1. Edward C. Jauch, MD MS 1 Current Management of Intracerebral Hemorrhage

2. Edward C. Jauch, MD MS 2 Edward C. Jauch, MD, MS Assistant Professor Director of Research Department of Emergency Medicine University of Cincinnati College of Medicine Faculty, Greater Cincinnati / Northern Kentucky Stroke Team

3. Edward C. Jauch, MD MS 3 Disclosure Novo Nordisk –Consultant & Site investigator phase III trial American Heart Association –ASA and ACLS Stroke Guidelines Committee –Various AHA Committee National Institutes of Health –Ventricular and hematoma aspiration trials (Genentech providing drug)

4. Edward C. Jauch, MD MS 4 Global Objectives Review epidemiology of ICH Discuss current treatment recommendations Review recent developments in ICH treatment Discuss lessons from acute ischemic stroke

5. Edward C. Jauch, MD MS 5 A Clinical Case

6. Edward C. Jauch, MD MS 6 Patient Initial Clinical History 57 yo male develops sudden onset headache and left sided weakness Family calls 911 (112, 115, etc) EMS transport to hospital Symptoms progress to full hemiplegia Initial VS: 210 / 120 mmHg, HR 110, R 24

7. Edward C. Jauch, MD MS 7 Patient ED Presentation PMHX:Hypertension for 10 years, hyperlipidemia SHX:Smoking 30 years Meds:ACE inhibitor, ASA ROS:No recent illness or injuries No new medications

8. Edward C. Jauch, MD MS 8 Patient ED Presentation Physical examination: VS - 220 / 140 mmHg, HR 110, RR 22, T 98.6 o F Neuro (NIHSS = 12) LOC mildly depressed (GCS 13) Left facial droop & partial gaze palsy Dense left hemiplegia Mild left sensory loss Speech slurred Laboratory and ECG normal Neuroimaging shows

9. Edward C. Jauch, MD MS 9 Key Questions What is your differential diagnosis? What medical management should be initiated in this patient? What additional imaging is required? What laboratory tests should be completed? What are treatment options and issues?

10. Edward C. Jauch, MD MS 10 Stroke Subtypes (Foulkes, NINCDS Stroke Data Bank Stroke, 1988) ICH 13% SAH 13% Lacunar 19% Thromboembolic 6% Cardioembolic 14% Other 3% Unknown 32% Ischemic 71% Hemorrhagic 26% Up to 65,000 ICH per year

11. Edward C. Jauch, MD MS 11 ICH Classifications Primary (80%) –Hypertensive arteriolopathies –Cerebral amyloid angiopathies Secondary (20%) –Vascular abnormalities –Neoplasms –Coagulation disorders –Anticoagulants or thrombolytic agents –Drugs (cocaine, ephedra, etc) –Trauma

12. Edward C. Jauch, MD MS 12 Location Lobar –Associated with amyloid angiopathy Nonlobar –Due to hypertension Cerebellar Brain stem Pons Cortex Basal ganglia Thalamus Cerebellum

13. Edward C. Jauch, MD MS 13 Clinical Presentation Symptoms and signs –82% change in mental status –>75% hemiparesis/plegia –63% headache –22% vomiting –Symptoms 2/3 with progression of symptoms 1/3 maximal at onset (Brott, Stroke 1997;28:1-5)

14. Edward C. Jauch, MD MS 14 Clinical Presentation by Location Lobar –Headache (headache location related to ICH site) –Motor, sensory deficit, or VF deficits (not all) Deep –Unilateral motor, sensory, VF loss –Aphasia (D) or neglect (ND) Cerebellum –Nausea, vomiting, ataxia, coma Pontine –Coma, quadriplegia, pinpoint pupils

15. Edward C. Jauch, MD MS 15 Primary Risk Factors Age Hypertension Alcohol intake Gender (M > F) Race Smoking Diabetes Vascular malformations –Moyamoya / aneurysms Infections –Vasculitis –Mycotic aneurysms Cerebral venous thrombosis Genetic –Apolipoprotein E ε4

16. Edward C. Jauch, MD MS 16 Pathophysiology Initial hemorrhage into tissues causes: –Cytotoxic and vasogenic edema formation –Mediators: MMP-9, inflammatory response, blood degradation products Elevated intracranial pressure due to: –Hematoma mass effect –Perihematomal edema –Intraventricular extension and hydrocephalus Decreased regional perfusion and herniation

17. Edward C. Jauch, MD MS 17 ICH Progression Symptoms often progress, associated with ICH growth Within 3 hours from onset: –26% with 33% or greater growth in next 1 hour –12% with 33% or greater growth 1-20 hours (Brott, Stroke 1997;28:1-5)

18. Edward C. Jauch, MD MS 18 Prognosis Worse –Volume > 60 cm 3 and GCS < 9 91% dead at 30 days –Patients with > 30 cm 3 1 / 71 independent at 30 days –Other: age, seizures, intraventricular extension Better –Volume < 30 cm 3 and GCS 9 or higher 19% dead at 30 days (Broderick, Stroke 1993;24:987- 93)

19. 28 mL 43 mL (Image courtesy T. Brott, MD)

20. Edward C. Jauch, MD MS 20 Hematoma Volume Formula for volume of an ellipsoid –4/3π (A/2)(B/2)(C/2) –Simplified A*B*C / 2 (Kothari, Stroke 1996;27:1304-5) A B C

21. Edward C. Jauch, MD MS 21 Mortality and Morbidity Outcome: –35-52% dead at 1 month –50% of deaths within 48 o –10% independent at 30 days –20% independent at 6 months Lifetime ICH cost $125K Modified Oxford Handicap Scale (Broderick, Stroke 1993;24:987- 93) # patients

22. Current Recommendations for Management of Intracerebral Hemorrhage (Broderick, Stroke 1999;30(4):905-15) New guidelines due 2005 Edward C. Jauch, MD MS FACEP

23. Edward C. Jauch, MD MS 23 Emergent Evaluation Baseline labs –CBC, coagulation parameters, electrolytes Neuroimaging –CT remains gold standard Identify ICH and complications (hydrocephalus, herniation) –MRI / MRA For structural abnormalities (AVM, aneurysms) –Angiography Rarely emergently indicated, identifies vascular issues

24. Edward C. Jauch, MD MS 24 ICH Management Immediate stabilization (ABC’s) Supportive medical care –Frequent comorbidities Neurologic specific care Hemorrhage specific interventions

25. Edward C. Jauch, MD MS 25 Medical Management ABC’s –Maintain oxygen saturation ≥92% –Rapid sequence intubation Medical management –Prevention of hyperthermia (<37.5 o C) –Glycemic control (<10 nmol/L) –Coagulopathy correction (FFP, vitamin K) –No glycerol, corticosteroids, hemodilution –Secondary complication prevention (EUSI, Cerebrovasc Dis 2003;16:311-318)

26. Edward C. Jauch, MD MS 26 Blood Pressure Management Hypertension very common –MAP > 140 in 34%, > 120 in 78% –Many ‘normalize’ over first 24 hours General goals –Maintain MAP < 130 mmHg with history of hypertension –Prevent hypotension (SBP < 90 mmHg) –Maintain: Cerebral perfusion pressure (CPP=MAP-ICP) CPP > 70 mmHg Central venous pressure from 5-12 mmHg Optimal blood pressure still to be determined

27. Edward C. Jauch, MD MS 27 Blood Pressure Management (Broderick, Stroke 1999;30(4):905-15) (Ohwaki, Stroke 2004;35:1364-1367) For now - Common agents Labetalol Nicardipine Nitroprusside (theoretical risk of increasing ICP) New data suggest SBP < 150 mm Hg

28. Edward C. Jauch, MD MS 28 Management of ICP Definition –ICP > 20 mm Hg for > 5 minutes Treatment goal –ICP 70 mm Hg Recommendations –ICP monitoring with GCS < 9 Management –Patient positioning –Osmotherapy –Hyperventilation –Ventricular drainage

29. Edward C. Jauch, MD MS 29 Management of ICP (Broderick, Stroke 1999;30(4):905-15) Osmotherapy –Mannitol 0.25-0.5 g/kg every 6 hours up to 5 days –Target mOsm < 310 mmol/L Hyperventilation –Tidal volume of 12-15 ml/kg –Target pCO 2 30-35 mm Hg Neuromuscular paralysis –Nondepolarizing agents

30. Edward C. Jauch, MD MS 30 Seizures More common in ICH than you think –Over 25% will seizure (vs 6% for ischemic stroke) –Much more common if lobar –Focal with secondary generalization –Most in first 72 hours Treatment –Phenytoin (minimizes sedation) –Does not convey life long epilepsy (Vespa, Neurology 2003;60:1441-6)

31. Edward C. Jauch, MD MS 31 What can be Fixed? Stop the bleeding –Until now no option Remove the blood –Multiple trials without clear impact Reduce the edema –No treatment yet

32. Edward C. Jauch, MD MS 32 Surgical Treatment Direct evacuation, endoscopic, stereotactic

33. Surgical Treatment Recommendations 7000 procedures a year in U.S. despite lack of data STICH: Largest surgical trial without general benefit (Mendelow, 2005;365:387-97) (Broderick, 1999;30(4):905-15)

34. Edward C. Jauch, MD MS 34 Hemostatic Therapy (Mayer, Stroke 2005;36:74-79) (Mayer, NEJM 2005;352:777-785) Few late studies (mostly in SAH*) –Aminocaproic acid –Tranexamic acid* Ultra-early studies –rFVIIa Pilot (n=48) F7ICH-1371 (n=399) Phase III (n=675) ongoing

35. Edward C. Jauch, MD MS 35 Study Design Patients presenting with stroke-like symptoms 2° Efficacy Mortality mRS Barthel Index E-GOS NIHSS GCS Euro-QOL 24-72 hours 90 days < 3 hours CT Baseline Safety Adverse events until discharge Serious adverse events until day 90 Exacerbation of edema CT 24 h Placebo N = 100 rFVIIa 40 µg/kg N = 100 rFVIIa 80 µg/kg N = 100 rFVIIa 160 µg/kg N = 100 ≤ 60 mins CT 72 h 20 Countries 73 Trial Sites 1° Efficacy Percent change in ICH volume at 24 hours Baseline CT scan (Mayer, NEJM 2005;352:777-785)

36. Edward C. Jauch, MD MS 36 -20 -15 -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 % 29% 11% 14% 16% *Combined treatment groups vs placebo: P = 0.0112. Estimated Mean Percent Change in ICH Volume at 24 Hours Percent Change in ICH Volume by Treatment -20 -15 -10 -5 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 Placebo40 µg/kg80 µg/kg160 µg/kg Treatment Groups 52% RR 45% RR 62% RR 14% Combined Treatment Groups % * (Mayer, NEJM 2005;352:777-785)

37. Edward C. Jauch, MD MS 37 0–1 no significant disability 100%80%60%40%20%0% 160 µg/kg 80 µg/kg 40 µg/kg Placebo 2–3 slight to moderate disability 4–5 moderately severe to severe disability 6 dead* Modified Rankin Scale at Day 90 (Mayer, NEJM 2005;352:777-785) * 29% vs 18% rFVIIa vs placebo, RRR 38%, Chi-square test; P = 0.02

38. Edward C. Jauch, MD MS 38 Thromboembolic SAEs Placebo40 µg/kg80 µg/kg 160 µg/kg P Value* 2%6%4%10%0.12 Frequency of Thromboembolic SAEs Arterial thromboembolic SAEs (myocardial ischemia 7 and cerebral infarction 9) with rFVIIa treatment (5%) vs placebo (0%), P = 0.01 Fatal or disabling thromboembolic SAEs in 2% of rFVIIa-treated patients compared with 2% in the placebo group Nonsignificant dose trend in events (P = 0.12) (Mayer, NEJM 2005;352:777-785)

39. Edward C. Jauch, MD MS 39 Potential Future Tools Medical therapies –Optimizing blood pressure (ATACH) –Tight glycemic control (THIS) –Neuroprotectives (CHANT, Fast-MAG, hypothermia) –Ultra-early hemostatic therapy (rFVIIa) Surgery –Surgical patient selection and new approaches Stereotactic evacuation with tPA Intraventricular evacuation with fibrinolysis (ITT, DITCH)

40. What Can We Learn From Acute Ischemic Stroke?

41. Edward C. Jauch, MD MS 41 Time Will Always Mean Brain! ICH continue to expand Early medical management essential Early coagulation correction critical (drip and ship) Hemostatic therapy may work best early (Lancet 2004; 363: 768–74)

42. Development:Protocol and pathway development Detection: Early recognition Dispatch: Early EMS activation Delivery: Transport & management Door: ED triage Data: ED evaluation & management Decision: Neurologic input, therapy selection Drug:Thrombolytic (hemostatic) agents Disposition:Admission or transfer Same Chain: No Weak Links

43. Edward C. Jauch, MD MS 43 NINDS Recommendations Same for ICH? Door-to-MD: 10 minutes Door-to-”Expert”? 15 minutes Door-to-CT scan: 25 minutes Door-to-Drug: 60 minutes Door-to-Admission 3 hours (NINDS Stroke Symposium 2003)

44. Edward C. Jauch, MD MS 44 There May Be Major Barriers Education Timely radiology involvement Access to neurologic expertise Post treatment management –Availability of ICU beds –Complications occur early Resources and cost

45. Edward C. Jauch, MD MS 45 ED Treatment & Patient Outcome Patient’s GCS declined to 11 over 48 o Mild edema & shift seen on 48 o CT Blood pressure managed with labetalol Patient required inpatient rehab Moderately disabled at 3 months but at home

46. Edward C. Jauch, MD MS 46 Key Learning Points ICH is a dynamic process Critical management frequently required and required early General management impacts outcome Targeted therapies time dependent Hemostatic therapies may play a role if administered early Surgery for selected cases

47. Edward C. Jauch, MD MS 47 Key Role of Emergency Medicine

48. Edward C. Jauch, MD MS 48 Questions?? www.ferne.org www.ferne.org ferne@ferne.org Edward C. Jauch, MD, MS edward.jauch@uc.edu ferne_2005_aaem_france_jauch_ich_fshow.ppt 8/29/2005 1:45 AM

49. Edward C. Jauch, MD MS 49 Ethnicity of ICH Risk Age and sex adjusted rate –U.S. 15 per 100,000 –World wide 10-20 per 100,000 Rates: 13.5 per 100,000 Caucasian 38 per 100,000 African Americans 55 per 100,000 Japanese

50. Edward C. Jauch, MD MS 50 ICH Rate by Age Incidence rate / 100,000 per year

51. Edward C. Jauch, MD MS 51 Systolic Blood Pressure & Incidence Incidence rate / 100,000 per year Systolic Blood Pressure (mmHg)

52. Edward C. Jauch, MD MS 52 Prognostic Information Hemorrhage volume Clinical presentation / Initial GCS Age Intraventricular extension Use of anticoagulants Associated seizures

53. Edward C. Jauch, MD MS 53 Similar Pathophysiology