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Minimally Invasive Surgery + rt-PA for ICH Evacuation SURGICAL TRAINING Protocol Overview Objectives • • • • • Overview of MISTIE 3 Major Findings: MISTIE 2 Key Elements of Procedures Minimally Invasive Procedure Considerations Overview • Phase III: Efficacy and Safety • Combination MIS and Clot Lysis w/rt-PA to remove ICH • 500 Patients • 1:1 Adaptive randomization • 250 Surgical vs 250 Medical Management • Funding: NIH/NINDS Overview (cont) • Performed by qualified neurosurgeon • Performed in OR (preferred) • Also in procedural CT/MRI scanner or ICU • Use introducer and catheter (commercially suitable kit is available) • Aspiration with 10 ml syringe • Antibiotic coverage Qualified Surgeon 3 Phases • Pre-Qualification: Everyone must participate , Letter of Attestation • Have performed 3 prior image-guided or stereotactic catheter aspiration or placement procedures • Have current privileges to perform these procedures at institution • Qualification w/Probation: Must have satisfactorily performed one MISTIE procedure for ICH in which catheter placement is reviewed by Surgical Center and Reading Center prior to or during this trial • M2 Veterans – you can get credit • New to MISTIE – • Need to be proctored on site or tele-proctored for your first case* • Proctor must be Fully Qualified MISTIE surgeon Qualified Surgeon 3 Phases (cont) • Full Qualification: Must have satisfactorily performed three MISTIE procedure for ICH in which catheter placement is reviewed by Surgical Center and Reading Center prior to or during this trial • We anticipate all surgeons will pass through this phase • Recognize review of catheter placement is part of protocol and is an ongoing activity • Take Home Message: After first 3 successful MISTIE procedures, you will reach Full Qualification status. • Additional Training: Surgeon’s Webinar once/month • One-time mandatory course for those not able to attend Investigator Meeting. Set up by Coordinating Center. Qualified Surgeon “To Do List” • Letter of Attestation • Send Letter of Attestation regarding performance and privileges • Credit for Prior MISTIE Procedures • MISTIE II surgeons may request that images be pulled from their M2 cases for review. • Reading Center is also pulling Veteran M2 scans for Surgical Center review. • Will notify site coordinators of individual surgeons’ status • Non-M2 surgeons who have performed off-label MISTIE procedures may send those images for review. • SEND YOUR LETTER, CASES , REQUEST MISTIE II CASES to either of Surgical Center Coordinators: • Agnieszka Stadnik , [email protected] • Lynn Money, [email protected] M3 Inclusion Criteria • • • • Age 18-80 GCS </=14 or NIHSS >/= 6 Spontaneous supratentorial ICH >/= 30cc Sx < 24 hrs prior to Dx CT (unknown time of Sx onset is exclusionary) • Intention to initiate surgery within 72 hrs after Dx CT • 1st dose can be given within 76 hrs of Dx CT Inclusion Criteria (cont) • Stable clot on 6-hour stability scan (within 5cc from diagnostic to stability scan) • (A*B*C)/2 method • SBP < 180mm HG sustained for 6 hrs recorded closest to time of randomization • Historical Rankin score of 0 or 1 • Negative pregnancy test Exclusion Criteria • Infratentorial hemorrhage • IVH, even when EVD placed, does not necessarily represent an exclusion* • Thalamic bleeds w/ midbrain extension and 3rd nerve palsy or dilated and NR pupils** • Irreversible impaired brain stem function - GCS </= 4 • Ruptured aneurysm, AVM, vascular anomaly, Moyamoya disease, tumor as source of hemorrhage Exclusion Criteria (cont) • Pts w/unstable mass or evolving intracranial compartment syndrome • PLT <100,000, INR > 1.4, or elevated PT/aPTT • Irreversible coagulopathy or known clotting disorder either due to medical condition or prior to randomization • Inability to sustain INR < or = 1.4 using short- and long-acting procoagulants (such as, but not limited to, NovoSeven, FFP and/or Vitamin K) • Pts requiring resumption of therapeutic anticoagulation within 30 days are excluded Exclusion Criteria (cont) • Use of Dabigatran (or other antithrombin drugs) prior to Sx onset • Internal bleeding, involving retroperitoneal sites or GI, GU or respiratory tracts • Superficial/surface bleeding (ie. venous cutdowns, arterial punctures) or surgical site • Positive urine/serum preg test in pre-menopausal female w/o documented hx surgical sterilization • Allergy/sensitivity to rt-PA Exclusion Criteria (cont) • Prior enrollment in the study • Planned or simultaneous participation (b/w screen and Day 30) in another interventional trial • Pts not expected to survive to day 365 visit due to comorbidities and/or are DNR/DNI status prior to randomization • Any concurrent serious illness that would interfere w/safety assessments* • Pts with a mechanical valve Exclusion Criteria (cont) • Known risk for embolization* • Any other condition that the investigator believes would pose a significant hazard to the subject if the therapy were initiated • Active drug/alcohol use or dependence that, in the opinion of the site investigator, would interfere w/adherence to study requirements • In investigator’s opinion, pt is unstable and would benefit from a specific intervention rather than supportive care plus/minus MIS + rt-PA • Inability/unwillingness of subject or legal guardian or representative to give written, informed consent 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. 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 Surgical Committee Roster • Dan Hanley • Mario Zuccarello • Issam Awad • Francois Aldrich • Paul Camarata • William Broaddus • Neil Martin • A. David Mendelow • Sagi Harnoff • Judy Huang • Jean Louis Caron • Robert Dodd • Michael Rosenblum Real Time Partnering Provide guidance, share expertise, answer questions (not to interfere with your patient care!) • Two surgical teams – will rotate call 50-50 to cover all sites worldwide 24/7 • Cincinnati • Mario Zuccarello, MD • Lynn Money, Coordinator • Chicago • Issam Awad, MD • Agnieszka Stadnik and Michael Jesselson, Coordinators Regional Surgical Monitors • Europe • David Mendelow • Middle East • Sagi Harnof • Asia • Craig Anderson • North America • Issam Awad • Mario Zuccarello Standardization • Precision, Accuracy, Safety are NOT Negotiable • Standardization of key elements • • • • Entry Point Trajectory Reposition Removal of clot = Aspiration • Stabilization • Dosing • Catheter removal • Will later discuss where there is latitude Trajectory Planning ICH Categories 1. 2. 3. Type A = Deep-seated occupying the anterior third of the basal ganglia with typical “oval” shape (football shape) Type B = Deep-seated occupying the posterior third of the basal ganglia; the shape can range from more roundish to elliptical Type C = Superficial (lobar) with variable shape, but often more spherical “Type A” (anterior basal ganglia) ^ Entry point ^ ^ Slice showing greatest cross section ^ ^ Trajectory ^ “Type B” (posterior basal ganglia) ^ Entry point ^ ^ Slice showing greatest cross section ^ ^ Trajectory ^ “Type C” (lobar and/or superficial) ^ Entry point ^ ^ Slice showing greatest cross section ^ ^ Trajectory ^ Plan for Procedure and Surgical Review • Site NS will review 3D reconstruction of ICH on CT • To determine burr hole location, catheter trajectory and hematoma target • Select representative slices reviewed for trajectory determination • Site coordinator will upload full set of thin-slice (1mm) DICOM images into EDC ASAP • Site NS and coordinator complete Surg Review Form and upload into EDC Surgical Center Review • SC review site’s plan within 3 hours • Notify site and document in EDC agreement w/planned approach • Or provide different recommendation • Site NS not required to follow recommendation • If disagreement, site neurosurgeon must state rationale for his/her plan before using surgical plan different from that proposed by the Surgical Center After Procedure Completed • After catheter placement, protocol calls for scan to check catheter placement • Send post procedure CT to SC to confirm placement—full DICOMs • Full DICOMs will be required, but for this particular scan, you will be allowed to send jpegs for an initial, quick review Before Performing MIS • Coordinating Center approval of inclusion/exclusion criteria • Reading Center confirmation of stability and volume • Surgical Center input on trajectory Summary Checklist • Confirm Inclusion/Exclusion Criteria met • Surgical Plan Completed that includes: • Entry Point • Trajectory • Target • Communications with Surgical Center and Coordinating Center • Upload DICOM images of each scan for review • Select planned trajectory on surgery page • Approval from Surgical Center Summary Checklist (cont) • Perform Procedure, leaving catheter open to drainage • Repeat CT to confirm catheter placement • Immediately after procedure • Allow 6 hours for stabilization • Begin dosing • With each catheter adjustment/replacement, repeat the steps on this slide* Instructional Surgical Presentation Minimally Invasive Surgery (MIS) for Intracerebral Clot Removal Antibiotics • Protocol states that 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 Skin Incision • Approx. 1 inch in length Skin Retraction • Allow for view of the skull Burr Hole Drilling • Burr hole is made at the appropriate site for the planned trajectory according to ICH Type (A, B, or C) 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) Inner Cannula Removal • Carefully remove the inner portion of the cannula while allowing the cannula to remain within the intracerebral clot 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 Catheter Insertion • Pass soft catheter through cannula into the residual hematoma Cannula Removal • While removing cannula ensure that soft catheter remains within residual hematoma Catheter Tunneling • Tunnel catheter subcutaneously away from the incision as is standard practice Skin Closure • Suture the skin incision Connect Catheter to Stopcock • Connect soft catheter to a three-way stopcock and then to closed drainage bag system Closed Drainage System Considerations for the Surgeon 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 Feb 7, 2013 ISC 2013 Late Breaking News 50 Image Guidance is Mandatory Stereotactic CT Guided Navigation (passive catheter introducer or equivalent device) Real Time Image Guidance (Procedural CT, intraop imaging, etc) 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 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 Real Time CT • May use twist hole • May use Dandy needle or large soft catheter to aspirate clot* • Insert soft catheter using planned trajectory • To reposition • Correct on the spot • Check placement at completion of procedure 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 • 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) 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 Large Difficult Shapes • Suggest 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 Figure 1. A, Shape (left) and density (right) categorical scales and (B) examples of homogeneous, regular ICH (left) and heterogeneous, irregular ICH (right). Barras C D et al. Stroke 2009;40:1325-1331 Copyright © American Heart Association IVH • IVH, even when EVD placed, does not necessarily represent an exclusion • 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 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 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 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. 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. WELCOME to