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

2. 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

3. 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

4. MISTIE Study Design

5. 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

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. Preliminary Data for ICES at UCLA Single center data
Phase 1: 10 randomized pts
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)

12. Preliminary Findings
21 ±3
Miller et al 2008

13. Preliminary findings
Miller et al 2008

14. 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

15. 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

16. 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

17. Patient Event Time Line

18. 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

19. Stereotactic endoscope placement at 2/3 depth

20. Stereotactic endoscope placement at 1/3 depth

22. Intraoperative Imaging

23. 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)

24. 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

25. 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

26. 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

27. Etc…

28. Imaging Plan

29. 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

30. Data Entry
Use of MISTIE website for data entry