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Evidence basedmanagement in acute
strokePerak Stroke Update 12 Nov Hospital Taiping
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Introduction
Stroke is a global health problem and is the second commonestcause of death and a leading cause of adult disability worldwide
Ministry of Health statistics show stroke consistently as one of ttop five leading causes of death since 2000s. Data in 2009 showcerebrovascular disease causing mortality of 8.43 per 100,000
population
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Reperfusion of Ischemic Brain byThrombolysis
The rationale:
1. 80% of all strokes are caused by occlusion of a cerebral artery
2. Plasminogen a precursor of plasmin, becomes trapped amongthe fibrin strands in the thrombus
3. Endogenous tissue plasminogen activator (t-PA), cleaves theplasminogen releasing active plasmin to lyse the thrombus,however the endogenous recanalization is too slow and usuallhappens after the ischemic brain has infarcted
4. Thus the need for exogenous rt-PA
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Potential to Reverse Neurologic Impairment With ThrombolyticReperfusion
Saver. SGonzlez.Am J Neuro
Donnan. Lancet
An untreated patient losesapproximately 1.9 millionneurons every minute in
the ischaemic area
Reperfusion offers thepotential to reduce the
extent of ischaemic injury
Ischaemic core(brain tissuedestined to die)
Penumbra(salvageablebrain area)
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Drugs used in trial (Cochrane Review)
1. Urokinase
2. Streptokinase
3. rt-PA
4. Recombinant pro urokinase or desmoteplase 26 trials of 7152 patients
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Trials Using rt-PA
1. ATLANTIS A (2000)
2. ATLANTIS B (1999)
3. ECASS (1995)
4. ECASS II (1998)
5. ECASS 3 (2005)
6. EPITHET (2008)
7. HALEY (1993)
8. JTSG (1993)
9. MORI (1992)
10. NINDS (1995)
11. WANG (2003)
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History
First uncontrolled and not CT-based series in the 1960s
Streptokinase
1. First small-size Japanese randomised-controlled trials (RCTs) in theearly 1990s
2. ASK, MAST-E, MAST-I
3. Some efficacy signal < 3 hours
SK currently abandoned: high haemorrhage risk and excess mortality
1. Advent of rt-PA in the late 1980s, first dose finding studies
Large scale RCTs of rt-PA in the 1990s
rt-PA: ECASS I, NINDS (1995), ECASS II (1998), ATLANTIS (1999
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NINDS
Tissue plasminogen activator for acute ischemic stroke. The National Institutof Neurological Disorders and Stroke rt-PA Stroke Study Group
BACKGROUND: Thrombolytic therapy for acute ischemic stroke has beenapproached cautiously because there were high rates of intracerebralhemorrhage in early clinical trials. We performed a randomized, double-blindtrial of intravenous recombinant tissue plasminogen activator (t-PA) for
ischemic stroke after recent pilot studies suggested that t-PA was beneficialwhen treatment was begun within three hours of the onset of stroke
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NINDS
METHODS: The trial had two parts. Part 1 (in which 291 patientswere enrolled) tested whether t-PA had clinical activity, asindicated by an improvement of 4 points over base-line values ithe score of the National Institutes of Health stroke scale (NIHSor the resolution of the neurologic deficit within 24 hours of the
onset of stroke. Part 2 (in which 333 patients were enrolled) usea global test statistic to assess clinical outcome at three monthsaccording to scores on the Barthel index, modified Rankin scaleGlasgow outcome scale, and NIHSS
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NINDS
RESULTS: In part 1, there was no significant difference between thegroup given t-PA and that given placebo in the percentages of patientwith neurologic improvement at 24 hours, although a benefit wasobserved for the t-PA group at three months for all four outcomemeasures. In part 2, the long-term clinical benefit of t-PA predicted bthe results of part 1 was confirmed (global odds ratio for a favorableoutcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As comparewith patients given placebo, patients treated with t-PA were at least 3
percent more likely to have minimal or no disability at three months othe assessment scales. Symptomatic intracerebral hemorrhage within hours after the onset of stroke occurred in 6.4 percent of patients givt-PA but only 0.6 percent of patients given placebo (P < 0.001). Mortaat three months was 17 percent in the t-PA group and 21 percent in thplacebo group (P = 0.30).
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NINDS
CONCLUSIONS: Despite an increased incidence of symptomatiintracerebral hemorrhage, treatment with intravenous t-PAwithin three hours of the onset of ischemic stroke improvedclinical outcome at three months
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ECASS 3
Intravenous thrombolysis with alteplase is the only approvedtreatment for acute ischemic stroke, but its efficacy and safetywhen administered more than 3 hours after the onset of symptohave not been established
To test the efficacy and safety of alteplase administered betwee
3 and 4.5 hours after the onset of a stroke
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ECASS 3
assigned patients with acute ischemic stroke in a 1:1 double-blifashion to receive treatment with intravenous alteplase (0.9 mgper kilogram of body weight) or placebo
Total 821 enrolled, 418 in alteplase group and 403 in placebogroup
Median time of administration of alteplase 3hrs and 59mins
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ECASS 3
Primary endpoint:
1. Disability at 90 days (MRS 0-6)
Safety endpoint:
1. Death2. Symptomatic intracranial hemorrhage
3. Other serious adverse events
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ECASS 3
Conclusions
As compared with placebo, intravenous alteplase administeredbetween 3 and 4.5 hours after the onset of symptoms significantlimproved clinical outcomes in patients with acute ischemic strokealteplase was more frequently associated with symptomatic
intracranial hemorrhage
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Fatal intracranial hemorrhage within 7-10 days
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type 1, a multifocal or pethechial hemorrhagic infarctiotype 2, an intra-infarct hematoma
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SITS-MOST
Summary
Background The aim of the Safe Implementation of Thrombolysis in Stroke-MonitoringStudy (SITS-MOST) was to assess the safety and efficacy of intravenous alteplase asthrombolytic therapy within the first 3h of onset of acute ischaemic stroke.
Methods :6483 patients were recruited from 285 centres
Primary outcomes: were symptomatic (a deterioration in National Institutes of Healthstroke scale score of 4) intracerebral haemorrhage within 24 h and mortality at 3
months. We compared mortality, the proportion of patients with symptomaticintracerebral haemorrhage as per the Cochrane definition, and functional outcome amonths
Interpretation These data confirm that intravenous alteplase is safe and effective inroutine clinical use when used within 3h of stroke onset, even by centres with littleprevious experience of thrombolytic therapy for acute stroke.
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SITS-ISTR
Summary
Background Intravenous alteplase is approved for use within 3 h of ischaemic stroke onset, altha meta-analysis of randomised controlled trials suggests treatment benefit up to 45h. Wecompared outcome in patients treated between 3h and 45h versus those treated within 3h, whwere recorded in the in the Safe Implementation of Treatments in Stroke (SITS), a prospectiveinternet-based audit of the International Stroke Thrombolysis Registry (ISTR)
Methods: We compared 664 patients presenting with ischaemic stroke and given intravenousaltepase (09 mg/kg total dose) between 3 h and 45 h with 11 865 patients treated within 3 h.Outcome measures were symptomatic intracerebral haemorrhage within 24 h (haemorrhage typassociated with National Institutes of Health Stroke Scale [NIHSS] 4 points deterioration), andmortality and independence (modified Rankin scale of 02) at 3 months
Interpretation: Alteplase remains safe when given at 345 h after ischaemic stroke, offerinopportunity for patients who cannot be treated within the standard 3-h timeframe.
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Who will benefit?
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How to Choose
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Indications
A. Diagnosis of ischemic stroke confirmed clinically
B. Time of ischemic stroke less than 4.5hrs from onset of stroke
C. Consent obtained from patient/guardian
D. Measurable and clinically significant deficit on NIHSS scaleexamination (6-22)
E. CT brain scan does not show haemorrhage or non-vascular cauof stroke
F. Patients age >18 years ,
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Absolute contraindications
A. Time of onset unknown or wake up stroke
B. coma or severe obtundation with fixed eye deviation and complete dense hemiplegia
C. only minor stroke deficit which appears to be rapidly improving
D. seizure observed or known to have occurred at onset of stroke
E. hypertension with systolic 180mmHg or diastolic > 110mmHg on repeated measurements
F. clinical presentation suggestive of subarachnoid haemorrhage even if CT brain scan is normal
G. presumed septic embolus
H. patient has received heparin within the last 48 hours and has elevated PTT or has a known heredor acquired haemorrhagic diathesis (PT or APTT greater than normal)
I. INR >1.7
J. Platelet count
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IV alteplase 0.9mg/kg (max 90mg)
10% to be given IV bolus
Remaining 90% to be given over 1 hour infusion
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Blood Pressure
Hypertension
Management of BP in acute stroke is controversial
Acute stroke, due to infarction or haemorrhage, is associated whigh BP in about 75% of patients (Britton et al.,1986;Oppenheimer et al.,1992)
Rapid lowering of BP by I.V nimodipine was shown to increase riof neurological deterioration (Wahlgren et al., 1994; Ahmed et a2000 INWEST trial)
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Blood Pressure
Interventions for deliberately altering blood pressure in acute stroke (Cochrareview 2008)
Twelve trialsinvolving 1153 participants were included (603 participants weassigned active therapy and 550 participants received placebo/control).Thetrials tested angiotensin converting enzyme inhibitors (ACEI), angiotensinreceptor antagonists (ARA), calcium channel blockers (CCBs), clonidine, glyctrinitrate (GTN), thiazide diuretic and mixed antihypertensive therapy. One t
tested phenylephrine. Insufficient evidence to evaluate the effect of altering blood pressure on
outcome during the acute phase of stroke. In patients with acute stroke, CCBACEI, ARA and GTN each lower blood pressure while phenylephrine probablyincreases blood pressure. Functional outcome and death were not altered bythe drugs
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Blood Pressure
Routine BP lowering in not recommended, except for extremely elevavalues ( >220-220mmHg sys BP or >120mmHg diastolic BP for ischemicstroke ) confirmed by repeated measurements
As a general rule lower BP by 10-15%; With prior hypertension, 180/100-105mmHg Without prior hypertension, 160-180/90-100mmHg;
Considering thrombolysis, lower BP below 180/110mmHg before commencingthrombolysis
Recommended drugs
IV labetolol, IV GTN, oral captopril
Avoid sublingual nifedipine
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Antiplatelet
Aspirin started within 48hrs of onset of presumed ischemic stroke isassociated with a small risk of bleeding (2 extra symptomatic ICHs andmajor extracranial hemorrhages for every 1000 patients treated)
Reduced recurrent ischemic stroke 7 in 1000
Net effects for every 1000 patients with acute ischemic stroke who artreated early with aspirin, there are 5 fewer early recurrent strokes oany type and in long term 13 fewer patients who are dead or depende
Among those alive and independent extra 10 recovered completely
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Antiplatelet implication for practice
Aspirin should be given as soon as possible
As benefits of aspirin have been proven in the long-term secondprevention of recurrent ischaemic stroke, aspirin should bestarted even if a patient presents with stroke after 48hrs
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Antiplatelet
Aspirin administered within 48hr of onset of acute ischaemicstroke reduces odds of PE (OR:0.71,95% CI:0.53 to 0.96)(Antiplatelet Trialists Collaboration, 1994).
Reduces the absolute risk of early recurrent ischaemic stroke ( babout 0.7% ) and the risk of VTE ( by about 0.1% ) without causi
an excess of haemorrhagic stroke. There is also long term beneffrom aspirin in reducing death and dependency (1.2%)
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Antiplatelet
Long term secondary prevention Aspirin vs control (IST 1997, CAST 1997)
1. High vascular risk factor (past history of stroke, myocardial infarction,peripheral artery disease or diabetes), aspirin reduced the relative risk (RRthe composite outcome of stroke, MI or death due to - vascular causes by 1compared to placebo
2. TIA and ischemic stroke patients, aspirin reduced the RR of recurrent seriovascular events by about 13%
- Adverse effects: dose dependent excess upper gastrointestinal upset, andabout 60-70% relative excess of non fatal extracranial hemorrhage (absolutexcess risk of about 2/1000 patients treated per year and an increased riskICH of about 1/1000 patients treated for 3 years
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Long Term Secondary Prevention
Dipyridamole vs control
1. High vascular risk patients: reduced RR of serious vascular events byabout 10% (95% CI:2-17%). There was no evidence that dipyridamole ismore effective in preventing vascular death vs control (RR:1.02, 95% C0.90-1.17)(De Schryver et al.,2002,2003)
2. TIA and ischemic stroke: reduced RR of serious vascular events by 13%(95% CI: 4-21%) (Diener et al., 1996; De Schryver et al.,2002,2003)
3. Adverse events : headache, may cause GI upset
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Long term Secondary Prevention
Ticlopidine1. High vascular risk patients: ticlopidine 250mg bd is associated with 32%
reduction in odds of subsequent major vascular events over 2-3 years2. Ischemic stroke patients: reduction in the RR of serious vascular events 23
(95% CI: 1.0-40.5%, P=0.02)3. Adverse events:
a) similar incidence of major bleeding vs placebo but twice as many minor bleedi
episodes (6.5% vs 3.0% placebo)b) Neutropenia/ pantocytopenia
c) Thrombotic thrombocytopenia purpura
d) GI upsete) Skin rash
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Long Term Secondary Prevention
Aspirin and dipyridamole vs control1. High vascular risk patients: reduce RR by 26%, 95% CI:20-32%) (Antithromb
Trialists Collaboration,2002; De Schryver et al.,2003)
2. TIA and ischemic stroke patients: 39% reduction in odds of stroke (LeonaBee et al.,2005)
3. Adverse eventsa) Headache
b) bleeding
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Long Term Secondary Prevention
Dipyridamole vs aspirin High vascular risk patients: no evidence dipyridamole is more effective i
preventing vascular events compared with aspirin
Ticlopidine vs aspirin High vascular risk patients: ticlopidine does not significantly reduce the
of serious vascular events compared to aspirin
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Long Term Secondary Prevention
Clopidogrel vs aspirin1. High vascular risk patients: reduces RR of stroke and all serious ischem
vascular events by 8.7% (95% CI: 0.3-16.3%)compared with aspirin (CAPRSteering Committee, 1996)
2. TIA and ischemic stroke patients: for patients with previous TIA orischemic stroke, clopidogrel does not significantly reduce the risk ofserious vascular events compared with aspirin
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Long Term Secondary Prevention
Aspirin plus clopidogrel vs clopidogrel1. TIA and ischemic stroke patients: combination did not significantly
reduce ischemic stroke, MI, re-hospitalization for acute ischemic even(MATCH trial)
2. Adverse effects: combination was associated with a significant increaslife threatening hemorrhage.
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Implication for Practice
If patient with TIA or ischemic stroke due toatherothromboembolism and is not taking antiplatelet consideraspirin if they are low risk of a recurrent ischemic event,clopidogrel if intolerant to aspirin, and clopidogrel or combinatof aspirin and dipyridamole if at high risk of a recurrent eventischemic event.
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Implication of practice
If taking aspirin then consider stopping aspirin and startclopidogrel or adding dipyridamole to aspirin
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Dual Antiplatelet
Randomized, double blind, placebo controlled trial in 114 centrin China randomly assigned 5170 patients within 24hrs after minischemic stroke or high risk TIA to clopidogrel (300mg stat and75mg od for 90days ) and aspirin (75mg od for 21 days ) vs placeand aspirin ( 75mg od for 90 days )
Results: addition of clopidogrel to aspirin reduced the relative rof recurrent stroke at 90 days by 32% ( 8.2% vs 11.7% ) withoutsignificant increase in haemorrhagic stroke. (CHANCE trial Wanet al 2013 )
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Antiplatelet and Anticoagualant
Truly un-confounded, randomised-controlled trials comparinganticoagulants with antiplatelet agents, or anticoagulants andantiplatelet agents with antiplatelet agents alone, given within days of onset of presumed or confirmed ischaemic stroke
A total of 16,558 patients from four trials contributed to theanalyses. The methodological quality was high in all four trials.
The anticoagulants tested were unfractionated heparin (UFH) alow molecular-weight heparin. Aspirin was used as control in alltrials
Anticoagulants offered no net advantages over antiplatelet agenin acute ischaemic stroke ( Cochrane review )
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Anticoagulation for patients with acuteischemic stroke in atrial fibrillation (AF)
Patients with acute ischemic stroke who are in AF, no evidencethat early anticoagulation within first few weeks improvesoutcome compared with no heparin (Cerebral Embolism StudyGroup, 1983; Saxena et al.,2001) or compared with aspirin (Beret al.,2002)
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Heparin vs No Heparin
18,451 patients randomised within 48hrs of onset of acuteischaemic stroke in the IST to 14 days treatment withsubcutaneous UFH or control, 3169 patients (17%) were in AF, ofwhom 784 were randomly allocated to UFH 12,500 U s.c. bid 77to UFH 5000U s.c. bid and 1612 to no heparin. Within each ofthese groups, half of the patients were randomly assigned to
aspirin 300mg od No effect of heparin on the proportion of patients dead or
dependent at 6mths was apparent
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Heparin vs Aspirin
The Heparin in Acute Embolic Stroke Trial (HAEST) compare theffect of LMWH (dalteparin 100U/kg sc bd) started within 30hrsstroke onset, with aspirin (160mg od), on the prevention ofrecurrent stroke during the first 14days among 449 patients witacute ischemic stroke and AF (Berge et al.,2000). The frequencyof recurrent ischemic stroke during the first 14days was 19/244
(8.5%) in dalteparin patients vs 17/225 (7.5%) in aspirin patients There was no benefit of dalteparin compared with aspirin on
secondary events during the first 14 days.
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Anticoagulation
Present data do not provide any evidence that UFH or LMWH issuperior to aspirin or no heparin for the treatment of acuteischaemic stroke in patients with AF
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Blood Glucose
Hyperglycaemia after stroke is associated with a poor outcome(Capes et al.,2001; Parsons et al., 2002; Lindsberg & Roine, 200
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Blood Glucose (Cochrane review)
Background:
Patients with hyperglycaemia concomitant with an acute strokehave greater stroke severity and greater functional impairmentwhen compared to those with normo glycaemia at strokepresentation
Objectives:To determine whether maintaining serum glucose within a specificnormal range (4 to 7.5 mmol/L) in the first 24 hours of acuteischaemic stroke influences outcome
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Blood Glucose
Cochrane Stroke Group Trials Register (June 2010), CENTRAL (TheCochrane Library 2010, Issue 2), MEDLINE (1950 to June 2010),EMBASE (1980 to June 2010), CINAHL (1982 to June 2010), ScienceCitation Index (1900 to June 2010), and Web of Science (ISI Web oKnowledge) (1993 to June 2010)
Selection criteria:
Eligible studies were randomised controlled trials comparingintensively monitored insulin therapy versus usual care in adultpatients with acute ischaemic stroke
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Blood Glucose
Main results: No difference in the treatment groups and control groups in the outcome of
death or disability and dependence or final neurological deficit. The rate ofsymptomatic hypoglycaemia was higher in the treatment group.
Authors conclusions
With the current evidence, we found that the administration of intravenousinsulin with the objective of maintaining serum glucose within a specific rangin the first hours of acute ischaemic stroke does not provide benefit in terms
functional outcome, death, or improvement in final neurological deficit andsignificantly increased the number of hypoglycaemic episodes. Specifically,those who were maintained within a more tight range of glycaemia withintravenous insulin experienced a greater risk of symptomatic andasymptomatic hypoglycaemia than those individuals in the control group
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Blood Glucose
Unless blood sugar is known, no glucose solution should be givento a stroke patient due to the potential detrimental effects ofhyperglycemia
Rapid correction of low blood glucose with iv dextrose bolus orinfusion of 10-20% glucose, avoid hypotonic solutions (NaCl 0.45or glucose 5%) to minimise brain oedema
Empirical recommendation to try to maintain the blood glucosewithin normal limits, and to actively correct blood glucose leveabove 15mmol/l (European Stroke Initiative, 2004 recommends lower raised blood glucose to about 10mmol/l and ASA aim forblood glucose
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Brain oedema
Hyperventilation:
Hyperventilation sufficient to reduce PCO2 by 5-10mmHg canlower ICP by 25-30% (Gujjar et al., 1998)
It also causes vasoconstriction that might compromise brainperfusion and aggravate ischaemia
It probably be used as temporary measure whilst preparing tointervene definitely
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Brain oedema
Corticosteroids:
Systemic review of 7 RCTs involving 453 patients with acuteischaemic stroke revealed that compared to control,corticosteroid treatment within 48hrs of stroke onset made nodifference to the odds of death within 1 mth or 1 yr
It also does not improve survival after haemorrhagic stroke
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Brain oedema
Osmotic diuresis:
Mannitol (0.25-0.5g/kg) iv over 20 min lowers ICP. It can be giveevery 6hrs to a max daily dose of 2gm /kg.
There is not enough reliable evidence to determine whethermannitol is effective or ineffective in patients with cerebral
oedema due to ischaemic or haemorrhagic stroke
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Brain oedema
CSF fluid drainage:
Via intra ventricular catheter can rapidly lower ICP ifhydrocephalus is present, but has not been evaluated in RCTs
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Brain oedema
Surgical decompression:
Uncontrolled studies suggest that those most likely to benefit ayounger patients with infarction confined to MCA territory, whoare developing brain oedema and deteriorating clinically, but donot have established signs of transtentorial herniation (eg notunconscious) and who are operated on early rather than late
(Brown,2003; Donnan and Davis, 2003; Schwab and Hacke,2003)
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Brain oedema
Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial.
Hofmeijer J, Kappelle LJ, Algra A, Amelink GJ, van Gijn J, van der Worp HB;HAMLET investigators.
Collaborators (21)
Source
Department of Neurology, Rijnstate Hospital, Wagnerlann 55, Arnhem, Netherlands. [email protected]
Abstract
BACKGROUND:
Patients with space-occupying hemispheric infarctions have a poor prognosis, with case fatality rates of up to 80%. In a pooled analysis of randomised trials, surgical decompression within 48 h of stroke onset reduced case fatality and improved functionahowever, the effect of surgery after longer intervals is unknown. The aim of HAMLET was to assess the effect of decompressive surgery within 4 days of the onset of symptoms in patients with space-occupying hemispheric infarction.
METHODS:
Patients with space-occupying hemispheric infarction were randomly assigned within 4 days of stroke onset to surgical decompression or best medical treatment. The primary outcome measure was the modified Rankin scale (mRS) score at 1 year, which dichotomised between good (0-3) and poor (4-6) outcome. Other outcome measures were the dichotomy of mRS score between 4 and 5, case fatality, quality of life, and symptoms of depression. Analysis was by intention to treat. This trial is registered,ISRCTN94237756.
FINDINGS:
Between November, 2002, and October, 2007, 64 patients were included; 32 were randomly assigned to surgical decompression and 32 to best medical treatment. Surgical decompression had no effect on the primary outcome measure (absolute risk redu0%, 95% CI -21 to 21) but did reduce case fatality (ARR 38%, 15 to 60). In a meta-analysis of patients in DECIMAL (DEcompressive Craniectomy In MALignant middle cerebral artery infarction), DESTINY (DEcompressive Surgery for the Treatment of malignanthe middle cerebral arterY), and HAMLET who were randomised within 48 h of stroke onset, surgical decompression reduced poor outcome (ARR 16%, -0.1 to 33) and case fatality (ARR 50%, 34 to 66).
INTERPRETATION:
Surgical decompression reduces case fatality and poor outcome in patients with space-occupying infarctions ware treated within 48 h of stroke onset. There is no evidence that this operation improves functional outcomewhen it is delayed for up to 96 h after stroke onset. The decision to perform the operation should depend on emphasis patients and relatives attribute to survival and dependency. (HAMLET)
http://www.ncbi.nlm.nih.gov/pubmed?term=Hofmeijer%20J[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Kappelle%20LJ[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Algra%20A[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Amelink%20GJ[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Gijn%20J[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=van%20der%20Worp%20HB[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=HAMLET%20investigators[Corporate%20Author]http://www.ncbi.nlm.nih.gov/pubmed?term=HAMLET%20investigators[Corporate%20Author]http://www.ncbi.nlm.nih.gov/pubmed/19269254http://www.ncbi.nlm.nih.gov/pubmed/19269254http://www.ncbi.nlm.nih.gov/pubmed?term=HAMLET%20investigators[Corporate%20Author]http://www.ncbi.nlm.nih.gov/pubmed?term=van%20der%20Worp%20HB[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=van%20der%20Worp%20HB[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=van%20der%20Worp%20HB[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=van%20der%20Worp%20HB[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Gijn%20J[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Gijn%20J[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Gijn%20J[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=van%20Gijn%20J[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Amelink%20GJ[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Amelink%20GJ[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Amelink%20GJ[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Algra%20A[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Algra%20A[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Algra%20A[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Kappelle%20LJ[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Kappelle%20LJ[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Kappelle%20LJ[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Hofmeijer%20J[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Hofmeijer%20J[Author]&cauthor=true&cauthor_uid=19269254http://www.ncbi.nlm.nih.gov/pubmed?term=Hofmeijer%20J[Author]&cauthor=true&cauthor_uid=192692548/13/2019 Evidence Based Management in Acute Stroke
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