IMPACT OF CURRENT MANAGEMENT OF ISCHAEMIC STROKE ON A GENERAL INTENSIVE CARE UNIT

Dr Aung Lwin Locum Consultant – Acute Medicine Norfolk & Norwich University Hospital

Aims and objectives

 To inform the evolving management of ischaemic stroke relevant to intensive care   To review the evidence of decompressive hemicraniectomy in the management of malignant middle cerebral artery territory infarction over last 10 years To help ICU physicians in decision-making in managing this particular group of patients

Outlines

        Background Clinical problem Brief notes on thrombolysis Malignant MCA Infarction Syndrome Decompressive Hemicraniectomy Current Evidence on efficacy Summary of Evidence Conclusion

BACKGROUND

How big is the problem?

   3 rd leading cause of death in developed countries 1  174 to 216 people per 100,000 population each year 2 In 1999, 11% of all deaths in England and Wales 2 Estimated to cost the economy around £7 billion per year in England 3 1. Wolfe C et al 2002: Incidence and case fatality rates of stroke 2. Mant J et al(2004): Health Care Needs Assessment 3. National Audit Office (2005)

Current Acute Ischaemic Stroke Management

  Established  Thrombolysis  Antiplatelet Emerging  Intra-arterial thrombolysis  Abciximab  Decompressive Hemicraniectomy

Clinical Problem

    Mr T B, 62 year old man with sudden collapse No PMH Right Leg Pain for 1 week GCS 12/15, Alert, Aphasic, dense right hemiplegia  Hypoxia, BP 120/80, normal CXR

Questions

Diagnosis/es?

Would you recommend thrombolysis?

Brief notes on Thrombolysis in Acute Ischaemic Stroke (AIS)

NINDS t-PA study.NEJM 1995; 333:1581-1587

 624 patients (18-80 yr) randomside to tPA or placebo  Within 3 hours of clear onset  Improved survival with good functional outcome (mRS<3) at 3 months   Odd ratio 1.7 (1.2-2.6), ARR 12%, RRR 32% Symptomatic ICH 6.4% vs. 0.6% ( ↑ pt with >deficit, NIHSS >20 vs. 14)  NIHSS > 4 and < 25

Cochrane Systematic Review (Wardlaw JM et al 2003)

  Within 3 hour  >effective in ↓ death or dependency [OR 0.66] with no statistically significant adverse effect on death [OR 1.13] Up to 6 hour   Net reduction in death or dependency at 3-6 months [OR 0.84] ↑ in odds of death within 10 days [OR 1.81] and fatal intracranial haemorrhage [OR 4.34]

Beyond 3hr window (<6 hr)

  Onging – IST 3 trial Intra-arterial thrombolysis in middle cerebral artery infarct and basilar artery infarct* * PROACT II trial. Neurology. 2001 Nov 13;57(9):1603-10

Clinical Problem continued

     Diagnosis:  Acute Ischaemic stroke presumed 2º venous embolism via PFO  DVT and PE Started on heparin infusion 4 hour later, sudden neurological deterioration (agitated).

Medic wants to do CT scan. Referred for ?endotracheal intubation

Would you intubate and ventilate stroke patients?

Futility Rationing

Futility. Does MV save life?

 Bushnell CD et al  131 patients ventilated in NICU  6 month mortality 61%  Mayer S et al.

 30 day mortality was 65% (50% for AIS)  mean ICU (LOS) 18.4 ± 17.4 days  The cost per QALY saved was $174 200*  Milhaud D et al  1 year mortality 70% *1996 $

Holloway R et al. JAMA 2005;294 (6):725-733     Mean age was 64 (59 to 75 ) yr Mortality: Inpatient 55% (48-70%), 30 day 58% (46 – 75%), 1 to 2 year 68% (59 -80%) A third of survivors had no or slight disability In one study with 27 AIS patients survived up to 3 year, 63% had no or minimal cognitive impairment [MMSE > 24]

Clinical Problem continued

     Intubated in A&E CT head (non-contrast) scan performed Admitted to ITU Extubated soon after admission 6 hr later, GCS drop to 8/15

HMCA Sign

What is the next course of action?

A.

Let the nature take it course?

B.

Re-intubate and repeat CT head? If so, for what?

A or B ?

What are the causes of sudden deterioration in AIS?

Weimar C et al.

Arch Neurol 2005     256/ 1964 patients (13%) had NIHSS ≥1 point after 48 to 72 hour 127 (6.5%) patients and 43 patients (2.2%) were intubated Attributable to  Progressive stroke (33.6%)  Increased ICP (27.3%)  Recurrent cerebral ischaemia (11.3%)  Secondary parenchymal haemorrhage (10.5%) Worsening of the NIH-SS ≥4: sensitivity 68.9%, specificity 68.4%  Internal carotid occlusion [OR 3.323 (2.008 – 5.501), p<0.001]  Middle cerebral artery (M1) occlusion [OR 3.019 (1.979 – 4.604), p<0.001]  territorial infarction [OR 1.917 (1.246 – 2.948), p = 0.003]

Malignant Middle Cerebral Artery Infarction Syndrome (MMCAIS)

Malignant Middle Cerebral Artery Infarction Syndrome   Large hemispheric infarction involving >50% of MCA territory associated with a massive cerebral oedema and brain-stem herniation Caused by complete/ near complete occlusion of either internal carotid artery (ICA trunk) or proximal middle cerebral artery

MMCAIS

  Dense pyramidal signs (initial) Neurological deterioration < 24-72 hr 1 due to elevated ICP leading to brain stem herniation  Very high mortality despite maximal medical treatment   70% (37/ 53 ) died in NICU (33/37 died within first 5 days) 2 78% (35/45) died within 1 week 1 1. NG L et al.

Stroke

1970 2. Berrouschot J et al. ICM 1998

How Common

Study

Ng L et al 1970 Berrouschot J et al. 1998 Kasner S et al, 2001 Qureshi AI et al 2003 Wang KW et al 2006

MMCAIS

45 /353 supratentorial infarcts 53/221 supratentorial infarcts 201/ 12000 stroke patients 59 /1214 supratentorial infarcts 40/418 MCA infarct 12.74% 23.9% 1.675% 4.859% 9.5% Reported between 5 to 10% of Acute Ischaemic Stroke.

Decompressive Hemicraniectomy (DH)      1 st described by Kocher in 1901 for the treatment of TBI 1 st reported by Rengachary S et al.

1 for the treatement of MMCAIS in 1981 Removal of an ipsilateral bone flap ≥ 12 cm in diameter and including parts of the frontal, parietal, temporal and occipital squama plus Duraplasty To relieve ICP Inadequate craniectomy size is associated with parencymal haemorrhage ± infarction and increased mortality 2 1.

2.

Rengachary S et al Wagner S et al.

Neurosurgery

1981: vol 8/3, 321-328

Journal of Neurosurgery

, May 2001, vol./is. 94/5(693-6)

Current Evidence on efficacy of DH in management of Malignant Middle Cerebral Artery Infarction Syndr0me

Does decompressive hemicraniectomy improve outcomes in management of malignant MCA infarction syndrome?

    Survival (mortality) Functional outcomes: impairment, disability, quality of life. Dependency = GOS 2 or 3, mRS 4 to 5, BI < 60.

Can we predict malignant brain oedema? Timing: when to operate?

Literature Search

  Ovid Medline, Embase, Cochrane & finally handsearch keywords “stroke, middle cerebral artery infarction, brain oedema, decompressive hemicraniectomy and decompressive surgery” from January 1998 to July 2009   Medline – 165, Embase 465, Cochrane 17 3 RCTs, one meta-analysis, 3 SR, 50 observational studies

Scoring system

  NIHSS  National Institute Health Stroke Scale  Motor / sensory / speech / vision  11 parts, scores -40  >25 severe stroke Barthel Index (BI)  Assess disability in regards to activity of daily living  Total score 0-100  Dependency - Score < 60

Scoring system

3 5 0 1 2 4 6  Modified Rankins Score No symptoms at all No significant disability despite symptoms; able to carry out all usual duties and activities Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance Moderate disability; requiring some help, but able to walk without assistance Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance Severe disability; bedridden, incontinent and requiring constant nursing care and attention Dead

Scoring system

 Glasgow Outcome Score 1 2 3 4 5 Dead

Persistent vegetative state

Patient exhibits no obvious cortical function.

Severe Disability

(Conscious but disabled). Patient depends upon others for daily support due to mental or physical disability or both

Moderate Disability

(Disabled but independent). Patient is independent as far as daily life is concerned. The disabilities found include varying degrees of dysphasia, hemiparesis, or ataxia, as well as intellectual and memory deficits and personality changes.

Good Recovery

Resumption of normal activities even though there may be minor neurological or psychological deficits.

Case series

  30 case series (4 prospective)  Early mortality : mean 23% (range 7% to 60%) [18 studies] Long term mortality, ≥6 months to 3.4 yr : mean 29.68% (15.7% to 49%) [19 studies]  

Barthel Index - mean 45 to 80 [9 studies] mRS – no/ mild in 20%, moderate/severe in 50% (9 studies)



GOS – similar to mRS

Comparative Studies

  Schwab et al – 63 pts, Early (<24 hr, b/4 MLS) vs. Late (>24 h), early mortality was 16% vs. 34.4% and BI 68.8 vs. 62 Cho et al – 52 pts, (<6h vs. > 6 h vs. Medical), early mortality ( 7.8% vs. 36.7% vs. 80%), better BI (70)and GOS (4)  6 studies compared DH with medical Rx. Early mortality was 4.8% - 21% in DH whereas 42-83% in Medical groups

Different outcomes in non randomised studies   Age Timing of surgery – before or after signs of brain herniation  Additional vascular territory involvement

Can we predict brain oedema?

 Kasner S et al, 2001  Hypertension, heart failure, ↑ WBC  CT - > 50% hypodensity and additional vascular involvement  Hofmeijer J et al 2008  Infarct size > 66%  additional vascular involvement  Thormalla G et al 2003  Quantitative analysis of early DWI & PWI can predict MMCAI

Systematic Reviews

  Cochrane (Morley N et al, 2002) – no RCT evidence to support DH (reviewed non randomised studies from 1971-2001) Hofmeijer J et al (CCM 2003; 31/2: 617-25) - 2 large non-randomised studies showed promising results in terms of reduction in mortality and functional outcome

Juttler E et al (DESTINY) 2007, Germany (RCT)       Age 18 to 60 years with clinical signs of MCA territory infarction Severity - NIHSS >18 for (D) and ≥ 20 for (ND) lesions, CT - ≥ 2/3 of MCA territory, Concious level - score ≥ 1 on item 1a of NIHSS Timing onset >12 hr and < 36hr , possibility to start within 6 hr after randomization       Surgery (n=17) vs. medical (n=15) Mean age: 43.2±9.7 vs 46.1±8.4

Dominant side 53% vs. 73% Median NIHSS 21 vs.24

Time to surgery 24.4±6.9 h 30 day survial : 88% vs. 47% mRS 0-3: 47% vs. 27% (NS)

Vahedi et al 2007 (DECIMAL), France

    Onset within 24 hr of malignant MCA infarct defined by – 3 criteria: NIHSS ≥ 16 (including score ≥ 1 on item 1a), CT ischaemic signs > 50% of MCA territory, DWI infarct volume > 145 cm 3       Surgery (n=20) vs. medical (n=18) Mean interval to surgery20.5 ± 8.3 (7-43) hr Mean age 43.5 ± 9.7 vs. 43.3 ± 7.1 yr 28 day mortality: (25%) vs. (77.7%), p<0.0001

mRS ≤ 3 at 12 months: 50% vs. 22.2% (NS) mRS ≤ 4 at 12 months: 75% vs. 2.2% (p 0.0029)

Hofmeijer et al 2009 [HAMLET] – Netherland

     Age 18 to 60 years with clinical signs of MCA territory infaction Severity - NIHSS >16 for (ND) and ≥ 21 for (D) lesions, CT - ≥ 2/3 of MCA territory + formation of space occupying oedema Concious level - GCS ≤ 13 for (R) or ≤ 9 for (L) Timing onset < 96hr , possibility to start within 3 hr after randomization      64 (DH vs. Medical) Age 50 vs. 47 yr Mean interval of randomisation – 31 hr Mortality 21 vs. 59% (ARR 38%, p 0.002) mRS 4-6 - no diff

Pooled analysis of 3 RCTs

At 12 month

mRS > 3 mRS > 4 Death

Surgery

35/58 – 60.3% 19/58 – 32.7% 12/58 – 20.6%

Medical

39/51 – 76%

ARR

16.3% (- 0.1- 33.1) 38/51 – 74.5% 41.9% (25.2 to 58.6) 36/51 – 70.5% 49.9% (33.9 to 65.9) 109 patients included (DESTINY+DECIMAL+ HAMLET) Inclusion – within 45 hr (DH < 48 hr) NNT To prevent mRS > 3 at one year is 6 To prevent mRS > 4 at one year is 2 To prevent death at one year is 2

Summary of Evidence

   Decompressive Hemicraniectomy if performed early (< 48 hr) improve survival and functional outcome in patients (< 60 yr) with malignant MCA infarction [RCT confirms the results of observational study) Level of evidence 1 + , Grade B Recommended by National Clinical Guideline for Stroke, 4.6.1.k, 3 rd edition July 2008

Future

 Quality of life by SF36 and SIS, and Aphasia by Aachen aphasia test at 2-3 year from DESTINY trial are still awaited  4 Ongoing trials  HeaDDFIRST  HeMMI  DEMITUR  DESTINY 2  Economic Assessment  ? DH + Therapeutic Hypothermia

Conclusion

 Malignant MCA syndrome should be considered   For ICU oncall - If indicated, mechanical ventilation should be offered in appropriate patients (age < 60 y, no significant comorbidity) Decompressive surgery is aggressive but life saving and should be discussed with patient/ family  Need s a hospital guideline agreed by all parties involved

Thank you