Disclosures Intracerebral Hemorrhage • No relevant disclosures • Non-related disclosures J. Claude Hemphill III, MD, MAS – Research Support: NIH/NINDS, Cerebrotech – Stock (options): Ornim Kenneth Rainin Chair in Neurocritical Care Professor of Neurology and Neurological Surgery University of California, San Francisco Chief of Neurology Service San Francisco General Hospital UC SF NEUROCRITICAL CARE PROGRAM ICH - Case ICH - Management • 55 yo construction exec • Evidence for optimal management in – Poorly controlled hypertension ICH has lagged behind ischemic stroke – Slumps over table at board meeting and subarachnoid hemorrhage • Arrives at ED 30 min after onset • Now improved understanding of – GCS 9 – BP 225/110 – Outcome predictors – Mechanisms of injury • What do you do? – Targets for treatment – Hematoma evacuation? – Lower BP to systolic < 140 mmHg? • New data from recent phase III medical – ICP monitor? and surgical trials have identified first – DNR? This is a bad disease effective ICH treatments (?) and these folks never do well. Page 1
The ICH Score and Outcome Outcome Predictors – The ICH Score Component ICH Score Points 3-4 2 100 100 GCS Score 5-12 1 80 80 30 day mortality 13-15 0 60 60 12m mRS > 30 1 < 3 (%) ICH Volume (cc) 40 40 < 30 0 20 20 Yes 1 Intraventricular Hemorrhage 0 0 No 0 Overall 0 1 2 3 4 5 Overall 0 1 2 3 4 5 ICH Score Yes 1 ICH Score Infratentorial Origin No 0 • Original retrospective cohort • Prospectively validated for > 80 1 long-term outcome Age (years) < 80 0 • Prospectively validated in many other cohorts worldwide Total ICH Score 0 - 6 Hemphill, Stroke 2001 Hemphill, Stroke 2001, Neurology 2009 ICH Volume Hematoma Expansion in ICH • Previously suggested as – rare A x B x C – suggestive of underlying AVM, coagulopathy 2 • Studies of early serial CT show as common – 72% of patients have some hematoma expansion over initial Select CT slice with largest ICH 24 hrs A = longest axis (cm) – 38% have significant (>33%) expansion over 24 hrs, usually B = longest axis perpendicular to A (cm) clinically significant C = # of slices x slice thickness (cm) » w/in 1 hr in 26% of cases Estimated volume of spheroid Correlates well w/ planimetric CT analysis • Hematoma expansion worsens outcome Davis et al. Neurology 2006 Kothari et al. Stroke 27:1304-1305, 1996 Brott et al. Stroke 1997 Page 2
Hematoma Expansion in ICH Hematoma Expansion in ICH • Characteristics – occurs mostly w/in 24 hours (esp. 6 hours) from onset – usually associated with clinical deterioration • Mechanism? – Associated with elevated BP? » interaction of elevated glucose (or Hgb A 1C ) and systolic blood pressure on admission > 200 mm Hg (Kazui 1998) » Lack of association b/t hemodynamic factors and ICH hematoma growth (Jauch, Stroke 2006) – Perihematoma coagulopathy/DIC? Initial CT 2’ 45” later • Is this a target for intervention? Images Courtesy of Jonathan Rosand, MD Hemostatic Agents FAST: Primary Results Hematoma Growth at 24 hrs Placebo 20 µ g/kg 80 µ g/kg P • FAST - Phase III Trial of rFVIIa in acute ICH • ICH patients <0.001 Mean % change 26% 18% 11% (80 µ g/kg vs – Without coagulopathy placebo) – CT scan w/in 3 hours 0.009 – Rx w/in 1 hour of CT scan Absolute difference 7.8 + 18.7 4.7 + 14.8 3.8 + 15.3 (80 µ g/kg vs placebo) – 841 patients randomized; 821 patients dosed • F/U of phase IIb trial that showed Modified Rankin Score > 5 at 90 days 24% 26% 29% NS – Decreased hematoma expansion Mortality 19% 18% 21% NS – Lower mortality and better functional outcome Arterial Thrombotic Events 4% 5% 8% 0.04 – Modest increase in thrombotic events Cerebral Infarction 1% 1% 3% 0.14 • First large ICH medical trial ever conducted • Reduces hematoma expansion • Protocol similar to phase IIb trial • No effect on clinical outcome • rFVIIa 80 µg/kg vs 20 µg/kg vs placebo • Increase in arterial thrombotic events Mayer et al., NEJM 358: 2117-2137, 2008 Mayer et al., NEJM 358: 2117-2137, 2008 Page 3
Multivariable analysis of predictors of CT “spot sign” hematoma expansion Variable OR (95% CI) p value Contrast extravasation 18 (2.1-162) 0.009 ICH volume (per 10cc) 0.8 (0.6-1.0) 0.1 Images courtesy of Joshua Goldstein, MD Time to CTA< 3hours 3.4 (0.5-22) 0.2 Age (per 10 years) 1.2 (0.6-2.3) 0.6 SBP (per 10mmHg) 0.94 (0.8-1.1) 0.5 Perihematoma Ischemia in ICH • Initial animals models suggested a zone of perihematoma “ischemia” based on findings of low CBF – Bullock (1988) - blood injection into primate caudate; CBF below ischemic threshold of 18 ml/100 gm/min • In patients with hematoma expansion – Mendelow (1993)- neuroprotection with nimodipine in rodent ICH � Positive predictive value 61% � Negative predictive value 78% Current Thinking - ongoing ischemia in the • Mortality and Outcome at 3 months perihematoma region is neither common nor � Spot sign positive 43% ( median mRS 5) the major mechanism of perihematoma injury � Spot sign negative 20% ( median mRS 3) Page 4
BP Lowering Trials in ICH BP in ICH - Expert Consensus • INTERACT – Australia/NZ, China • Guidelines for the Management of Spontaneous ICH – Randomized open-label study – AHA Stroke Council, 2010 – Entry criteria - ≥ 2 SBP measurements ( ≥ 150 to ≤ 220 mm Hg) – BP-lowering regimen < 6 h of onset • Blood Pressure – BP Rx goals – SBP < 180 v. SBP < 140 – If concern for elevated ICP – “Vanguard” phase completed – 404 patients, 95% in China (Lancet, 2008) » Maintain SBP < 180 mmHg and MAP < 130 mmHg and » Possible modest effect on hematoma expansion in adjusted keep CPP 60-80 mmHg analysis – If no concern for elevated ICP » No clinical efficacy signal » ~2500 patient pivotal trial started in late 2008 » Target MAP < 110 mmHg or BP < 160/90 • ATACH – NIH ( CCM 2010) – Lowering systolic BP acutely to < 140 mmHg is probably safe – PI – Adnan Qureshi; N=60 – “Dose-escalation” study of safety & feasibility of achieving 3 successive BP goals for 24 hours after acute ICH Arbitrary expert opinion based on recognized paucity of data – Conclusions -safe and less overall concern for perihematoma ischemia 3.6% Published online May 29, 2013 • Randomized 2839 subjects • Same protocol as INTERACT No difference in hematoma expansion between groups • Outcome at 90 days tested 2 ways • Rankin scale dichotomized at 2/3 1. So does it work? • Proportional odds analysis across entire Rankin scale 2. Is it a clinically meaningful effect? • 68% of subjects from China Page 5
Surgical Trial for ICH (STICH) STICH - Results Early Surgery Initial Conservative tx P=0.71 Mortality Alive 304 (64%) 316 (63%) • Completed in 2003 Dead 173 (36%) 189 (37%) • Largest study of surgery in ICH (>1000 pts) Primary Outcome P=0.41 • Does a policy of “Early Surgery” improve (“Prognosis based” Early Surgery Initial Conservative tx outcome in patients with spontaneous functional outcome) Favourable 112 (26%) 118 (24%) supratentorial ICH compared with a policy of Unfavourable 346 (74%) 351 (76%) “Initial Conservative Treatment”? – Randomisation within 72 hours of ictus • No Difference – Surgery within 24 hours of randomisation • 26% of patients randomised to Initial Conservative Treatment – Selection based on “uncertainty principle” later had surgery • Early surgery is not harmful Mendelow Lancet , 2005 • There is no evidence favoring early surgery in supratentorial ICH Mendelow Lancet , 2005 • Lobar ICH within 1 cm of cortical surface • Hematoma volume 10-100 cc • Randomized within 48 hours of onset • Best motor score on GCS of > 5 • Conscious • No intraventricular hemorrhage • Randomly assigned to surgery within 12 hours or not • 6 month GOSE • “Prognosis-based” outcome • Enrolled ~5% of patients screened • 21% of non-surgical group received delayed surgery Page 6
Poor prognosis subgroup • Score to identify patients with poor prognosis at baseline • 10 x GCS – age – 0.64 x volume • < 27.672 predicts poor outcome CLEAR IVH Novel Approaches to ICH/IVH Mass Effect • CLEAR IVH trial (Naff Stroke 2011) (n=48) • Randomized placebo-controlled trial of t-PA 3 mg/3 ml (versus saline) intraventricular every 12 hours • Symptomatic bleeding – t-PA group 23% – Placebo group 5% • Predicted mortality 75% – t-PA group 19% – Placebo group 23% Aspiration +/- thrombolysis. This makes intuitive sense. Does it work? • CLEAR III (phase 3 pivotal trial) ongoing Page 7
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