1. Edward C. Jauch, MD MS 1 Optimizing the Management of Emergency Department Intracerebral Hemorrhage Patients FERNE Satellite 2005 ACEP Scientific Assembly Washington, DC 2005

2. Edward C. Jauch, MD MS 2 Ten Things to Know in Intracerebral Hemorrhage

3. Edward C. Jauch, MD MS FACEP 3 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

4. Edward C. Jauch, MD MS FACEP 4 Disclosure Novo Nordisk –Consultant & Site investigator phase III trial American Heart Association –ASA and ACLS Stroke Guidelines Committee –Various AHA Committees NINDS v entricular and ICH aspiration trials –Genentech providing drug

5. Edward C. Jauch, MD MS 5 Point 1 Intracerebral Hemorrhage is Bad!

6. Edward C. Jauch, MD MS FACEP 6 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

7. Edward C. Jauch, MD MS FACEP 7 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 mos Lifetime ICH cost $125K Modified Oxford Handicap Scale (Broderick, Stroke 1993;24:987- 93) # patients

8. Edward C. Jauch, MD MS 8 Point 2 Intracerebral Hemorrhage is Like Acute Ischemic Stroke Sort of

9. Edward C. Jauch, MD MS FACEP 9 Similar Pathophysiology

10. Edward C. Jauch, MD MS FACEP 10 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

11. Edward C. Jauch, MD MS FACEP 11 Location Lobar –Associated with amyloid angiopathy Nonlobar –Due to hypertension Cerebellar Brain stem Pons Cortex Basal ganglia Thalamus Cerebellum

12. Edward C. Jauch, MD MS 12 Point 3 ICH is Dynamic

13. Edward C. Jauch, MD MS FACEP 13 ICH Progression Symptoms often progress, associated with ICH growth –2/3 with progression of symptoms –1/3 maximal at onset Within 3 hours from onset: –26% with >33% growth in next 1 o –12% with >33% growth 1-20 o (Brott, Stroke 1997;28:1-5)

14. Edward C. Jauch, MD MS 14 Point 4 Size Matters

15. 28 mL 43 mL (Image courtesy T. Brott, MD)

16. Edward C. Jauch, MD MS FACEP 16 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)

17. Edward C. Jauch, MD MS FACEP 17 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)

18. Edward C. Jauch, MD MS FACEP 18 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

19. Edward C. Jauch, MD MS 19 Point 5 Medical Management The Basics are Important

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

21. 21 ICH Management Immediate stabilization (ABC’s) Supportive medical care –Frequent comorbidities Neurologic specific care Hemorrhage specific interventions

22. Edward C. Jauch, MD MS FACEP 22 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

23. Edward C. Jauch, MD MS FACEP 23 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)

24. Edward C. Jauch, MD MS 24 Point 6 Medical Management is Important Blood Pressure

25. Edward C. Jauch, MD MS FACEP 25 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

26. Edward C. Jauch, MD MS FACEP 26 Blood Pressure Management (Broderick, Stroke 1999;30(4):905-15) (Ohwaki, Stroke 2004;35:1364-1367) Common agents Labetalol Nicardipine Nitroprusside (theoretical risk of increasing ICP) New data suggest SBP < 150 mm Hg

27. Edward C. Jauch, MD MS 27 Point 7 Medical Management is Important Intracranial Pressure

28. Edward C. Jauch, MD MS FACEP 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 Point 8 Medical Management is Important Seizures

30. Edward C. Jauch, MD MS FACEP 30 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

31. Edward C. Jauch, MD MS FACEP 31 Seizures More common in ICH than you think –Over 25% will seize (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)

32. Edward C. Jauch, MD MS 32 Point 9 Medical Management is Important Coagulation Correction

33. Edward C. Jauch, MD MS FACEP 33 Coagulation Correction Warfarin –FFP 10 ml/kg –Vit K10 mg IV over 10 mins Heparin (and some LMWH) –Correct with protamine 10 – 50 mg IVP over 1 – 3 mins Direct thrombin inhibitors –No antidote, consult hematology Platelet disorders –Correct with platelets (>100,000) –DDAVP 0.3 µg/kg IV over 30 mins (MGH Stroke Service, 2005)

34. Edward C. Jauch, MD MS 34 Point 10 There is Hope on the Horizon

35. Edward C. Jauch, MD MS FACEP 35 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

36. Edward C. Jauch, MD MS FACEP 36 Potential Future Tools Surgery –Surgical patient selection and new approaches Stereotactic evacuation with tPA Intraventricular evacuation with fibrinolysis (ITT, DITCH) Medical therapies –Optimizing blood pressure (ATACH) –Tight glycemic control (THIS) –Neuroprotectives (CHANT, Fast-MAG, hypothermia) –Ultra-early hemostatic therapy (rFVIIa)

37. Edward C. Jauch, MD MS FACEP 37 Surgical Treatment Direct evacuation, endoscopic, stereotactic

38. 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)

39. Edward C. Jauch, MD MS FACEP 39 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

40. Edward C. Jauch, MD MS FACEP 40 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)

41. Edward C. Jauch, MD MS FACEP 41 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)

42. Edward C. Jauch, MD MS FACEP 42 -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)

43. Edward C. Jauch, MD MS FACEP 43 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

44. Edward C. Jauch, MD MS FACEP 44 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)

45. Edward C. Jauch, MD MS 45 Bonus Point Learn from Your Mistakes

46. Edward C. Jauch, MD MS FACEP 46 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)

47. 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

48. Edward C. Jauch, MD MS FACEP 48 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

49. Edward C. Jauch, MD MS FACEP 49 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

50. Edward C. Jauch, MD MS FACEP 50 Questions? www.ferne.org www.ferne.org ferne@ferne.org Edward C. Jauch, MD, MS edward.jauch@uc.edu ferne_acep_2005_ich_jauch_rx_notes_100206