BCC4: Pierre Janin on Targets in Neuro-ICU

TARGETS IN
NEURO-ICU
The Case of ICH

DR P. JANIN
RNSH – ICU
24.09.2013

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

MODERN CONCEPT:
HEMATOMA EVOLUTION

6 hrs

3 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

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

Mean (95%CI) systolic BP differences

Absolute increase in hematoma volume
6
P=0.13

Relative increase in hematoma volume
30
P=0.06

20

4

10

2

%

ml

0

0
Δ-1.7ml
-2

Δ-10%
-5

Guideline

Intensive

Guideline

Intensive

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

matoma volume)

multisite study in
BP above 140 to
ciated with more
or dependency.
onsistent U- or
d poor outcome
as shown a poor
0 mm Hg).77 For
kely explanation
hereby very low
severe cases, so
ated with a high

sly and sophistitify an ischemic
NTensive Blood
emorrhage Trial
8.79 INTERACT
ial undertaken in
assessed, treated,
f ICH; 203 were
able intravenous

bral Hemorrhage (ATACH) trial,81 also confirms the feasibility and safety of early rapid BP lowering in ICH.82 This
study used a 4-tier, dose escalation of intravenous
nicardipine-based BP lowering in 80 patients with ICH.
Thus, advances have been made in our knowledge of the
mechanisms of ICH and the safety of early BP lowering since
the publication of the 2007 American Heart Association ICH
Guidelines for theINTERACT and ATACH now represent the Guideline
guidelines. Management of Spontaneous Intracerebral Hemorrhage: A best
for Healthcare Professionals From the American Heart Association/American Stroke
available evidence to help guide decisions about BP lowering
Association
Lewis B. Morgenstern, J. Claude Hemphill III, Craig Anderson, Kyra Becker, Joseph P.
in ICH. Although these studies have shown that intensive BP
Broderick, E. Sander Connolly, Jr, Steven M. Greenberg, James N. Huang, R. Loch Macdonald,
Steven is clinically feasible and Selim and Rafael J. Tamargo
lowering R. Messé, Pamela H. Mitchell, Magdypotentially safe, the BP
pressure target, duration of therapy, and whether such treatStroke. 2010;41:2108-2129; originally
ment improves clinical outcomes published online July 22, 2010;
remain unclear.
doi: 10.1161/STR.0b013e3181ec611b
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2010 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

Recommendations

1. Until ongoing clinical trials of BP intervention for
ICH are completed, physicians must manage BP on
the basis article, present incomplete efficacy evidence.
The online version of thisof thealong with updated information and services, is located on the
World Wide Web at:
Current suggested recommendations for target BP
http://stroke.ahajournals.org/content/41/9/2108
in various situations are listed in Table 6 and may be
considered (Class IIb; Level of at:
Data Supplement (unedited) Evidence: C). (Unhttp://stroke.ahajournals.org/content/suppl/2012/03/12/STR.0b013e3181ec611b.DC1.html
changed from the previous guideline)
2. In patients presenting with a systolic BP of 150 to
220 mm Hg, acute lowering of systolic BP to
140 mm Hg is probably safe (Class IIa; Level of
Evidence: B). (New recommendation)

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

new england
journal of medicine
The

established 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 t r ac t

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

PROTOCOL
SCHEMA
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

R

Intensive
BP
lowering

SBP
<140
mmHg

Standard
BP
management

Guidelines
SBP
<180
mmHg)

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

N=2800
gives
90%
power
for

7%
absolute
(14%
relaNve)

decrease
(50%
standard
vs

43%
intensive)
in
outcome

Independent
90
day
outcome
with

modified
Rankin
scale
(mRS)

PATIENT FLOW
2839 pts: 10/2008 to 08/2012
28,829
Total
esNmated
screened

6411
Screening
logs
completed

2839
Randomised

1403
Intensive
BP
lowering

3
no
consent

1
missing
baseline
data

2
lost
to
follow-‐up

3
withdrew
consent

12
alive
without
mRS
data

1382
(98.5%)
for
primary

outcome

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

1436
Standard
BP
lowering

5

no
consent

1
missing
baseline
data

5
lost
to
follow-‐up

4
withdrew
consent

9
alive
without
mRS
data

1412
(98.3%)
for
primary
outcome

BASELINE
Demographic and clinical*

*all
non-‐signiﬁcant

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%

179/101

179/101

History
of
hypertension

72%

73%

NIHSS
median
(iqr)
score

10
(6-‐15)

11
(6-‐16)

14
(12-‐15)

14
(12-‐15)

11
(6-‐19)

11
(6-‐20)

Deep
locaNon

83%

83%

Intraventricular
extension

29%

28%

BP
(mmHg)

GCS
median
(iqr)
score

ICH
volume
median
(iqr)
mL

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

Systolic
BP
Nme
trends

1
hour
-‐
Δ14
mmHg
(P<0.0001)

6
hour
-‐
Δ14
mmHg
(P<0.0001)

PRIMARY CLINICAL OUTCOME
Death or major disability (mrs 3-6) at 90 days
60

Odds
raNo
0.87
(95%CI
0.75
to
1.01)

P=0.06

55.6%

52.0%

50

40

% 30

40.0

Major

Disability

(3-‐5)

43.6

Death
(6)

12.0

20

10

0

12.0

Intensive

(N=1399)

Standard

(N=1430)

Among
survivors

Odds
RaNo
0.85

(95%CI
0.73-‐0.99)

P=0.05

KEY SECONDARY OUTCOME
Ordinal shift in MRS scores (0-6)
Odds ratio 0.87 (95%CI 0.77 to 1.00); P=0.04
6

0

3

4

5

8.1%

21.1%

18.7%

15.9%

18.1%

6.0%

Standar
d

2

Intensive

1

7.6%

18.0%

18.8%

16.6%

19.0%

12.0%

8.0%

12.0%

Disability
but
independent

Major
disability

Death

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

%
with
problems

80

70

60

50

40

30

20

10

0

Intensive

P=0.13

64

P=0.02

67

P=0.006

61

47

Standard

66

P=0.01

P=0.05

52

40

45

34

38

SAFETY
Cause-specific mortality, n(%)

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)

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)

0.54

21

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)

160
(11.4)

152
(10.6)

Renal
failure

5
(0.4)

7
(0.5)

Severe
hypotension

7
(0.5)

8
(0.6)

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)

Non-‐cardiovascular
disease

0.49

0.83

MAJOR FINDINGS OF INTERACT2
¡  Early intensive BP lowering treatment is:

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
Ø 

¡  No heterogeneity of the treatment effect across different

patient and disease characteristics

META-ANALYSIS COMBINING TRIALS ON
BP LOWERING IN ACUTE ICH

BENEFIT IN INTERACT 2
Vs other acute stroke interventions

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

SURGICAL INTERVENTION

¡  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

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

30

OUTSTANDING SCIENTIFIC CREDIBILITY
STICH
Subgroup analysis

Data provide
rationale for
STICH2
- ongoing

31

Surgery for primary supratentorial intracerebral
haemorrhage (Review)
Prasad K, Mendelow AD, Gregson B

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

n/N

n/N

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 ]

25/26

22/27

0.4 %

5.68 [ 0.62, 52.43 ]

378/468

408/496

35.0 %

0.91 [ 0.65, 1.25 ]

8/15

11/16

2.3 %

0.52 [ 0.12, 2.25 ]

33/36

29/33

1.2 %

1.52 [ 0.31, 7.35 ]

4/9

7/11

1.6 %

0.46 [ 0.08, 2.76 ]

996

998

100.0 %

0.71 [ 0.58, 0.88 ]

Juvela 1989
Mendelow 2005
Morgenstern 1998
Teernstra 2003
Zuccarello 1999

Total (95% CI)

Weight

M-H,Fixed,95% CI

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

Favours surgery

1

2

5

Odds Ratio

10

Favours conservative

eatment in
STICH II
l lobar intracerebral
Early surgery versus initial conservative treatment in
l patients with spontaneous supratentorial lobar intracerebral

Art

haematomas (STICH II): a randomised trial
tchell, for the STICH II Investigators

A David Mendelow, Barbara A Gregson, Elise N Rowan, Gordon D Murray, Anil Gholkar, Patrick M Mitchell, for the STICH II Investigators

Summary

Background The balance of risk and benefit from early neurosurgical intervention for conscious patients with
superficial 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 surgeryLancet 2013; 382: 397–408
compared with initial conservative treatment
could improve outcome in these patients.

vention for conscious patients with
ar haemorrhage admitted within 48 h 78 Published Online we compared early
Methods In this international, parallel-group trial undertaken in
centres in 27 countries,
surgical haematoma evacuation within 12 h randomisation plus
May 29, 2013
ed with initial conservativeoftreatment medical treatment with initial medical treatment
alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation

http://dx.doi.org/10.1016/
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
S0140-6736(13)60986-1
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.
This online publication has

Lancet 20

Published
May 29, 2
http://dx.
S0140-67

This onlin
been corr
version fi
thelancet

See Comm

Copyright
Open Acc
under the

Newcastl

95% CI 0·26–0·92; p=0·02; figure 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 differences 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
five [7%] of 69) and less likely to die from intracerebral
haemorrhage or rebleed (eight [15%] vs 20 [29%]), chest
1·0

STICH II
MAIN RESULT
Early surgery
Initial conservative treatment

0·8

Probability of survival

ment), six (1%) had an ischaemic
spectively), six (1%) a pulmonary
e, respectively), 16 (3%) a major
seven, respectively), and 71 (12%)
respectively).
sed dichotomy of GOSE, 123 (41%)
ly surgery group had a favourable
compared with 108 (38%) of 286
conservative treatment group
to 1·20; p=0·367). Early surgery
of 3·7% (table 4) and a relative
4 to 30·8). Adjustment for the
aemorrhage volume, and neurodifference to the prognosis-based
1·22; p=0·384).
6 months was 18% in the early
4% in the initial conservative
4; OR 0·71, 95% CI 0·48 to 1·06;
erence in favour of early surgery
the relative difference was 7·3%
al survival advantage during the
arly surgery was not significant
98 patients died at 30 days and
he early surgery group, whereas
s died at 30 days and 63 (22%) at
nservative treatment group.
ll extended GOSE, Rankin, and
t group. The prognosis-based
rable outcome in 47% of the
gery group and in 44% of those in
reatment group (p=0·46; table 4);
in favour of early surgery was
e relative difference was 7·0%
The actual distribution of GOSE
r the early surgery group than for
e treatment group (figure 3),

0·6

0·4

0·2
log-rank p=0·073

0

0

Number at risk
Early surgery 300
Initial conservative 292
treatment

30

60

271
252

260
232

Figure 2: Kaplan–Meier survival curve

90
120
Days since randomisation
255
237

251
222

150

180

231
202

169
148

Minimally Invasive Surgery
compared with conservative management
100

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

90

Craniopuncture group (n=195)

80

Control group (n=182)

70
60

%

Inclusion
criteria

50
40
30
20
10
0
Mild

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

Moderate

Severe

Neurological function (SSS)
(trend P=0.02)

90 days

Dependency
(mRS)
(P <0.0001)

14 days

90 days

Death
(P = NS)

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.

BCC4: Pierre Janin on Targets in Neuro-ICU

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Was ist angesagt?

Was ist angesagt? (20)

Ähnlich wie BCC4: Pierre Janin on Targets in Neuro-ICU

Ähnlich wie BCC4: Pierre Janin on Targets in Neuro-ICU (20)

Mehr von SMACC Conference

Mehr von SMACC Conference (20)

Kürzlich hochgeladen

Kürzlich hochgeladen (20)

BCC4: Pierre Janin on Targets in Neuro-ICU