1. SURGICAL PERSPECTIVES ISSAM AWAD, MD MARIO ZUCCARELLO, MD CO-STUDY CHAIRS Minimally Invasive Surgery + rt-PA for ICH Evacuation 10 July 15

2. Protocol Overview

3. Objectives About MISTIE 2 Lessons Learned from MISTIE 2 8 Essential Elements of MISTIE 3 Minimally Invasive Procedure Considerations

4. M2 Results 1.The MIS procedure can reduce clot size safely without increased mortality or morbidity 2.The reduction is associated with an estimate between 10% - 14% improved outcome across multiple modified Rankin cut points 3.The intervention is associated with shorter (39-day) hospital stay and a $45,000 savings/patient 4.An estimate of 14% fewer patients reside in long-term nursing facilities at 180 and 365 days post procedure.

5. M2 Surgical Results Optimal catheter placement within the clot is critical to successful outcome – Achieved by catheter trajectory planning – Surgical Review Required Not required to follow Surgical Review Recommendation If disagreement, site NS must demonstrate rationale of his/her plan

6. MISTIE 2 – Lesson Learned

7. Overview Performed by certified neurosurgeon Performed in OR (preferred) – Also in procedural CT/MRI scanner or ICU Use introducer and catheter (commercially suitable kit is available) Gentle Aspiration with 10 ml syringe Antibiotic coverage

8. Site Neurosurgeon Qualification Requirements Pre-qualification – Each surgeon applying to participate in M3 must attest that they have performed at least 3 prior image guided or stereotactic catheter aspiration or placement procedures – Each surgeon must attest that they have current privileges to perform these procedures at their institution Qualification with probation – One MISTIE procedure for ICH must have been performed prior to the start of the trial - SC will review images – If surgeon hasn’t done a MISTIE procedure, surgeon will need to be proctored on site or tele- proctored with their first case – The proctoring or tele-proctoring of a first case MISTIE procedure may only be performed by a fully qualified MISTIE surgeon Full Qualification – Review of 3 MISTIE procedures prior to or during the trial. – Also a requirement for proctoring each site’s new surgeons

9. Standardization Precision, Accuracy, Safety are NOT Negotiable Standardization of 8 Essential Elements: – Plan the Approach – Choose the Trajectory – Aspirate the Clot – Place the Catheter – Assess catheter placement – Stabilization = Wait 6 hours – Administer TPA – Remove the Catheter Will later discuss where there is latitude

10. Dosing Day: 1 2 3 4 5 = CT scan = MRI= Dose Diagnostic Stability MIS Surgery Post- Surgery *green indicates surgical patients only 24hr post- removal Catheter Removal  1. Plan the Approach  2. Choose the Trajectory  3. Aspirate the Clot  4. Place the Catheter  5. Assess the Placement  6. Wait 6 hours  7. Administer tPA  8. Remove the Catheter

11. Trajectory Planning ICH Categories 1.Type A = Deep-seated occupying the anterior third of the basal ganglia with typical “oval” shape (“American” football shape) 2.Type B = Deep-seated occupying the posterior third of the basal ganglia; the shape can range from more roundish to elliptical 3.Type C = Superficial (lobar) with variable shape, but often more spherical

12. “Type A” (anterior basal ganglia) ^ Entry point ^ ^ Trajectory ^ ^ Slice showing greatest cross section ^

13. “Type B” (posterior basal ganglia) ^ Entry point ^ ^ Trajectory ^ ^ Slice showing greatest cross section ^

14. “Type C” (lobar and/or superficial) ^ Entry point ^ ^ Trajectory ^ ^ Slice showing greatest cross section ^

15. Instructional Surgical Presentation Minimally Invasive Surgery (MIS) for Intracerebral Clot Removal

16. Antibiotics Protocol states it is up to local hospital protocol or 1 to 2G Ancef IV – To be given pre-operatively and every 8 hours following until catheter is removed

17. Skin Incision Approx. 1 inch in length

18. Skin Retraction Allow for view of the skull

19. Burr Hole Drilling Burr hole is made at the appropriate site for the planned trajectory according to ICH Type (A, B, or C) Large burr hole as needed for angle of approach

20. Cannula Introduction Dura is opened with a small incision 14 French Cannula illustrated It is placed with a single pass into central core (2/3 of overall hematoma diameter)

21. Inner Cannula Removal Carefully remove the inner portion of the cannula while allowing the cannula to remain within the intracerebral clot

22. Hematoma Aspiration Using a 10 cc syringe aspirate hematoma until there is no longer a fluid component of clot noted in aspirate Continue aspiration until surgeon appreciates significant resistance Document aspirate volume

23. Catheter Insertion Pass catheter with image guidance stylet through cannula into the residual hematoma

24. Cannula Removal While removing cannula ensure that soft catheter remains within residual hematoma

25. Catheter Tunneling Tunnel catheter subcutaneously away from the incision as is standard practice Suture catheter before skin closure

26. Skin Closure Suture the skin incision

27. Connect Catheter to Stopcock Connect soft catheter to a three-way stopcock and then to closed drainage bag system

28. Closed Drainage System

29. Considerations for the Surgeon

30. Autonomy vs Standardization of Surgical Elements We don’t want to restrict the procedure and how it’s done – Each veteran MISTIE surgeon has their own technique, have to allow for variation – Variability could cause fewer complications but also may take away generalizability Technical variations OK if goal is met – Standardization of key elements – Optimal catheter placement within the clot, for example, as we have discussed

31. Feb 7, 2013ISC 2013 Late Breaking News Image Guidance is Mandatory For both cannula (if used) and catheter 31 Stereotactic CT Guided Navigation (passive catheter introducer or equivalent device) Real Time Image Guidance (Procedural CT, intraop imaging, etc)

32. Acceptable Image Guidance Modalities Image guidance restrictive in M2, now can have procedural CT in OR, even in CT, with real-time guidance – Must be flexible with image guidance issues There are 2 algorithms for catheter placement – Stereotactic Image Guided using passive catheter introducer – Real Time Image Guidance using CT

33. Stereotactic Image Guidance Create Burr Hole w/Drill Use cannula large enough to pass final catheter through (14 F, 16 F) Catheter inserted passively inside cannula which is then removed To Reposition, must re-target clot with new cannula/catheter Variation: Larger, soft catheter with stylet

34. Real Time CT May use twist hole May use Dandy needle, brain needle or other suitable hard cannula to aspirate clot, then Insert soft catheter using planned trajectory – More than 2 passes discouraged, would need further stabilization To reposition – Correct on the spot – Check placement at completion of procedure

35. Accuracy of Trajectory Influenced By: Image guidance protocol – Use modality that yields greater # slices (MRI vs CT) – Improves accuracy – 1mm Slices Place fiducials both anteriorly and posteriorly – Typically done on 6 facial landmarks – Critical for Type B clots: 3 posterior landmarks – Per MOP, highly recommend obtaining fiducials at 6 hour stabilization scan - or at least early once pt appears to be good potential candidate

36. SC Analysis – Trajectory B Clots Greater Proportion of Sub-Optimal Placements Most difficult often end up w/catheter medial to clot – Location burr hole relative to Angles of Freedom – Cannula/Catheter will take path of least resistance If on edge of clot, the clot will move to the side If going through center of clot, it won’t move away Traj B must factor in Angles of Freedom – Move burr hole more lateral – Enlarge burr hole, particularly inner table of skull

37. Red arrow shows natural trajectory

38. Repositioning or replacement before dosing Reposition defined as: – Partial removal or “pull back” – Remove non-optimally placed catheter/replace using second MIS procedure using same or different trajectory Complete replacement of the catheter is allowed if there is disturbance by inadvertent catheter movement or partial clot reduction In any subject, complete replacement to occur only once Never have > 2 passes with a rigid cannula

39. Repositioning or replacement before dosing (cont) If after placement and subsequent CT you decide to reposition, you do not need Surgical Center confirmation for your decision Only after you have your final placement do you need to submit images for Surgical Center review (important to remember, you need to submit images to the Surgical Center when you feel you have the final position) Eventually must upload all CT images into EDC

40. Repositioning or replacement after dosing begun If dosing has begun, there is a different procedure for repositioning/replacement You must wait at least 24 hours after the most recent dose before manipulating the catheter You must repeat all stability protocols as if it were the original catheter placement – Post placement, must upload DICOMs showing final placement – Obtain SC approval – Wait 6 hours for stability before resuming dosing

41. Large Difficult Shapes Consider 2 catheters from the beginning – Each using a different trajectory Consult SC for issues regarding – Catheter management – Dosing considerations SC and CC will adjudicate such matters on a case by case basis

42. IVH IVH, even when EVD placed, does not necessarily represent an exclusion unless casting/mass effect – Proceed with evaluation – Send CT scans – Case will be adjudicated by SC and CC Cases with IVH and more than one EVD cannot be included If your patient has more than one catheter, they should be clearly labeled to ensure the study rt- PA is injected only into the ICH – To promote ICH catheter drainage, also clamp EVD drain for one hour after dosing if ICP will allow

43. Helpful CPT Codes 61781: Stereotactic image guidance 61156: Burr hole for ICH 61210: Placement of brain catheter 61070: Aspiration or injection through brain tubing – Injection is standard – Drug is research 61795: PI as Surgeon 76355: CT guidance of stereotactic localization = PI management of stereotaxis = PRO-FEE

44. Consideration of Surgical Endpoint We confirm we wish to leave the primary surgical endpoints unchanged from the MISTIE Phase II study – The goal is to decrease clot volume to 10-15 cc – May ideally achieve <10 if possible

45. Consideration of Surgical Endpoint The MISTIE II multivariable outcome prediction model demonstrates that the greater the removal of clot the greater the benefit. Animal models are consistent but have not been performed with detailed dose injury studies. Epidemiologic models of human outcome after ICH have however confirmed volume severity relationships. Thus our surgical endpoint is to decrease to 10-15 cc.

46. Consideration of Surgical Endpoint The failure to reach 10-15cc is a practical matter. As removal is limited when the catheter does not contact the clot, the surgeon must be allowed to individualize the goal for each patient's specific catheter situation.

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