, renal insuffi ciency, and

prolonged QTc on electrocardiogram (ECG) are atparticularly high risk.17

Myocardial infarctionA systematic review of 39 cohort studies that includedpopulation-based and hospital-based cohorts, as well asrandomised controlled trials, reported an annual linearrisk of about 2% for both myocardial infarction andnon-vascular death in patients with transient ischaemicattack and strokes.16 Most studies analysed patientsseveral weeks after their stroke. Studies that specificallyassessed the early risk of myocardial infarction andcardiac death after a stroke report a higher percentage,17,18

indicating a more immediate physiological consequenceof stroke on the cardiovascular system. Stroke-inducedautonomic dysregulation and a physiological stress

response might be the causative factors. Assays of specificcardiac enzymes, which are markers for myocardialinjury, often indicate increased concentrations after astroke.19 In many patients, these increased concentrationsare minor and below the established cut-off point for amyocardial infarction. These changes possibly indicateneurally induced myocardial damage (myocytolysis).Voxel-wise lesion analysis of infarcted brain regions onMRI have shown that infarction of the right insula isassociated with such patterns of increased enzymeconcentrations.20 However, no definite threshold levelshave been established that can reliably distinguishbetween cardiac-induced and neurally induced mech-anisms for increased enzyme concentrations.19

Accurate identification of patients who are at high riskfor coronary events might help improve surveillance andprevent such complications. Patients with establishedcoronary artery disease, diabetes, peripheral vasculardisease, and severe strokes have a higher risk of myocardial infarction early during stroke recovery thanpatients without these comorbidities.18 Patients withstroke also frequently have concomitant but asymptomaticcardiac disease, although there are no precise estimates.There seems to be a differential risk of coronary arterydisease based on the stroke subtype of the patient—individuals with large-vessel atherosclerosis generallyhave a higher prevalence of coronary artery disease than

Kalra et al4 Davenport et al5 Johnston et al1 Langhorne et al6 Roth et al7 Weimar et al2 Bae et al9 Hong et al3 Indredavik et al8

Design Prospective

(IS and HS),subacute

Retrospective


Prospective,

RCT (IS),acute-subacute

Prospective

(IS and HS),acute-subacute

Prospective


Prospective

(IS), acute

Prospective

(IS), acute

Prospective

(IS), acute

Prospective,

(IS and HS),acute-subacute

Participants 245 607 279 311 1029 3866 579 1254 489

Study setting Single-centre Single-centre Multicentre Multicentre Single-centre Multicentre Single-centre Multicentre Single-centre

Complication rate (total) 60% 59% 95% 85% 75% 29·2% 27·6% 24·2% 64%

Chest infection 12% 12% 10% 22% 4% 7·4% 10·7% 12% 11·2%

Urinary tract infection 20·4% 16% 11% 23% 30·5% 6·3% 8·3% 6·9% 16%

Fever NR 4% 16% NR NR 13·2% 1·2% 2% 24%

Pain 25·3% NR NR 43% 14·2% NR NR NR 26%

Pressure sores 3·3% 18% NR 21% 4·3% NR 1·4% 3·3% 0·6%

Falls NR 22% NR 25% 10% NR NR 2·2% 8·4%

Depression 25·3% 5% NR 16% 13% NR NR NR NR

Deep vein thrombosis 4% 3% 2% 2% 4% 0·2% NR NR 0·6%

Pulmonary embolism 1% 1% 1% 1% 1% 0·2% NR NR 0·6%

Myocardial infarction/angina NR NR 6% NR 3% 0·5% 1·2% 1·9% 4·5%

Congestive heart failure NR NR 11% NR 2% 2·9% NR NR NR

Cardiac arrest/arrhythmia NR NR 2% NR 3·2% 8·2% NR NR NR

Gastrointestinal bleed NR NR 5% NR 3·1% NR NR NR NR

Dysphagia NR NR 5% NR NR NR NR NR NR

Urinary incontinence NR NR 5% NR NR NR NR NR NR

HS=haemorrhagic stroke. IS=ischaemic stroke. NR=not reported. RCT=randomised controlled trial.

Table: Reported frequencies of medical complications after stroke



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do individuals with small-vessel disease.21 Assessment of an individual’s risk profile by use of measures such asFramingham scoring has also been suggested to screenpatients with stroke who have asymptomatic coronaryartery disease.22 However, there is a large amount of uncertainty regarding the type of cardiac tests to pursueand the optimum timing for these investigations inpatients with stroke. Use of modified cardiac stress testsin selected groups of high-risk patients might be a safeapproach for diagnosing coronary artery disease in thepost-stroke phase, although this approach requiresfurther validation.23

Cardiac arrhythmiasCardiac arrhythmias, including atrial fibrillation,supraventricular tachycardia, ventricular ectopic beats,

and ventricular tachycardia, have been observed afterstroke.12,24,25 However, there are no precise estimates of their occurrence, particularly within the first few daysafter stroke. Cardiac arrhythmias can lead to haemo-dynamic instability and can increase the risk of cardiacdeath;26 arrhythmias such as atrial fibrillation can alsoincrease the risk of subsequent brain and systemicthromboembolism. Abnormalities in ECG and cardiacarrhythmias might predate the stroke or arise as acomplication. Earlier studies have reported ECGabnormalities in patients with stroke during theirhospitalisation,24,27 although these findings might not bespecifically related to stroke and could occur from pre-existing cardiac diseases.28 More recent data show that

prolongation of QTc in individuals who have had a strokeis independently associated with decreased heart ratevariability, increased left ventricular mass, and increasedrisk of cardiac death.17,29 Prolongation of the QTc intervalmight predispose individuals to ventricular arrhythmias,although the neural substrates that cause arrhythmo-genesis remain unclear.

As with myocardial infarction, much attention hasbeen focused on the insula because of its rich connectionswith the limbic system and other brain areas of autonomiccontrol. Insular infarction is associated with abnormalcardiac repolarisation and increased risk of vascularmortality.15,26,30 In patients with right insular involvement,increased QTc interval and left bundle branch block on

ECG independently predict vascular mortality.30

Someevidence indicates that damage to the right insular regionmight also increase the risk of tachyarrhythmias.11–14,31 However, data available from these studies are stillinsuffi cient to guide practice. Future research could leadto early identification of patients at high risk forarrhythmias and might help with clinical managementand influence the duration of cardiac monitoring.

Congestive heart failure and cardiomyopathyCongestive heart failure in patients with stroke has asubstantial effect on risk of stroke fatality.17 As with othercardiac complications, few studies have separately

collated data on the incidence of congestive heart failureafter acute stroke, and estimates about new-onsetcongestive heart failure after stroke remain imprecise.New-onset myocardial infarction, arrhythmia, acutehypertension, or iatrogenic complications such as fluidoverload or changes in medications might precipitatecongestive heart failure in susceptible individuals.Careful attention to a patient’s hydration status bymonitoring daily weights and fluid intake and outputmeasurements can help prevent congestive heart failure.

A characteristic cardiomyopathy with left ventricularapical ballooning can occur as a complication of haemorrhagic or ischaemic strokes (figure 1). This stresscardiomyopathy or takotsubo syndrome is indicated by temporary ST segment elevation on a 12-lead ECG in theacute phase followed by large negative T waves, most

frequently in leads V3 and V4.32,33

Plasma concentrationsof brain natriuretic peptide can be substantially increased,although ischaemic myocardial markers are usuallywithin the normal range.34 A hospital-based clinicalcohort study from Japan reported an incidence of takotsubo syndrome of 1·2% in consecutive patientswithin the first 2 weeks after an ischaemic stroke.35 Asimilar incidence has been reported in patients withsubarachnoid haemorrhage at the Mayo Clinic inMinnesota, USA.36 Patients, particularly women, withstrokes involving the insular region or with extensivebrainstem involvement seem to have a greaterpredisposition towards developing this complication.35 Takotsubo syndrome has been associated with sudden

death, congestive heart failure, and recurrentthromboembolism;37 prompt recognition could helpavoid these events.

Pulmonary complicationsPneumoniaPneumonia is one of the most frequent medicalcomplications of stroke1–6,8,9 and the most common causeof fever within the first 48 h after an acute stroke.1,38 Afteradjusting for important confounders and covariates inindividuals who have had stroke, pneumonia led to athreefold increased risk of death.39 Most stroke-relatedpneumonias are believed to result from aspiration:1

A B C

End diastole

RV

RA LV

LA

End systole LGE

Figure 1: Cardiac MRI of a patient with takotsubo syndrome (stress cardiomyopathy)

(A) Steady-state free precession MRI shows the four chambers of the heart at the end of diastole. (B) Cardiac

chambers at the end of systole are shown; the arrows point to th e hinge point where the basal segment contracts,

but the apical to mid-segments do not contract—a characteristic finding in takotsubo syndrome. (C) LGE phase of

fat-saturated inversion recovery gradient echo sequence does not show any enhancement to indicate cardiac

scarring. LA=left atrium. LGE=late gadolinium enhancement. LV=left ventricle. RA=right atrium. RV=right

ventricle.




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inhalation of colonised bacteria that seed pharyngealmaterial or that reside in the gingival crevices can lead toaspiration pneumonia, whereas aspiration of acidicgastric contents usually produces aspiration pneu-monitis, a sterile lung injury. Aspiration pneumonitis isoften self-limited and does not require antimicrobialtherapy; occasionally it causes severe lung inflammationand acute respiratory distress. Aspiration pneumoniarequires empirical antimicrobial treatment for gram-negative bacilli and gram-positive cocci. Appearance of abnormaliites on chest radiography can be delayed,lagging behind the clinical symptoms and physicalfindings, and typically shows patchy areas of consolidation(figure 2). In aspiration pneumonitis, the radiographicopacities might resolve rapidly if precipitating factorsare controlled, whereas the opacities associated with

aspiration pneumonia can take weeks to resolve.Researchers have attempted to identify the clinicalvariables that are most associated with the risk of pneumonia in patients with stroke. Old age (>65 years),speech impairment, severity of post-stroke disability,cognitive impairment, and dysphagia were independentrisk factors in a prospective cohort of patients with acutestroke.40 Other variables favouring development of pneumonia include decreased level of consciousness,severe facial palsy, mechanical ventilation, brainstemstrokes, and infarcts in several locations.41,42 Presence of these conditions can alert the clinician to the anticipatedrisk of pneumonia in an individual patient and can affectearly decisions about further surveillance, diagnostics,

and feeding. Patients with dysphagia are at particularlyhigh risk for developing pneumonia, and severedysphagia is estimated to lead to an 11-fold increase inthis risk.43–45 Therefore, a formal evaluation of swallowingfunction and appropriate dietary modifications in patientswith dysphagia are crucial for preventing chest infections.Weakness of expiratory muscles and an impaired coughalso contribute to a high susceptibility to pneumonia in

these patients.46,47 Transcranial magnetic stimulationstudies in patients with stroke have shown that evenunilateral hemispheric strokes can lead to impairment of voluntary peak cough flow rates and other corticallycontrolled measures of expiratory muscle function,resulting in a weakened cough.48 Objective voluntarycough assessments can therefore further improveidentification of patients at risk of aspiration.47,49

The nursing of patients who are unable to handle theirown secretions in a semi-upright position with frequentoral suctioning might help decrease the risk of aspiration. Paying close attention to dental hygiene andoral care also reduces the likelihood of development of pneumonia.50 In mechanically ventilated patients,application of oral antiseptics as well as a frequent tooth-brushing regimen lowers the risk of ventilator-associated

pneumonia.51,52

The effi cacy of these measures inpreventing pneumonia has not been formally studiedin non-ventilated patients with stroke but given thesuccess in patients on ventilators with little increase inmorbidity or costs, there is a persuasive reason foradopting these measures in routine stroke care.Prophylactic broad-spectrum antibiotic treatment forprevention of infections in patients with stroke who aresusceptible to pneumonia has been investigated withconflicting results.53,54 As such, there is insuffi cientevidence to support its use for prevention of pneumonia.The consequences of such an approach, includingemergence of drug-resistant bacteria and infectiouscolitis, also warrants further consideration and

investigation in future studies.

Oxygen desaturation and apnoeaSmall hospital-based cohort studies reveal that almost20% of patients with stroke develop some degree of oxygen desaturation within the first few hours afterstroke and almost two-thirds of patients are affectedwithin the first 48 h.55–57 This drop in oxygen saturationcould aggravate brain injury by compromising oxygendelivery to penumbral brain tissue. Patients with strokecan develop hypoxaemia for several reasons. Stroke-induced brain injury can alter the central regulation of respiration, leading to sleep apnoea or producingweakness of the respiratory muscles. Additionally,

complications of stroke such as pneumonia, aspiration,atelectasis, and pulmonary emboli can impair lung airexchange. Patients with larger strokes, increased age,swallowing impairments, and pre-existing cardiac andpulmonary disease are more likely to develop oxygendesaturation.55 A daytime study of patients with acutestroke showed that major hypoxaemia mostly occurred inindividuals with pre-existing cardiopulmonary conditionsand was associated with higher mortality but not withgreater dependence than in patients without majorhypoxaemia.57

Although maintaining normal oxygen saturation is alogical goal of care, whether such brief episodes of

A B

Figure 2: Routine chest radiograph of aspiration pneumonia and aspiration pneumonitis

(A) Chest radiograph of a patient with stroke with aspiration pneumonia shows patchy right lower and middle

lobe infiltrates (arrows). (B) Dense right upper lobe opacity (arrows) in a patient with stroke who aspirated on his

vomit. The basal segments of the lower lobes are usually affected in patients who aspirate in an upright or

semi-recumbent position. The posterior segments of the upper lobe and apical segments of lower lobes are most

commonly involved when aspiration occurs in a supine position. However, any lung segment can be affected

depending on the position of the patient at the time of the event.




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desaturation have a detrimental effect on the brain isunclear.57 A small trial that used normobaric oxygentherapy in acute ischaemic stroke showed that high-flowoxygen might be associated with transient improvementsin neurological deficits.58 In patients with mild tomoderate strokes, supplemental oxygen therapy did notimprove either survival or disability.59 However, patientswith acute stroke are recommended to be monitored withpulse oximetry to maintain a target oxygen saturationlevel at or above 92%.60

Sleep-disordered breathing, including obstructivesleep apnoea and central periodic breathing duringsleep, are commonly observed in patients with acutestroke56,61,62 but the exact incidence of newly diagnosedsleep disorders after a stroke remains unknown.Sleep-disordered breathing is accompanied by episodes

of hypoxia, decreased cardiac output, and fluctuationsin blood pressure that can exacerbate brain injury. 63 Advanced age and having a reduced left ventricularejection fraction and a severe stroke are important riskfactors for developing central periodic breathing duringsleep.56,64 Stroke severity or clinical measures of majorpharyngeal weakness do not correlate well with risks forobstructive sleep apnoea; most patients with stroke withobstructive sleep apnoea have typical risk factors suchas high body-mass index and increased neckcircumference.65 Greater degrees of upper airwayobstruction during the acute stroke phase have beenassociated with poor functional outcomes.66 In mostpatients, sleep apnoea improves with time,64,67 although

it is possible that treatment of sleep apnoea during theearly phases of stroke recovery could ameliorate some of the deleterious consequences of sleep-disorderedbreathing mentioned above. Thus far, treatment of sleep-disordered breathing after an acute stroke withcontinuous positive airway pressure has beeninvestigated only in small preliminary studies with nonotable benefit.68,69 However, these results are likely tobe limited by the small study size, and larger, betterdesigned studies are necessary to provide a more reliableestimate of its treatment effi cacy.

Gastrointestinal complicationsDysphagia

Between 37% and 78% of patients with stroke developdysphagia.45 This wide range indicates differences instudy designs and investigative techniques that havebeen used to identify cases. Dysphagia leads to restrictionof oral intake, putting patients at risk of undernutritionand dehydration. Dysphagia is also a major risk factorfor stroke-associated pneumonia and is associated withpoor outcomes and institutionalisation.43,45 Although theswallowing centres are located in the lower brainstem,dysphagia occurs frequently after a unilateralhemispheric stroke.70,71 In most patients, swallowingfunctions improve spontaneously; however, in somepatients, it proves to be a long-lasting disability.72

Nutritional requirements of patients with dysphagiaare usually met via placement of a nasogastric tube. Apercutaneous endoscopic gastrostomy (PEG) is used inindividuals who remain unable to swallow after a fewdays. Although a nasogastric tube is easy to insert, it isuncomfortable and can get easily dislodged, leading totreatment failures and aspiration; PEG placement is aninvasive procedure and can be complicated by peritonitisor bowel perforation.73 Furthermore, neither of thesemethods offers any protection against aspirationpneumonia.41

Small studies have shown that feeding via PEG is moreeffective than feeding via nasogastric tube in sustainingnutrition and less likely to result in treatment failures.74 However, these studies did not adequately answerquestions about the timing (early versus delayed

treatment) and methods of feeding (nasogastric tube orPEG) after a stroke. These questions were the motivationbehind a recently concluded large multicentre trial(FOOD).75 The trial was stopped prematurely because of inadequate funds and might have been underpowered todetect more modest differences. Overall, no significantadvantages were seen for initiating early enteral tubefeeding (≤7 days of stroke onset), although patients whowere treated early showed a trend towards better survival.Feeding via PEG was associated with a non-significantincrease in the absolute risk of death of 1% (p=0·9) and aborderline significant increase in the combined absoluterisk of death or poor outcome of 7·8% (p=0·05). Thereasons for these findings are not apparent but these

results do not support early use of PEG placement inpatients with stroke. Feeding via nasogastric tube mightbe preferable for the first few weeks after stroke; thistime could also enable some patients to recuperate theirswallowing functions, as was seen in this trial.

Gastrointestinal bleedingThe frequency of gastrointestinal bleeding after strokehas been reported in some prospective studies 1,7 butdetails about severity and risks for bleeding have notbeen analysed. In a retrospective review of gastro-intestinal haemorrhage in patients with stroke, Davenportand colleagues reported a frequency of 3% in a hospitalcohort of almost 600 patients with both ischaemic stroke

and intracerebral haemorrhages, half of which weresevere.76 In a more recent study involving 6853 patientswith ischaemic strokes, 1·5% developed gastrointestinalbleeding during hospitalisation.77 The risk of gastrointestinal haemorrhage might be higher in patientsof Asian descent.78 Stroke severity, history of peptic ulcerdisease, cancer, sepsis, renal failure, and abnormal liverfunction tests are independent predictors of gastrointestinal haemorrhage after an acute stroke butuse of antithrombotic treatment or proton-pumpinhibitors and histamine 2 (H2) receptor blockers arenot.76–78 In the FOOD trial, patients who were fed vianasogastric tube had a significantly higher incidence of




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bleeding than those with PEG (p=0·005).75 Delayedgastric emptying, development of stress ulcers, andmucosal irritation from gastric feeding are some of themechanisms that are speculated to cause bleeding.Gastrointestinal haemorrhage has a statisticallysignificant effect on stroke morbidity and mortality, 76,77 and is associated with recurrent strokes, venousthromboembolism, and myocardial infarction, possiblyowing to haemodynamic instability or cessation of antithrombotic therapies and drug interactions.77,79

A systematic analysis of treatment strategies forpreventing stress ulcers in critically ill patients indicatedthat prophylactic use of H2 receptor antagonists, antacids,and sucralfate were all effective in reducing the risks of gastrointestinal bleeding, but that use of H2 receptorantagonists was associated with an increased risk of

pneumonia.80

There are no similar studies on patientswith stroke, but these drugs could potentially increasethe risk of pneumonia, particularly in high-risk patientssuch as those with dysphagia. More recent studies havereported that proton-pump inhibitors are effective forprophylaxis against stress ulcers in critically ill patients,81 although the acid suppression produced by these drugsalso seems to increase pneumonia risk.82 The otherdisadvantage of proton-pump inhibitors is a clinicallysignificant interaction between these drugs and theantiplatelet drug clopidogrel, which diminishes theantithrombotic effect of the latter.79 In the absence of more definitive data, use of these drugs for ulcerprophylaxis should be reserved for patients at substantial

risk of upper gastrointestinal bleeding. These patientsshould be carefully monitored for chest infections anddrug interactions.

Faecal incontinenceThe presence of constipation and faecal incontinence inpatients with stroke remains poorly investigated. Theoccurrence of faecal incontinence after an acute strokeis between 30% and 56%,83–85 although bowel controlimproves with time in many patients. Bowel and urinaryincontinence can coexist.83 Advanced age, large anddisabling strokes, and alterations of consciousness areimportant predictors of faecal incontinence in the acutestroke period.83,85,86 Patients requiring assistance for toilet

access because of poor mobility, loss of manual dexterity,impairment of vision, or cognition or communicationdiffi culties are more likely to have persistent faecalincontinence at 3 months after stroke.83 Use of medications with anticholinergic properties (such asantipsychotics, tricyclic antidepressants, oxybutynin, orantiemetics) significantly increases the risk of faecalincontinence in individuals who have had stroke(OR 3·1, 95% CI 1·1–10·2),83 probably by decreasing gutmotility and causing constipation with overflowincontinence.

There has been little research on this topic to guidetreatment. A systematic assessment of bowel habits by

nursing staff with a simple practice-based approachtowards bowel management and patient and caregivereducation has been shown to be helpful in patients withstroke.87 Avoiding dehydration and polypharmacy,improving toilet access, and dietary modification can allfacilitate bowel control after a stroke.

Genitourinary complicationsUrinary tract infectionsUrinary tract infections are a frequent occurrence inpatients with acute stroke.1–9 Increased age, use of urinarycatheters, stroke severity,88,89 and female sex89,90 areindependent predictors of urinary tract infections after astroke. Most patients seem to have uncomplicated urinarytract infections;1,7 some studies have found an associationbetween urinary tract infections and poor outcome88,89 but

this association is attenuated when examined in thepresence of other factors such as stroke severity andpremorbid status.88 Avoiding unnecessary catheterisationand meticulous catheter care can help prevent urinarytract infections. Use of antimicrobial-coated cathetersseems to minimise catheter-associated urinary tractinfections, at least in the short term.91 Catheter-associatedurinary tract infections are usually caused by Eschericiacoli. Polymicrobial and enterococci infections are lesscommon. Urine cultures can be helpful to confirmdiagnosis and guide appropriate antibiotic treatment.

Urinary incontinenceElderly patients with stroke can have pre-existing

diffi culties with micturition or this can develop as a newcomplication after a stroke. Overall, many hospitalisedpatients with stroke have problems with urinarycontrol.85,86,92 Incontinence can adversely affect the moraleand self-esteem of individuals who have had stroke andimpose a substantial burden on their caregivers. Thiscomplication frequently delays hospital discharge andcan lead to institutionalised care.93 In a multivariateanalysis, advanced age, lesion size, diabetes, hypertension,premorbid disabilities, and initial stroke severity weresignificant risk factors for urinary incontinence.85

Attempts to correlate the neuroanatomical site of ischaemic or haemorrhagic injury with urodynamicfindings have so far provided inconclusive results.94 In a

prospective study of patients with subacute stroke thatused urodynamic evaluations, Gelber and colleagues95 reported a high occurrence of detrusor hyper-reflexia,suggesting damage to corticospinal pathways. However,some patients in this study who were diabetic or onanticholinergic medications had a hyporeflexic bladder,suggesting that concurrent neuropathy or medication usecould cause overflow incontinence in these individuals.95 Neurological impairments after a stroke might lead to apatient being unable to use the toilet or to ask for help.Patients with an altered sensorium such as those withmore extensive brain involvement might also be unawareof their bladder needs. These individuals have worse




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outcomes compared with those with incontinence butpersevered bladder awareness.96

Several behavioural interventions that involvespecialised professional input, as well as pharmaco-therapy, have been studied in patients with urinaryincontinence after stroke in small trials. There is a largeamount of heterogeneity among these studies withregard to study designs and times to enrolment.97 Ingeneral, there is scarce evidence from these investigationsto guide practice, but systematic assessment andmanagement of urinary symptoms with specialisedprofessional input seems helpful in the acute phase of stroke recovery.97

Venous thromboembolismDeep vein thrombosis

DVT is a major concern in the post-stroke period,particularly in patients with limb paralysis. Older studiesthat used ¹²⁵I-fibrinogen screening showed a highprevalence of DVT of about 50% within the first 2 weeksafter a hemiparetic stroke, in the absence of thrombo-prophylaxis.98 The reported incidence is lower in studiesthat used venography and Doppler ultrasound.99 Aprospective study that have used MRI for direct thrombusimaging of the lower extremities and pelvis detectedvenous thromboembolism in 40% of patients (41 of 102) and pulmonary emboli in 12% of patients (12 of 102) withacute ischaemic stroke who were on aspirin and withgraded compression stockings, 3 weeks after strokeonset.100 Most DVTs develop early, possibly within the

first week of a stroke.98

Old age, severity of paralysis, anddehydration are important risk factors for the develop-ment of DVT.101–103 DVT can cause limb oedema, pain,tenderness, and fever, although it is usually asympto-matic.98,104 The most feared complication of a DVT is fatalpulmonary embolism, which has been estimated to occurin about 15% of patients with untreated proximal DVT.104 Untreated symptomatic DVT can also cause apost-thrombotic syndrome characterised by persistentlimb pain, swelling, and venous ulcerations.

Pulmonary embolismPulmonary embolism is an important cause of earlydeath after stroke. The incidence of pulmonary embolism

in patients with stroke shows great variation,99

althoughthe frequency might have declined in recent years owingto more widespread use of thromboprophylaxis (table).Most fatal pulmonary embolisms occur between thesecond and fourth weeks after a stroke. 1,105 Making adiagnosis can, however, be challenging in individualswho have had a stroke because of accompanying cognitivedeficits, speech impairment, or dysphagia. Concurrentpneumonia and fever can also complicate the clinicalpicture.106 Much vigilance is therefore necessary to makean early diagnosis and initiate timely treatment.Traditionally, ventilation/perfusion scans or pulmonaryangiograms have been used to secure the diagnosis but

newer imaging modalities such as helical CT scans andCT pulmonary angiograms are increasingly being usedfor this purpose (figure 3).

Prophylaxis with low-dose subcutaneous unfractionatedheparin (UFH) or low molecular weight heparin (LMWH)can be effective in preventing DVT and pulmonaryembolism and in lowering the risk of death in patients

with stroke, but these treatments can increase the risk of major bleeding. Many studies have investigated theeffi cacy of anticoagulation in preventing DVT andpulmonary embolism in patients with stroke. Data froma pooled analysis of 16 trials involving 23 043 patientsshowed that high-dose UFH (≥15 000 IU per day) reducedthe incidence of pulmonary embolism but led to anincreased risk of intracranial haemorrhages, whereaslow-dose UFH (<15 000 IU) decreased the risk of DVTsbut had no effect on pulmonary embolism or the risk of haemorrhage.107 High-dose LMWH (>6000 IU daily)decreased incidence of both DVT and pulmonaryembolism but was associated with an increased risk of bleeding, whereas low-dose LMWH (<6000 IU daily)

reduced the incidence of both DVT and pulmonaryembolism without an increased risk of intracranial orsystemic haemorrhage.107 Proximal or symptomatic DVTswere reported separately in only two trials that usedLMWH108,109 and in three trials that used high-doseLMWH109–111 but not in studies that used UFH; overall,there was a slight but significant reduction in theincidence of symptomatic DVTs with both low doses andhigh doses of LMWH (OR 0·19, 95% CI 0·13–0·27).107 Adisproportionately high number of patients included inthe analysis of the effect of UFH in this study werederived from the International Stroke Trial (IST),112 whereas many more participants from the Trial of

Figure 3: Appearance of pulmonary embolism on chest CT

CT scan of the chest with intravenous contrast in a patient admitted with left

hemispheric intracerebral haemorrhage who later developed restlessness and

hypoxaemia during hospitalisation. The arrows indicate the presence of thrombi

in segmental pulmonary arteries.




Review

ORG 10172 in Acute Stroke Treatment (TOAST)111 andFraxiparine in Ischaemic Stroke (FISS)109 studiescontributed to the analysis of LMWH. An open-labelledtrial (PREVAIL; Prevention of VTE After Acute IschemicStroke with LMWH Enoxaparin) involving 1762 patientswith acute ischaemic stroke and leg weakness reportedthat enoxaparin (LMWH) 40 mg subcutaneously oncedaily was more effective than UFH 5000 IU sub-cutaneously twice daily for reducing venous thrombo-embolism when started within 48 h after stroke.113 Asymptomatic DVT was the major component of thecomposite endpoint that affected the overall result, whichhas led some to question the importance of clinicalevents that were prevented with LMWH in this trial.The results, however, show that, in general, LMWHseems to have greater biological effi cacy in preventing

DVT than does UFH at the doses used, but is associatedwith a higher risk of extracranial haemorrhage. The trialdoes not fully dispel enduring uncertainties about theoptimum duration of such treatment in patients withstroke and whether all patients with stroke shouldreceive prophylactic anticoagulation for DVT prevention.Current guidelines recommend the use of subcutaneousanticoagulation with either UFH or LMWH forprevention of DVT in all patients with stroke who areimmobile or who have other risk factors.60

Management of DVT or pulmonary embolism is morecomplicated in patients with intracranial haemorrhage. Adecision analysis model has been suggested to aid decisionmaking but there are few adequate data on the risks and

benefits of anticoagulation in patients with intracranialhaemorrhage.114 Placement of an inferior vena cava filter isanother option for preventing pulmonary embolism inhigh-risk patients, although this approach can promoteDVT formation.115 No systematic studies have investigatedthe use of filter placement in patients with stroke. Earlyuse of low-dose heparin has been a concern in patientswith intracranial haemorrhage as it can provokerebleeding. Data from a small randomised trial in patientswith intracranial haemorrhage have shown that heparinprophylaxis initiated on the second day after stroke is safeand more effective in preventing pulmonary embolismcompared with treatment started at later dates (fourth ortenth day after stroke).116

Graded compression stockings and intermittentpneumatic compression has been advocated as an effectivemethod for preventing DVT that could reduce the risks of bleeding associated with anticoagulation in patients witheither ischaemic or haemorrhagic stroke. In a recentlyconcluded large multicentre trial that investigated theeffectiveness of graded compression stockings inpreventing DVT after ischaemic or haemorrhagic stroke(CLOTS trial; Clots in Legs Or Stockings after Stroke),

graded compression stockings did not reduce DVT,pulmonary embolism, or mortality, and use of thesestockings was associated with a fourfold increase in skinulcers and necrosis and a small increase in lower-limb

ischaemia.117 Use of these stockings thus poses seriousconcerns in patients with stroke as some might haveperipheral vascular disease and could have furtherreduction in blood flow to their lower extremities.

Musculoskeletal complicationsHip fracturesPatients with stroke are at increased risk for fractures,particularly those that involve the hip joint.118–120 Hipfractures are associated with high morbidity and mortalityin the elderly. In a large hospital-based study, the risk of fractures was found to be sevenfold higher during the firstyear after stroke, compared with the general population,and declined thereafter.121 This finding seems to coincidewith an increase in mobility of patients during the firstyear after their stroke putting these patients at risk for

falls.6

Elderly patients with stroke are also likely to haveage-associated osteopenia. Limb weakness and reducedweight-bearing accelerates bone loss after stroke,particularly in the paretic limbs.122,123 Use of anticoagulantscould further contribute to bone loss.124 Brittle bones aremore susceptible to fractures with trauma or falls. Beinga woman, advanced age, and having moderate disabilitiesare associated with a higher risk.118,119 Fractures in patientswith stroke predominantly involve the paretic side.125 Associated arm weakness might lead to a loss of protectivereflexes such as outstretching the arm or grabbing withhands to break the fall.

As falls are the major precipitating events of hip

fractures, all patients should be carefully assessed for riskof falls. Individuals with evidence of balance diffi culties,neglect,126 seizures,6 cognitive and motor impairments,127 or leukoariosis on brain imaging128 are at high risk. Use of sedative medications or drugs that can affect thesensorium should be minimised in patients with stroke.Use of hip protectors as shock absorbers has beenadvocated to prevent hip fracture in individuals who havehad a stroke. A pooled analysis of 15 trials has shown aslight benefit of hip protectors in elderly patients. 129 Resumption of walking within the first 2 months afterstroke, even with physical assistance, can help reducebone loss due to immobilisation.130 Supplementation withergocalciferol131 and oral bisphosphonate therapy132 also

seem to be helpful in preventing hip fractures in patientswith stroke.

PainPain assessment in patients with stroke can be diffi cult if the patient has language and cognitive diffi culties. Apopulation-based estimate has shown that pain isfrequent in individuals who have had stroke with almosta third having moderate to severe pain in the first fewmonths after stroke.133 Pain improves spontaneously inmost cases, although it can worsen with time in somepatients.133 Post-stroke pain mainly involves the limbs(particularly shoulders); headaches and pain at other




Review

body sites occur less frequently.6,133,134 Pain can interferewith physical therapy, interrupt sleep, and contribute todepression and fatigue.

The cause of pain can often be multifactorial. Elderlypatients with stroke can have pre-existing painfuldisorders such as arthritis, and decreased mobility,changes in gait, and adoption of abnormal body posturescan contribute to pain in others. A central post-strokepain syndrome can develop in a few patients withstroke.135 Most of these patients have some disruption of spinothalamic tracts with accompanying loss of sensationin the affected body parts. Central post-stroke painsyndrome can be diffi cult to treat, although smallrandomised controlled trials have shown effi cacy withamitriptyline136 and lamotrigine.137

Pain involving the shoulder joint is particularly

common after stroke and usually affects the hemipareticside.134,138,139 Loss of support to the shoulder girdle frommuscle paralysis, joint inflammation, soft tissuecontracture, and nerve injury cause this pain in mostpatients. A recent study has implicated the weakness of the vertical stabilisers of the shoulder joint, which affectglenohumeral stabilisation, as a cause of the hemiplegicshoulder pain syndrome.140 In this study, patientsfrequently had tenderness over the biceps, supraspinatus,and had a positive Neer’s sign; these three symptomsoccurred together in 13 of the 25 affected individuals.Resting hand splints, shoulder supports, and a dailypassive range of motion exercises are helpful inpreventing shoulder pain. Mild shoulder pain can

respond to analgesics and local heat or ice application.Data from small randomised controlled trials suggestthat injection of botulinum toxin in shoulder girdlemuscles is a promising strategy.141,142 Stellate ganglionblockade can be tried in more severe cases.

Other complications FatigueMany patients report substantial fatigue after a stroke,which can cause functional limitations.143 Post-strokefatigue has usually been attributed to an adjustmentreaction or depression.144,145 Patients with depression andsevere disabilities seem to be at increased risk. 146 Thecause of post-stroke fatigue is probably multi-factorial.

Physical deconditioning, associated medical ailments,and effects of medications are likely to play an importantpart. A recent population-based study has reporteda higher incidence of fatigue in patients with minorstroke (with no residual disabilities) compared withthose with transient ischaemic attack, a finding that wasindependent of confounders such as depression orother comorbidities.147 Central mechanisms might con-tribute to the development of post-stroke fatigue.147

Treatment of post-stroke fatigue needs to beindividualised with assessment and treatment of coexisting disorders such as anaemia, infection,hypothyroidism, adrenal insuffi ciency, and depression.

Pharmacological treatments including fluoxetine andtirilazad, as well as chronic disease self-managementinterventions, have been studied for post-stroke fatigue insmall trials without appreciable benefit.148 However, thesestudies have been too small to provide definite conclusions.There are two ongoing studies for treating post-strokefatigue: one is investigating the effi cacy of cognitiveintervention and graded activity training149 and the otheris assessing the use of continuous positive airway pressurein patients with sleep-disordered breathing.150

DepressionThere is much variation in the reported frequency of depression in observational studies, probably owing todifferences in methods of ascertaining symptoms of depression and differences in enrolled populations. A

pooled

estimate from population-based studies of individuals who have had a stroke indicated a prevalenceof depression of about 33% at any time during follow-up.151 There are no precise estimates on severity of depressionafter stroke, although most patients seem to have minorsymptoms of depression.152 Identification of patients withstroke who have depression can be challenging whenthere are language and cognitive impairments. Women,younger patients, and those with greater disabilities areat a higher risk of developing post-stroke depression.151,153

Disruption of neurotransmitter pathways at specificneuroanatomical sites was previously thought to producepost-stroke depression. Systematic analysis of publishedstudies, however, does not support this hypothesis. 154,155

Depression can contribute to post-stroke mortality,including suicide.156,157 Patients with depression mightalso be less likely to participate in rehabilitative therapies,be less compliant with medications, and have poorerrecovery after stroke than patients without depression.

Physicians should be vigilant about screening patientswith stroke who have depression. Specific treatmentstrategies, including counselling, cognitive behaviouraltherapy, and treatment with antidepressants, have beenused for treating post-stroke depression with variableresults. A systematic analysis involving 1655 patientswith stroke who underwent treatment for depressionafter stroke was recently published;158 this included13 trials that assessed pharmacological treatments and

four that tested psychotherapy. There was muchheterogeneity between trial designs, time to studyenrollment after stroke, outcome assessment, andmethods of analysis. Pooled data showed some effect of pharmacotherapy (ie, tricyclic antidepressants, selectiveserotonin re-uptake inhibitors, monoamine oxidaseinhibitors, and others such as flupentixol/melitracen,reboxetine, and trazadone) in improving mood but noeffect on cognitive functions, activities of daily living, orreducing disability; these drugs were also associated withsignificant adverse events. Psychotherapy was ineffectivein improving mood or overall functioning in patientswith stroke and depression and had no effect on activities




Review

of daily living or social functioning. As most patientswith stroke do not have major depression, appropriatecaution with regard to the adverse event profile should betaken when prescribing these drugs. Psychotherapy,however, seems to be helpful in preventing depressionafter stroke.159

FeverFever is a common occurrence in patients with stroke. Inone hospital-based cohort study, a prevalence of 5% wasreported among patients hospitalised within a few hoursafter an acute ischaemic stroke,160 whereas in anotherstudy almost 60% of patients with ischaemic strokedeveloped fever within the first 72 h.161 Frequency of fevermight be increased in patients with intracranialhaemorrhage; one hospital-based cohort reported anincidence of almost 90% within the first 72 h. 162 Rises intemperature are more common in patients with severestrokes.160,161,163,164 In patients with intracranial haem-orrhage, presence of intraventricular blood is an

important determinant of fever.162

Fever can indicatea systemic stress or, more likely, an underlyinginfection.161,164 In most studies, increased body temp-eratures have been slight. In a few patients, fever can becaused by an impairment of central thermoregulation.Central hyperthermia characterised by rapid onset of high fever, notable temperature fluctuation, and highmortality has been recently reported to occur with strokesinvolving the brainstem, either by direct involvement ordue to secondary compression.165

Fever can exacerbate neuronal injury by increasingmetabolic demands on injured brain tissues. Pyrexia hasbeen associated with poor outcomes in several clinical

studies, particularly in patients who have an early rise inbody temperature after their stroke.160,161,163 Theseobservations imply that prompt treatment of hyper-thermia might be effective in improving neurologicaloutcomes in these patients. However, inducedhypothermia can lead to infections, cardiac arrhythmias,haemorrhagic transformation of infarcts, and venousthrombosis.166–168 A pooled analysis of eight trials thatinvestigated the effect of lowering temperature in423 patients showed no significant difference betweenthe effects of the active treatment and the control inpreventing deaths or dependency.169 Five of these trialsassessed pharmacological means (four with paracetamoland one with metamizole), and three of these trialsstudied physical cooling (including one trial of endovascular cooling for 24 h). A recently concluded

phase 3 multicentre trial assessed the effect of routinelygiving paracetamol within 12 h of stroke symptomonset.170 A total of 1400 patients with acute ischaemicstroke or intracranial haemorrhage were enrolled. In aprespecified analysis, no difference between the placeboand paracetamol groups was seen, although a post-hocanalysis of patients with a baseline body temperature of 37–39°C showed that treatment with paracetamol wasassociated with improved outcome. These findingssuggest a potential benefit of paracetamol in patientswith febrile stroke but require further validation.

Decubitus ulcersPatients with stroke are susceptible to developing

decubitus ulcers, particularly those who are bedriddenfrom their stroke for prolonged periods of time (table).Poor mobility and incontinence increases the risk of skinbreaks. The sacrum, buttocks, and heels are the usualsites for pressure sores and should be examinedfrequently. Early mobilisation, turning the patients every2 h, use of padded heel boots, and special air mattressescan prevent their development.

ConclusionsCare of patients with stroke is often complicated by theoccurrence of adverse medical events. These events notonly affect the overall wellbeing of the patient but somecomplications, such as infections, pyrexia, and hypoxia,

can have more directly injurious consequences on thebrain. In recent years, there has been a rapid growth of modern stroke care units fuelled by reports of betteroutcomes of patients managed in these units.171 Thisimprovement in outcomes has been largely attributed tomore effective prevention as well as treatment of medicaland neurological complications that arise during strokerecovery. Nevertheless, medical complications inpatients with stroke remain inadequately researcheddespite their obvious importance in day-to-day manage-ment. Our understanding of their pathogenesis is farfrom complete, and information to guide treatmentremains inadequate. Implementing therapies by simply

Search strategy and selection criteria

References for this Review were identified through searches of PubMed, the Cochrane Library, and related articles from

January, 1970, to September, 2009, by use of the terms “stroke

and medical complications”, “cardiac complications of stroke”,

“myocardial infarction and stroke”, “cardiac arrhythmias and

stroke”, “congestive heart failure and stroke”, “infections and

stroke”, “pneumonia and stroke”, “urinary tract infection and

stroke”, “fever and stroke”, “venous thrombosis and stroke”,

“pulmonary embolism and stroke”, “dysphagia and stroke”, “

depression and stroke”, “fatigue and stroke”, “decubitus ulcers

and stroke”, “fractures and stroke”, “gastrointestinal

hemorrhage and stroke”, “fecal incontinence and stroke”,

“urinary incontinence and stroke”, “pain and stroke”, “hypoxia

and stroke”, and “sleep apnea and stroke”. Guidelines for

management of acute ischaemic stroke and intracerebralhaemorrhage by the American Heart Association and the

European Stroke Organisation were also reviewed. Articles

resulting from these searches and relevant references cited in

those articles were reviewed. Articles were also identified

through searches of the authors’ own files and talks on this

subject. Only papers published in English were included.




Review

extrapolating data from non-stroke populations isinsuffi cient for appropriate management. Fortunately,there is increasing recognition of these problems withmore recent publications in the neurological literatureon these topics. This attention has also provided a freshimpetus for research into the role of specificinterventions that can reduce the effect of suchcomplications. Close interdisciplinary collaborationbetween neurologists and other medical specialties is aprerequisite for the success of such work. Educationalefforts aimed at caregivers of individuals who have hada stroke are also needed to improve their awarenessabout these complications. It is hoped that thesemeasures will eventually translate into better care forpatients and reduce stroke-related morbidity.

Contributors

SK undertook the literature search and wrote the paper. MHS draftedand made critical revisions of this paper. LRC reviewed and made criticalrevisions of this paper.

Conflicts of interest

LRC is on the advisory boards of Boehringer Ingelheim, Genentech, LyticsLifecycle, Reneuron, NovoVision, and Avanir Pharmaceuticals. He alsoserves as an advisory consultant to Micromedex, AstraZeneca, Bayer,Takeda Pharmaceuticals, CoAxia, Millennium, Jones-Davis, andNovo-Nordisk. He has previously served on the neurology advisory boardsfor GlaxoSmithKline and Wyeth. He is on the speaker lists for BoehringerIngelheim, Bristol-Myers Squibb, Sanofi Synthelabo, AstraZeneca, andOtsuka. He gets no fixed remuneration from any of the board orconsultant activities. SK and MHS have no conflicts of interest.

Acknowledgments

SK and MHS receive grant support from the National Institute of Neurological Disorders and Stroke (5 U01 NS044876-03 and1R01-NS057127-01A1, respectively). Figure 1 provided by Yuchi Han,

Division of Cardiology, Beth Israel Deaconess Medical Center, Boston,MA, USA.

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