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.
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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 [email protected].
* 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, [email protected]
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, [email protected]
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.
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