TARGETS IN NEURO-ICU

DR P. JANIN

RNSH – ICU

24.09.2013

The Case of ICH

BLOOD PRESSURE MANAGEMENT IN PATIENTS WITH ICH

PROGRESS STUDY

¡ Perindopril vs Perindopril +Indapamide vs Placebo

¡ >6000 patients (mean age 64y) ¡ Normal BP or HTN ¡ Stroke, TIA ≤ 5 y ¡ Mean baseline BP 147/86

The Lancet, 358 (9287), 1033 - 1041, 29 September 2001

PROGRESS STUDY

MODERN CONCEPT: HEMATOMA EVOLUTION

3 hrs 6 hrs

Onset-CT Interval (hrs)

Prospective Retrospective Brott 1997 Fujii Kazui Takizawa

0-3 38% 18% 36% 17%

3-6 N/A 8% 16% 6%

6-24 N/A 2% 10% 0%

 Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot

trial.

Lancet Neurol. 2008 may;7(5):391-9. Anderson CS, huang Y, wang JG, arima H, neal B, peng B, heeley E, skulina C, parsons MW,

kim JS, tao QL, li YC, jiang JD, tai LW, zhang JL, xu E, cheng Y, heritier S, morgenstern LB, chalmers J; INTERACT investigators

Mean (95%CI) systolic BP differences

Δ 14 mmHg at 1 hour (P<0.0001) Δ 10.8 mmHg 1-24 hours (P<0.0001)

6

2

-2

Absolute increase in hematoma volume

Guideline Intensive

30

10

-5

Relative increase in hematoma volume

Guideline Intensive

0

4 20

0

P=0.13 P=0.06

Δ-10% Δ-1.7ml

ml %

Adjusted mean (95%CI) values for absolute and relative increase in hematoma volume

5. Patients with ICH should have intermittent pneu-matic compression for prevention of venous throm-boembolism in addition to elastic stockings (Class I;Level of Evidence: B). (Unchanged from the previousguideline)

6. After documentation of cessation of bleeding, low-dose subcutaneous low-molecular-weight heparin orunfractionated heparin may be considered for pre-vention of venous thromboembolism in patients withlack of mobility after 1 to 4 days from onset (ClassIIb; Level of Evidence: B). (Revised from the previousguideline)

Blood PressureBlood Pressure and Outcome in ICHBlood pressure (BP) is frequently, and often markedly,elevated in patients with acute ICH; these elevations in BPare greater than that seen in patients with ischemic stroke.72,73

Although BP generally falls spontaneously within severaldays after ICH, high BP persists in a substantial proportion ofpatients.72,73 Potential pathophysiologic mechanisms includestress activation of the neuroendocrine system (sympatheticnervous system, renin-angiotensin axis, or glucocorticoid sys-tem) and increased intracranial pressure. Hypertension theoreti-cally could contribute to hydrostatic expansion of the hematoma,peri-hematoma edema, and rebleeding, all of which may con-tribute to adverse outcomes in ICH, although a clear associationbetween hypertension within the first few hours after ICH andthe risk of hematoma expansion (or eventual hematoma volume)has not been clearly demonstrated.25,74

A systematic review75 and a recent large multisite study inChina73 show that a measurement of systolic BP above 140 to150 mm Hg within 12 hours of ICH is associated with morethan double the risk of subsequent death or dependency.Compared with ischemic stroke, where consistent U- orJ-shaped associations between BP levels and poor outcomehave been shown,76 only 1 study of ICH has shown a pooroutcome at very low systolic BP levels (!140 mm Hg).77 Forboth ischemic stroke and possibly ICH, a likely explanationfor such association is reverse causation, whereby very lowBP levels occur disproportionately in more severe cases, sothat although low BP levels may be associated with a highcase fatality, it may not in itself be causal.

Effects of BP-Lowering TreatmentsThe strong observational data cited previously and sophisti-cated neuroimaging studies that fail to identify an ischemicpenumbra in ICH78 formed the basis for the INTensive BloodPressure Reduction in Acute Cerebral Hemorrhage Trial(INTERACT) pilot study, published in 2008.79 INTERACTwas an open-label, randomized, controlled trial undertaken in404 mainly Chinese patients who could be assessed, treated,and monitored within 6 hours of the onset of ICH; 203 wererandomized to a treatment with locally available intravenousBP-lowering agents to target a low systolic BP goal of140 mm Hg within 1 hour and maintained for at least the next24 hours, and 201 were randomized to a more modest systolicBP target of 180 mm Hg, as recommended in an earlier AHAguideline.80 The study showed a trend toward lower relative

and absolute growth in hematoma volumes from baseline to24 hours in the intensive treatment group compared with thecontrol group. In addition, there was no excess of neurolog-ical deterioration or other adverse events related to intensiveBP lowering, nor were there any differences across severalmeasures of clinical outcome, including disability and qualityof life between groups, although the trial was not powered todetect such outcomes. The study provides an important proofof concept for early BP lowering in patients with ICH, but thedata are insufficient to recommend a definitive policy. An-other study, the Antihypertensive Treatment in Acute Cere-bral Hemorrhage (ATACH) trial,81 also confirms the feasi-bility and safety of early rapid BP lowering in ICH.82 Thisstudy used a 4-tier, dose escalation of intravenousnicardipine-based BP lowering in 80 patients with ICH.

Thus, advances have been made in our knowledge of themechanisms of ICH and the safety of early BP lowering sincethe publication of the 2007 American Heart Association ICHguidelines. INTERACT and ATACH now represent the bestavailable evidence to help guide decisions about BP loweringin ICH. Although these studies have shown that intensive BPlowering is clinically feasible and potentially safe, the BPpressure target, duration of therapy, and whether such treat-ment improves clinical outcomes remain unclear.

Recommendations1. Until ongoing clinical trials of BP intervention for

ICH are completed, physicians must manage BP onthe basis of the present incomplete efficacy evidence.Current suggested recommendations for target BPin various situations are listed in Table 6 and may beconsidered (Class IIb; Level of Evidence: C). (Un-changed from the previous guideline)

2. In patients presenting with a systolic BP of 150 to220 mm Hg, acute lowering of systolic BP to140 mm Hg is probably safe (Class IIa; Level ofEvidence: B). (New recommendation)

Inpatient Management and Prevention ofSecondary Brain Injury

General MonitoringPatients with ICH are frequently medically and neurologi-cally unstable, particularly within the first few days after

Table 6. Suggested Recommended Guidelines for TreatingElevated BP in Spontaneous ICH

1. If SBP is "200 mm Hg or MAP is "150 mm Hg, then consideraggressive reduction of BP with continuous intravenous infusion, withfrequent BP monitoring every 5 min.

2. If SBP is "180 mm Hg or MAP is "130 mm Hg and there is thepossibility of elevated ICP, then consider monitoring ICP and reducing BPusing intermittent or continuous intravenous medications whilemaintaining a cerebral perfusion pressure !60 mm Hg.

3. If SBP is "180 mm Hg or MAP is "130 mm Hg and there is notevidence of elevated ICP, then consider a modest reduction of BP (eg,MAP of 110 mm Hg or target BP of 160/90 mm Hg) using intermittent orcontinuous intravenous medications to control BP and clinicallyreexamine the patient every 15 min.

Note that these recommendations are Class C. SBP indicates systolic bloodpressure; MAP, mean arterial pressure.

Morgenstern et al Intracerebral Hemorrhage Guideline 2115

at University of Sydney on September 18, 2013http://stroke.ahajournals.org/Downloaded from

Steven R. Messé, Pamela H. Mitchell, Magdy Selim and Rafael J. TamargoBroderick, E. Sander Connolly, Jr, Steven M. Greenberg, James N. Huang, R. Loch Macdonald,

Lewis B. Morgenstern, J. Claude Hemphill III, Craig Anderson, Kyra Becker, Joseph P.Association

for Healthcare Professionals From the American Heart Association/American Stroke Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 2010 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/STR.0b013e3181ec611b

2010;41:2108-2129; originally published online July 22, 2010;Stroke.

http://stroke.ahajournals.org/content/41/9/2108World Wide Web at:

The online version of this article, along with updated information and services, is located on the

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Examples of cerebral blood flow (CBF) and cerebral blood volume (CBV) maps and corresponding CT images in patients after acute blood pressure reduction to

<150 mm Hg (top) and <180 mm Hg (bottom)

Butcher K et al. Stroke 2013;44:620-626

n engl j med 368;25 nejm.org june 20, 2013 2355

The new england journal of medicineestablished in 1812 june 20, 2013 vol. 368 no. 25

Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage

Craig S. Anderson, M.D., Ph.D., Emma Heeley, Ph.D., Yining Huang, M.D., Jiguang Wang, M.D., Christian Stapf, M.D., Candice Delcourt, M.D., Richard Lindley, M.D., Thompson Robinson, M.D.,

Pablo Lavados, M.D., M.P.H., Bruce Neal, M.D., Ph.D., Jun Hata, M.D., Ph.D., Hisatomi Arima, M.D., Ph.D., Mark Parsons, M.D., Ph.D., Yuechun Li, M.D., Jinchao Wang, M.D., Stephane Heritier, Ph.D., Qiang Li, B.Sc.,

Mark Woodward, Ph.D., R. John Simes, M.D., Ph.D., Stephen M. Davis, M.D., and John Chalmers, M.D., Ph.D., for the INTERACT2 Investigators*

A bs tr ac t

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Anderson at the George Institute for Global Health, Royal Prince Alfred Hospital and the University of Sydney, P.O. Box M201, Missenden Rd., Sydney NSW 2050, Austra-lia, or at canderson@georgeinstitute.org.au.

* Investigators in the second Intensive Blood Pressure Reduction in Acute Cere-bral Hemorrhage Trial (INTERACT2) are listed in the Supplementary Appendix, available at NEJM.org.

This article was published on May 29, 2013, at NEJM.org.

N!Engl!J!Med!2013;368:2355-65.DOI:!10.1056/NEJMoa1214609Copyright © 2013 Massachusetts Medical Society.

BackgroundWhether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known.

MethodsWe randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician’s choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups.

ResultsAmong the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The ordinal analysis showed significantly lower modi-fied Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P = 0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively.

ConclusionsIn patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indi-cated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.)

The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF SYDNEY on September 18, 2013. For personal use only. No other uses without permission.

Copyright © 2013 Massachusetts Medical Society. All rights reserved.

PRIMARY AIM

To  determine  if  a  management  policy  of:  n  Early  intensive    blood  pressure  (BP)  lowering  (target  

of  <140  mmHg  systolic)  as  compared  to  the  n  Guideline-­‐recommended  ‘standard’  control  of  BP  

(target  of  <180  mmHg  systolic)  improves.    Ø  survival  free  of  major  disability  in  acute  

spontaneous  intracerebral  haemorrhage  (ICH)    

Standardised  treatment  protocols  –  locally  available  intravenous  (IV)  BP  lowering  agents  of  physician’s  choice  

Acute  spontaneous  ICH  confirmed  by  CT/MRI  Definite  Nme  of  onset  within  6  hours  

Systolic  BP  150  to  220  mmHg  No  indicaNon/contraindicaNon  to  treatment  

In-­‐hospital  vital  signs,  NIHSS,  GCS  and  BP  over  7  days    

Intensive  BP  lowering  SBP  <140  mmHg  

Standard  BP  management  Guidelines  SBP  <180  mmHg)  

R  

Independent  90  day  outcome  with  modified  Rankin  scale  (mRS)  

 

N=2800  gives  90%  power  for  7%  absolute  (14%  relaNve)  decrease  (50%  standard  vs  43%  intensive)  in  outcome  

PROTOCOL SCHEMA

1382  (98.5%)  for  primary  outcome  

1412  (98.3%)  for  primary  outcome        

2839  Randomised  

28,829  Total  esNmated  screened  

   3  no  consent      1  missing  baseline  data      2  lost  to  follow-­‐up      3  withdrew  consent  12  alive  without  mRS  data    

Reasons  for  exclusion  (n=3572)      39%    Outside  Nme  window      16%    Judged  unlikely  to  benefit        11%    BP  outside  criteria            8%    Planned  early  surgery            5%    Refused        21%    Other  reasons  

6411  Screening  logs  completed  

1403  Intensive  BP  lowering                

1436  Standard  BP  lowering                        

5    no  consent  1  missing  baseline  data  5  lost  to  follow-­‐up  4  withdrew  consent  9  alive  without  mRS  data

PATIENT FLOW 2839 pts: 10/2008 to 08/2012

BASELINE

Demographic and clinical*

 Variable  

Intensive  (N=1399)  

Standard  (N=1430)  

Time  to  randomisaNon,  mean(SD)   3.8(1.2)   3.8(1.2)  

Age,  mean(SD),  yr   63(13)   64  (13)  

Male   64%   62%  

Chinese   68%   68%  

BP  (mmHg)   179/101   179/101  

History  of  hypertension   72%   73%  

NIHSS  median  (iqr)  score   10  (6-­‐15)   11  (6-­‐16)  

GCS  median  (iqr)  score        14  (12-­‐15)      14  (12-­‐15)  

ICH  volume  median  (iqr)  mL   11  (6-­‐19)   11  (6-­‐20)  

Deep  locaNon   83%   83%  

Intraventricular  extension   29%   28%  

*all  non-­‐significant  

Systolic  BP  Nme  trends  1  hour  -­‐  Δ14  mmHg  (P<0.0001)  6  hour  -­‐  Δ14  mmHg  (P<0.0001)  

SYSTOLIC BP CONTROL Median (iqr) time to treatment

intensive 4 (3-5), standard 5 (3-7)

Intensive  group  to  target  (<140mmHg)  462  (33%)  at  1  hour  731  (53%)  at  6  hours  

PRIMARY CLINICAL OUTCOME Death or major disability (mrs 3-6) at 90 days

12.0   12.0  

40.0   43.6  

0  

10  

20  

30  

40  

50  

60  

Intensive   Standard  

Major  Disability  (3-­‐5)  

Death  (6)  

%

(N=1399)   (N=1430)  

52.0%  55.6%  

Among  survivors  Odds  RaNo  0.85    (95%CI  0.73-­‐0.99)  

P=0.05  

Odds  raNo  0.87  (95%CI  0.75  to  1.01)        P=0.06  

KEY SECONDARY OUTCOME Ordinal shift in MRS scores (0-6)

Odds ratio 0.87 (95%CI 0.77 to 1.00); P=0.04

   

 

 

 

 

 

 

 

 

   

 

 

   

 

 

 

   

 

 

 

   

 

 

 

   

 

 

   

 

 

 

 

18.0%  

 

 

 

   

 

 

 

 18.8%  

   

 

 

 

 16.6%  

   

 

 

 

 19.0%  

     

 

 

 

 

 

 

\    

 

 

 

 12.0%  

 

8.0%  

0 1 2 3 4 5 6

Intensive  

Standard  

Major  disability     Death  Disability  but  independent  

18.7%   15.9%   18.1%     6.0%  21.1%  8.1%   12.0%  

7.6%  

HEALTH-RELATED QUALITY OF LIFE Euroqol EQ-5D domains ‘any problems’ versus ‘no problems’

64  

47  

61  

40  34  

67  

52  

66  

45  38  

0  10  20  30  40  50  60  70  80  

Intensive   Standard  

P=0.006  

P=0.05  

%  with  problems  

P=0.13  

P=0.01  

P=0.02  

SAFETY Cause-specific mortality, n(%)

21  

 Cause  of  Death    

Intensive  (N=1394)  

Standard  (N=1421)  

 P  

Direct  effects  of  primary  ICH  event   103  (7.4)   111  (7.8)   0.67  

Cardiovascular  disease      14  (1.0)      15  (1.1)   0.90        ICH        0  (0.0)      2  (0.1)  

     Ischaemic/undifferenNated  stroke        1  (0.1)      1  (0.1)  

     Acute  MI/coronary  event/other        3  (0.2)      1  (0.1)  

     Other  vascular  disease        2  (0.1)      2  (0.1)  

     Other  cardiac  disease        8  (0.6)      9  (0.6)  

Non-­‐cardiovascular  disease   50  (3.6)   45  (3.2)   0.54        Renal  failure    2  (0.1)      2  (0.1)  

     Respiratory  infecNons   17  (1.2)   12  (0.8)  

     Sepsis  (includes  other  infecNons)      6  (0.4)      4  (0.3)  

     Non-­‐vascular  medical     25  (1.8)   27  (1.9)  

SAFETY Non-fatal serious adverse events (saes), n(%)

 Serious  Adverse  Event  

Intensive  (N=1399)  

Standard  (N=1430)  

 P  

Direct  effects  of  primary  ICH  event    47  (3.4)   55  (3.8)   0.49  

Cardiovascular  disease    37  (2.6)   41  (2.9)   0.72  

     ICH        4  (0.3)      4  (0.3)  

     Ischaemic/undifferenNated  stroke        8  (0.6)      8  (0.6)  

     Acute  MI/coronary  event/other        5  (0.4)      5  (0.3)  

     Other  vascular  disease   13  (0.9)   14  (1.0)  

     Other  cardiac  disease        9  (0.6)   12  (0.8)  

Non-­‐cardiovascular  disease   160  (11.4)   152  (10.6)   0.49  

     Renal  failure          5  (0.4)      7  (0.5)  

     Severe  hypotension          7  (0.5)      8  (0.6)   0.83  

     Respiratory  infecNons      48  (3.4)   53  (3.7)  

     Sepsis  (includes  other  infecNons)      21  (1.5)   20  (1.4)  

     Non-­‐vascular  medical  /injury      132  (9.4)   125  (8.7)  

¡  Early intensive BP lowering treatment is: Ø  safe - no increase in death or harms Ø  effective – borderline significant effect on the primary

endpoint secondary analyses - improved recovery of physical functioning and health-related quality of life in survivors

¡  No heterogeneity of the treatment effect across different patient and disease characteristics

MAJOR FINDINGS OF INTERACT2

META-ANALYSIS COMBINING TRIALS ON BP LOWERING IN ACUTE ICH

BENEFIT IN INTERACT 2 Vs other acute stroke interventions

SURGERY IN ICH ANYTHING NEW ?

CONTINUED UNCERTAINTY REGARDING ROLE OF SURGICAL DECOMPRESSION IN ICH

SURGICAL INTERVENTION

ü  Indicated if cerebellar hemorrhage>3 cm with neurological deterioration or brain stem compression and/or hydrocephalus

ü Cerebrospinal fluid drainage if GCS 8 or less

¡  Craniotomy :

ü  STICH1 (1033 patients, within 72h, with clot>2 cm, GCS>5)

“Surgery does not appear to be helpful in treating most supratentorial ICH

and is probably harmful in those patients presenting in coma”

Lancet 2005, 365 : 387-397

SURGICAL INTERVENTION

30

OUTSTANDING SCIENTIFIC CREDIBILITY

Inclusion criteria §  Supratentorial ICH <72 hrs §  Volume >20 mL §  GCS score ≥5 §  Uncertainty over benefit of either

treatment Exclusion criteria §  Cerebellar / brainstem ICH §  Per-morbid disability §  Unable to undertake surgery

<24 hours of randomisation

31

OUTSTANDING SCIENTIFIC CREDIBILITY STICH Subgroup analysis

Data provide rationale for STICH2 - ongoing

Surgery for primary supratentorial intracerebralhaemorrhage (Review)

Prasad K, Mendelow AD, Gregson B

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 1

http://www.thecochranelibrary.com

Surgery for primary supratentorial intracerebral haemorrhage (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

2009

Analysis 1.1. Comparison 1 Surgery plus medical versus medical, Outcome 1 Death or dependence at end

of follow up.

Review: Surgery for primary supratentorial intracerebral haemorrhage

Comparison: 1 Surgery plus medical versus medical

Outcome: 1 Death or dependence at end of follow up

Study or subgroup Surgery Conservative Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Auer 1989 28/50 37/50 7.5 % 0.45 [ 0.19, 1.04 ]

Batjer 1990 6/8 11/13 1.0 % 0.55 [ 0.06, 4.91 ]

Cheng 2001 86/263 98/231 32.2 % 0.66 [ 0.46, 0.95 ]

Hattori 2004 60/121 82/121 19.0 % 0.47 [ 0.28, 0.79 ]

Juvela 1989 25/26 22/27 0.4 % 5.68 [ 0.62, 52.43 ]

Mendelow 2005 378/468 408/496 35.0 % 0.91 [ 0.65, 1.25 ]

Morgenstern 1998 8/15 11/16 2.3 % 0.52 [ 0.12, 2.25 ]

Teernstra 2003 33/36 29/33 1.2 % 1.52 [ 0.31, 7.35 ]

Zuccarello 1999 4/9 7/11 1.6 % 0.46 [ 0.08, 2.76 ]

Total (95% CI) 996 998 100.0 % 0.71 [ 0.58, 0.88 ]Total events: 628 (Surgery), 705 (Conservative)

Heterogeneity: Chi2 = 10.64, df = 8 (P = 0.22); I2 =25%

Test for overall effect: Z = 3.22 (P = 0.0013)

0.1 0.2 0.5 1 2 5 10

Favours surgery Favours conservative

20Surgery for primary supratentorial intracerebral haemorrhage (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

STICH II

Articles

www.thelancet.com Vol 382 August 3, 2013 397

Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trialA David Mendelow, Barbara A Gregson, Elise N Rowan, Gordon D Murray, Anil Gholkar, Patrick M Mitchell, for the STICH II Investigators

SummaryBackground The balance of risk and benefi t from early neurosurgical intervention for conscious patients with superfi cial lobar intracerebral haemorrhage of 10–100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients.

Methods In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967.

Findings 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute di! erence 3·7% [95% CI –4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367).

Interpretation The STICH II results confi rm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superfi cial intracerebral haemorrhage without intraventricular haemorrhage.

Funding UK Medical Research Council.

IntroductionSpontaneous supratentorial intracerebral haemorrhage is a heterogeneous disorder with clinical manifestations that range from none to rapid death. It a! ects 4 million patients worldwide each year and median case fatality at 1 month is 40%.1 Many survivors remain severely disabled and therefore are an enormous burden on stroke services with only a quarter having a good outcome.2

Surgery has the potential to reduce the volume of intracerebral haemorrhage and there is clinical and experimental evidence that mass removal might reduce nervous tissue damage, possibly by relieving local ischaemia3–6 or removal of noxious chemicals.7–9 Never-theless, responses to surgery do not seem to be homogeneous, with trial data, expert opinion, and mechanistic reasoning all indicating that early surgery benefi ts only some clots. For example, large, surgically accessible clots exerting a mass e! ect might benefi t from early surgery; whereas inaccessible clots, with surgical approach paths that cross eloquent speech and motor regions probably do not. Therefore, most neuro-surgeons would remove a large frontopolar intracerebral haemor rhage with recent deterioration in conscious-ness and would not remove a small intracerebral

haemorrhage in the internal capsule or basal ganglia. Also some clots are too small or the patient is too well to consider intervention. The hypothesis in the present STICH II study was based on the results of a subgroup analysis from the fi rst STICH trial that accorded with these ideas.10

Several prospective randomised controlled trials11–19 were undertaken during the previous century, cul min-ating in the fi rst large trial of early surgery for spon-taneous supratentorial intracerebral haemor rhage,20 the results of which were neutral. This outcome seemed to occur because some groups of patients did worse with surgery (those with deep-seated bleeds or with intra-ventricular haemorrhage and hydrocephalus) and some better (patients with superfi cial lobar haematomas without intraventricular haemorrhage).10 The same e! ect was noted in a meta-analysis of other studies: a benefi t with surgery that was not signifi cant.21

These fi ndings led to the STICH II trial, designed to fi nd out whether early surgery would improve outcomes compared with initial conservative treatment in patients with superfi cial lobar supratentorial intracerebral haemor rhage without intraventricular haemorrhage. The hypothesis was that early surgery could improve outcome

Lancet 2013; 382: 397–408

Published OnlineMay 29, 2013http://dx.doi.org/10.1016/S0140-6736(13)60986-1

This online publication has been corrected. The corrected version fi rst appeared at thelancet.com on Aug 2, 2013

See Comment page 377

Copyright © Mendelow et al. Open Access article distributed under the terms of CC BY-NC-ND

Newcastle University, Neurosurgical Trials Unit, Newcastle upon Tyne, UK (Prof A D Mendelow FRCS[SN], B A Gregson PhD, E N Rowan PhD, P M Mitchell FRCS); Edinburgh University, Centre for Population Health Sciences, Medical School, Edinburgh, UK (Prof G D Murray PhD); and Royal Victoria Infi rmary, Newcastle upon Tyne, UK (A Gholkar FRCR)

Correspondence to:Dr Barbara A Gregson, Neurosurgical Trials Unit, 3–4 Claremont Terrace, Newcastle upon Tyne NE2 4AE, UKbarbara.gregson@ncl.ac.uk

Articles

www.thelancet.com Vol 382 August 3, 2013 397

Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trialA David Mendelow, Barbara A Gregson, Elise N Rowan, Gordon D Murray, Anil Gholkar, Patrick M Mitchell, for the STICH II Investigators

SummaryBackground The balance of risk and benefi t from early neurosurgical intervention for conscious patients with superfi cial lobar intracerebral haemorrhage of 10–100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients.

Methods In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967.

Findings 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute di! erence 3·7% [95% CI –4·3 to 11·6], odds ratio 0·86 [0·62 to 1·20]; p=0·367).

Interpretation The STICH II results confi rm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superfi cial intracerebral haemorrhage without intraventricular haemorrhage.

Funding UK Medical Research Council.

IntroductionSpontaneous supratentorial intracerebral haemorrhage is a heterogeneous disorder with clinical manifestations that range from none to rapid death. It a! ects 4 million patients worldwide each year and median case fatality at 1 month is 40%.1 Many survivors remain severely disabled and therefore are an enormous burden on stroke services with only a quarter having a good outcome.2

Surgery has the potential to reduce the volume of intracerebral haemorrhage and there is clinical and experimental evidence that mass removal might reduce nervous tissue damage, possibly by relieving local ischaemia3–6 or removal of noxious chemicals.7–9 Never-theless, responses to surgery do not seem to be homogeneous, with trial data, expert opinion, and mechanistic reasoning all indicating that early surgery benefi ts only some clots. For example, large, surgically accessible clots exerting a mass e! ect might benefi t from early surgery; whereas inaccessible clots, with surgical approach paths that cross eloquent speech and motor regions probably do not. Therefore, most neuro-surgeons would remove a large frontopolar intracerebral haemor rhage with recent deterioration in conscious-ness and would not remove a small intracerebral

haemorrhage in the internal capsule or basal ganglia. Also some clots are too small or the patient is too well to consider intervention. The hypothesis in the present STICH II study was based on the results of a subgroup analysis from the fi rst STICH trial that accorded with these ideas.10

Several prospective randomised controlled trials11–19 were undertaken during the previous century, cul min-ating in the fi rst large trial of early surgery for spon-taneous supratentorial intracerebral haemor rhage,20 the results of which were neutral. This outcome seemed to occur because some groups of patients did worse with surgery (those with deep-seated bleeds or with intra-ventricular haemorrhage and hydrocephalus) and some better (patients with superfi cial lobar haematomas without intraventricular haemorrhage).10 The same e! ect was noted in a meta-analysis of other studies: a benefi t with surgery that was not signifi cant.21

These fi ndings led to the STICH II trial, designed to fi nd out whether early surgery would improve outcomes compared with initial conservative treatment in patients with superfi cial lobar supratentorial intracerebral haemor rhage without intraventricular haemorrhage. The hypothesis was that early surgery could improve outcome

Lancet 2013; 382: 397–408

Published OnlineMay 29, 2013http://dx.doi.org/10.1016/S0140-6736(13)60986-1

This online publication has been corrected. The corrected version fi rst appeared at thelancet.com on Aug 2, 2013

See Comment page 377

Copyright © Mendelow et al. Open Access article distributed under the terms of CC BY-NC-ND

Newcastle University, Neurosurgical Trials Unit, Newcastle upon Tyne, UK (Prof A D Mendelow FRCS[SN], B A Gregson PhD, E N Rowan PhD, P M Mitchell FRCS); Edinburgh University, Centre for Population Health Sciences, Medical School, Edinburgh, UK (Prof G D Murray PhD); and Royal Victoria Infi rmary, Newcastle upon Tyne, UK (A Gholkar FRCR)

Correspondence to:Dr Barbara A Gregson, Neurosurgical Trials Unit, 3–4 Claremont Terrace, Newcastle upon Tyne NE2 4AE, UKbarbara.gregson@ncl.ac.uk

STICH II MAIN RESULT

Articles

www.thelancet.com Vol 382 August 3, 2013 403

initial conservative treatment), six (1%) had an ischaemic stroke (fi ve and one, respectively), six (1%) a pulmonary embolism (one and fi ve, respectively), 16 (3%) a major cardiac event (nine and seven, respectively), and 71 (12%) pneumonia (31 and 40, respectively).

With the prognosis-based dichotomy of GOSE, 123 (41%) of 297 patients in the early surgery group had a favourable outcome at 6 months compared with 108 (38%) of 286 patients in the initial conservative treatment group (OR 0·86, 95% CI 0·62 to 1·20; p=0·367). Early surgery had an absolute benefi t of 3·7% (table 4) and a relative benefi t of 9·7% (–11·4 to 30·8). Adjustment for the covariates age, GCS, haemorrhage volume, and neuro-logical defi cit made little di! erence to the prognosis-based outcome (0·85, 0·59 to 1·22; p=0·384).

The mortality rate at 6 months was 18% in the early surgery group and 24% in the initial conservative treatment group (table 4; OR 0·71, 95% CI 0·48 to 1·06; p=0·095); absolute di! erence in favour of early surgery was 5·6% (table 4) and the relative di! erence was 7·3% (–1·3 to 16·0). The actual survival advantage during the fi rst 6 months with early surgery was not signifi cant (fi gure 2). 27 (9%) of 298 patients died at 30 days and 43 (14%) at 90 days in the early surgery group, whereas 43 (15%) of 291 patients died at 30 days and 63 (22%) at 90 days in the initial conservative treatment group.

Table 4 shows the full extended GOSE, Rankin, and EuroQoL by treatment group. The prognosis-based Rankin showed favourable outcome in 47% of the patients in the early surgery group and in 44% of those in the initial conservative treatment group (p=0·46; table 4); the absolute di! erence in favour of early surgery was 3·1% (table 4) and the relative di! erence was 7·0% (95% CI –11·4 to 25·3). The actual distribution of GOSE was more favourable for the early surgery group than for the initial conservative treatment group (fi gure 3), although the di! erence was not signifi cant (p=0·091; table 4). The proportional odds model analysis of these data (OR 0·77, 95%CI 0·58 to 1·03; p=0·075) was consistent with the "# trend analysis.

Figure 4 shows prespecifi ed subgroup analyses and analyses for the poor and good prognosis groups. No prespecifi ed subgroups showed heterogeneity of treat-ment response.

At 6 months, 79 (39%) of 203 patients in the poor prognosis group died and 67 (33%) had lower severe disability, whereas 44 (12%) of 380 patients died in the good prognosis group and 63 (17%) had lower severe disability. Patients in the good prognosis group were much more likely to have a good recovery (85 [22%] of 380) or moderate disability (89 [23%]) than were those in the poor prognosis group (12 [6%] of 203 and 13 [6%], respectively). Subgroup analysis of the prognosis-based prediction group showed signifi cant heterogeneity (I#=79%, p=0·03). Patients in the poor prognosis group were more likely to have a favourable outcome with early surgery than with initial conservative treatment (OR 0·49,

95% CI 0·26–0·92; p=0·02; fi gure 4). By contrast, there was no advantage for surgery in the good prognosis group (1·12, 0·75–1·68; p=0·57).

There were di! erences in the causes of death between the two groups. Patients in the early surgery group were more likely to die from cardiac events (14 [26%] of 54 vs fi ve [7%] of 69) and less likely to die from intracerebral haemorrhage or rebleed (eight [15%] vs 20 [29%]), chest

Figure !: Kaplan–Meier survival curve

0

300292

271252

260232

255237

251222

231202

169148

30 60 90Days since randomisation

Prob

abili

ty o

f sur

viva

l

120 150 1800

Number at riskEarly surgery

Initial conservativetreatment

0·2

0·4

0·6

0·8

1·0 Early surgeryInitial conservative treatment

log-rank p=0·073

Figure ": Extended Glasgow Outcome Scale at 6 monthsProportional odds model p=0·075.

Lower severe disabilityUpper severe disability

Dead Lower moderate disabilityUpper moderate disability

Lower good recoveryUpper good recovery

Early surgery

Initialconservative

treatment

0 20 40 60Percentage of cases

80 100

MINIMALLY INVASIVE APPROACHES

0

10

20

30

40

50

60

70

80

90

100

Mild Moderate Severe 90 days 14 days 90 days

Craniopuncture group (n=195) Control group (n=182)

Neurological function (SSS) (trend P=0.02)

Dependency (mRS)

(P <0.0001)

Death (P = NS)

%

Inclusion criteria

•  onset <72 hrs •  age 40-75 yrs •  vol 25-40ml, •  paresis •  GCS >8

Minimally Invasive Surgery compared with conservative management

Wang et al. Int J Stroke 2009; 4: 11-16

Minimally Invasive Surgical Approaches

(e.g. D Hanley and MISTIE in US)

CONCLUSION

¡  Interventions that proved to be helpful in ICH remain very limited.

¡  Intensive BP reduction seems safe and may have some benefit.

¡  Shift of concept. BP reduction in acute ischemic stroke ?

¡  Surgical options still questionable ; less invasive techniques to be tested.

Thank you.