BCC4: Pierre Janin on Targets in Neuro-ICU

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Pierre Janin talks targets in neuro-icu, zoning in on blood pressure management in patients with ICH. This resource was recorded at Bedside Critical Care Conference 4.

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BCC4: Pierre Janin on Targets in Neuro-ICU

  1. 1. TARGETS IN NEURO-ICU The Case of ICH DR P. JANIN RNSH – ICU 24.09.2013
  2. 2. BLOOD PRESSURE MANAGEMENT IN PATIENTS WITH ICH
  3. 3. 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
  4. 4. PROGRESS STUDY
  5. 5. 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%
  6. 6.  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
  7. 7. 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
  8. 8. 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
  9. 9. 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)
  10. 10. 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
  11. 11. 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
  12. 12. 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  
  13. 13. 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)  
  14. 14. 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      
  15. 15. 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  
  16. 16. 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)  
  17. 17. 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  
  18. 18. 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  
  19. 19. 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  
  20. 20. 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  
  21. 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  
  22. 22. 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
  23. 23. META-ANALYSIS COMBINING TRIALS ON BP LOWERING IN ACUTE ICH
  24. 24. BENEFIT IN INTERACT 2 Vs other acute stroke interventions
  25. 25. SURGERY IN ICH ANYTHING NEW ?
  26. 26. CONTINUED UNCERTAINTY REGARDING ROLE OF SURGICAL DECOMPRESSION IN ICH
  27. 27. 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
  28. 28. 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
  29. 29. 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
  30. 30. OUTSTANDING SCIENTIFIC CREDIBILITY STICH Subgroup analysis Data provide rationale for STICH2 - ongoing 31
  31. 31. Surgery for primary supratentorial intracerebral haemorrhage (Review) Prasad K, Mendelow AD, Gregson B 2009
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. MINIMALLY INVASIVE APPROACHES
  36. 36. 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)
  37. 37. Minimally Invasive Surgical Approaches (e.g. D Hanley and MISTIE in US)
  38. 38. 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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