Intraoperative CT guided Endoscopic Surgery for Intracerebral Hemorrhage (ICES) Paul M. Vespa (Medical PI) Neil Martin (Surgical PI) UCLA Department of Neurosurgery

Outline Introductions of centers and investigators Overview of MISTIE and how ICES fits in Describe Specific Aims of ICES Review preliminary data Discuss the surgical technique Describe key steps in the study Describe processes for data aquistion, data submission, data analysis, safety analysis, investigator feedback Outline the timelines for the study

General plan for ICES-MISTIE partnership Modify MISTIE to a three arm, Phase 2 Study Stereotactic Thrombolysis, Endoscopic, and Medical Arms MISTIE abandons 3 mg q 8 hr tier (20 subjects) ICES randomizes 3:1 those 20 subjects ICES studies safety, surgical technique development, training, center validation Outcome comparison using MISTIE and ICES controls Continue tissue gene substudy Planning for Phase 3 comparison trial

MISTIE Study Design

The ICES centers UCLA: Neil Martin, Paul Vespa MGH: Bob Carter, Chris Ogilvy Pittsburgh: Amin Kassam, Johnathan Engh UVA: Neal Kassell Fairfax/Georgetown: Jim Ecklund Columbia: Sander Connolley, Stefan Mayer UCSF: Geoffrey Manley, Shirley Stiver Jefferson: Robert Rosenwasser Case Western: Warren Selman

Central Aim of ICES The central aim of this study is to demonstrate that Intraoperative stereotactic CT-guided Endoscopic Surgery (ICES) is a feasible, safe, and technically effective treatment for patients with acute intracerebral hemorrhage.

Aim 1 Specific Aim 1: To determine that intraoperative stereotactic CT-guided endoscopic surgery results in an immediate reduction in hemorrhage volume by ≥ 66% in 80% of surgically treated patients and to determine strategic methods that ensure successful evacuation. Hypothesis 1: Surgical Technique 1a. It will be feasible to use an image guidance method of planning the surgical trajectory that bisects the long axis of the hematoma and ends at the deepest portion of the hematoma, while avoiding eloquent cortex. A formal scoring system will be used to determine a trajectory score based on trajectory and depth. 1b. The extent of hematoma volume reduction will be a function of the surgical trajectory score. 1c. To determine the minimal suction pressure necessary to obtain maximal hematoma removal. Sub Aim 1: To determine if recurrent bleeding occurs within the immediate post-operative period. Hypothesis for Sub Aim 1: Recurrent bleeding will occur after 1 hour and before 24 hours after surgery.

Aim 2 Specific Aim 2: To determine that intraoperative stereotactic CT-guided endoscopic surgery has a similar safety and hematoma reduction profile as compared with the MISTIE technique. Hypothesis 2: Outcome Assessment and Comparisons of ICES to MISTIE 2a. The percentage of hematoma reduction will be greater for the ICES procedure as compared with MISTIE at 1 hour after surgery. 2b. The percentage of hematoma reduction will be greater for the ICES procedure as compared with MISTIE at 24 hours after surgery. 2b. The percentage of rebleeding or other immediate surgical complication will be similar between ICES and MISTIE. 2c. The mortality rate will be similar between ICES and MISTIE surgical arms. 2d. The mortality rate in the surgical arms, ICES and MISTIE, will be lower than that of the medical control arm. 2e. The rates of cerebritis and meningitis will be similar between the ICES and MISTIE surgical arms.

Sub Aim 2 Sub-Aim 2: To determine that intraoperative stereotactic CT-guided endoscopic surgery and MISTIE results in a reduction FLAIR positive edema surrounding the hematoma as compared with medical arm patients. Hypothesis for Sub-aim 2: 2f. The presence of a perihematomal FLAIR positive edema will be less than that seen in medical arm patients. 2g. There will be no new FLAIR positive tracts along the endoscopy or MISTIE trajectory.

Aim 3 Specific Aim 3: To develop a endoscopic registry that enables development of innovations in the endoscopic technique and compare the safety of these innovations with the standard endoscopic technique. Hypothesis for Aim 3: Modifications to the endoscopic technique will enable complete evacuation of the hematoma, including intraventricular blood.

Preliminary Data for ICES at UCLA Single center data Phase 1: 10 randomized pts 2002-2007 6 surgical and 4 medical controls Productivity: 4 manuscripts Miller et al: Image Guided Endoscopic Evacuation of Intracerebral Hemorrhage. Surgical Neurology 2008 May;69(5):441-6. Burgess et al: Development and validation of a simple conversion model for comparison of intracerebral hemorrhage volumes measured on CT and gradient echo MRI (in press) Carmichael et al: Genomic profiles of damage and protection in human intracerebral hemorrhage (submitted)

Preliminary Findings 21 ±3 Miller et al 2008

Preliminary findings Miller et al 2008

Comparison Endoscopic Arm 80 ± 13 % reduction in ICH volume 20% Mortality 1 patient with post-op rebleed Medical Arm 72 ± 132 % growth in ICH volume 50% mortality

Genomic profiles of damage and protection in human intracerebral hemorrhage Carmichael et al, JCBFM 2008 1. Surgical tissue has high quality RNA for gene expression analysis. 2. The gene expression differences between peri- hematomal tissue and control tissue are highly significant 3. Bioinformatics analysis: Induction of molecular networks of inflammatory chemokine and cytokine signaling and counter-inflammatory networks: annexin and TGFb 4. Hemorrhage induces a coordinated down regulation of NMDA receptor and downstream intracellular neuronal signaling pathways This correlates with microdialysis data showing elevated extracellular glutamate in the brain surrounding the ICH (Miller et al 2007) Addresses mechanism of surgical success resulting from less excitotoxic edema

Steps in the ICES protocol Initial Evaluation of patient with intracerebral hemorrhage in the emergency department Initial CT or MRI of the brain Stereotactic CT scan performed ( 6 hour stabilization scan) Additional diagnostic testing based on clinical suspicion: Cerebral Angiogram or CTA Initial treatment with standard of neurocritical care for ICH (Broderick et al, 2007). Decision about placement of external ventricular drain will based on standard of care guidelines (ie intraventricular blood, hydrocephalus, suspected elevated intracranial pressure). Patient and family discussion, consent, and randomization into the study protocol. Preoperative planning using the Stereotactic CT scan that is registered into the image guidance system ICES Operation within 48 hours of bleed onset Neurointensive care delivered as per standard of care Ongoing study activities (imaging, neurologic scoring, etc) in the ICU Structured follow up exam and imaging Images and other data sent electronically to the Surgical Center for quality control and data analysis

Patient Event Time Line

Surgical Technique Initial Screen and MRI Prepare for OR Stereotactic placement of burr hole Stereotactic trajectory for endoscope Graded Suction of hematoma at 2/3 and 1/3 depth Hemostasis Leave catheter in cavity Post evacuation imaging

Stereotactic endoscope placement at 2/3 depth

Stereotactic endoscope placement at 1/3 depth

Intraoperative Imaging

Surgical Key Steps – 1 General anesthesia Formal time out Preliminary endoscopic trajectory Avoid eloquent cortex Position the patient Apply stereotactic Guide and register the patient Simulation of trajectory using offset Take Picture 1 (screenshot)

Surgical Key Steps - 2 Scalp Incision and burr hole Examine cortical surface Registration of endoscope sheath Simulation of endoscope sheath trajectory Use Offset Take Picture 2 Insert endoscope sheath to desired depth – position 1 2/3 of hematoma depth Take picture 3 (no offset) Begin graded suction of hematoma 50 mm Hg starting, 50 mm Hg increments

Surgical Key Steps - 3 Record volume of blood aspirated at each suction grade Pull back endoscope sheath to position 2 1/3 depth of hematoma Repeat graded suction process Start at 50 mm Hg, 50 mm Hg increments Record volume of blood aspirated at each suction grade at position 2

Surgical Key Steps - 4 Use endoscope to visualize hematoma bed Perform hemostasis Review the volume of blood evacuated Visually inspect cortical surface Remove the endoscope sheath and endoscope Insert 3mm Ventricular catheter into hematoma bed to position 1 depth Close the surgical wound in standard fashion Place catheter to drainage at +5 cm height Perform post-evacuation scan

Etc…

Imaging Plan

Run-in cases Each center will do a run-in test case Data will be reviewed by the Surgical Center Each center will be approved for randomization

Data Entry Use of MISTIE website for data entry