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Supraphysiologic Insulin to Improve Outcomes After Surgical Treatment of Unruptured Cerebral Aneurysms


Trial Overview

StatusConditionSponsor/Collaborator(s)First ReceivedLast ChangedVerification Date
Withdrawn Intracranial Aneurysm Northwestern University Other January 21, 2008 January 20, 2010 January 2010

Study TypeStudy DesignPhaseEnrollmentStart DateEnd Date
Interventional Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment N/A 300 January 2009 -

Locations

FacilityAddressContactPhoneEmailStatus
Northwestern Memorial Hospital Chicago Illinois 60611 United States - - - -

Intervention

TypeInterventionDescription
Drug Novolin R (Human Recombinant Insulin) insulin infusion (0-10 U/hr) vs. 0.3 U/kg/hr and boluses (0-8 U) adjusted every 15 minutes during the intraoperative period to maintain intraoperative euglycemia (blood glucose levels 80-120 mg/dL)

Outcome

TypeMeasureTime FrameSafety Issue
Primary Neurologic Outcome--"poor" vs. "good." A "poor" outcome is assigned if the patient who arrived independently from home is discharged to a nursing home or rehabilitation hospital or dies. Discharge from hospital after surgery No
Secondary Neuropsychiatric outcomes Postoperative day 7, 90+/- 14 days, and 365+/-30 days No
Secondary Neurologic Status (Glasgow Outcome Scale <=4; Modified Rankin Disability Scale >=2, NIH Stroke Scale <=10) Postoperative day 7, 90+/- 14 days, and 365+/-30 days No
Secondary Amount of time blood glucose concentration is outside the target glucose concentration range (80-120 mg/dL) Perioperative Period (Induction of anesthesia + 24 hrs) Yes
Secondary Biomarkers of the Perioperative Inflammatory Response Perioperative Period (Induction of anesthesia + 48 hrs) No

Official Title

Clinical Trial of Euglycemia Maintenance With Supraphysiologic Insulin vs Conventional Intensive Insulin Therapy to Improve Outcomes (Neurologic, Neuropsychiatric, and Biomarkers) After Surgical Treatment of Unruptured Cerebral Aneurysms

Description

PREOPERATIVE NEUROPSYCHIATRIC & NEUROLOGIC TESTING Up to thirty days before the scheduled
elective surgical repair of his or her intracranial aneurysm, each patient will undergo
neuropsychological examination by a neuropsychologist or psychometrician and assessment of
neurologic status by a research nurse or the neurosurgical attending from the Department of
Neurological Surgery.

The battery of neuropsychological tests will include the following:

- Benton Visual Retention Test

- Controlled Oral Word Association

- Rey-Osterrieth Complex Figure Copy

- Grooved Pegboard

- Trial Making Test

- Hopkins Verbal Learning Test

The assessment of neurologic status and the time to administer each assessment is as
follows:

- Glasgow Outcome Scale (2 minutes)

- Modified Rankin Disability Scale (5 minutes)

- NIH Stroke Scale (2 minutes)

ANESTHETIC MANAGEMENT

Because of the possible effects of various anesthetic agents on immune function (in vitro
and in vivo), all patients will undergo a standardized anesthetic:

1. Premedication with 0— 0.03 mg/kg midazolam

2. Induction of anesthesia with 0.05—0.5 mcg/kg/min remifentanil, 1—2 mg/kg propofol, and
0.6—1.2 mg/kg rocuronium

3. Maintenance with 0.5—0.7 MAC desflurane and 0.05-1.0 mcg/kg/min remifentanil with
rocuronium 0.1-0.2 mg/kg to maintain adequate neuromuscular blockade. FIO2 = 1.0±0.1

4. Maintenance of core temperature 36.0±0.5°C

5. Propofol 50-200 mcg/kg/min to produce an EEG burst suppression ratio of 0.7—0.8
immediately before temporary occlusion of the feeding artery proximal to the
intracranial aneurysm (to increase the length of time that focal ischemia is tolerated)

6. 2 mcg/kg fentanyl upon placement of the last dural stitch

7. discontinuation of desflurane and remifentanil upon removal of the head from the
Mayfield head fixation

8. Postoperative analgesia with 0.2 mg dilaudid every 15 minutes, PRN

9. Antiemetic rescue with 4 mg odansetron (no standard prophylaxis)

Additional standard care & standardized therapeutics/medications are as follows:

1. Dexamethasone 10 mg after tracheal intubation followed by 4 mg every 4 hours for 48
hours

2. Mannitol 0.5—1 g/kg after completion of positioning, if requested by surgeon

3. Maintenance intravenous fluids ("4-2-1" rule) with 0.9% NaCl up to 20 mL/kg

4. Replacement of blood loss with 6% Hetastarch (1 mL : 1 mL) up to 1000 mL followed by
5% Albumin (1 mL : 1mL) up to 2500 mL

5. Nicardipine (5-15 mg/hr) ± Labetolol (5-50 mg) to keep systolic blood pressure ≤ 140
mmHg

6. Phenylephrine (10-100 mcg/min) titrated to keep systolic blood pressure ≥ 90 mmHg

7. Glycopyrollate (0.2 mg every 5 minutes) titrated to keep heart rate > 50 beats per
minute

RANDOMIZATION On the day of surgery, after confirming entry into the study (i.e.,
confirmation of research consent and confirmation of completion of preoperative
neuropsychiatric and neurologic testing), each patient will be randomly assigned to a
specific protocol—Supraphysiologic Insulin vs. Normal Insulin (Appendix 1).

Randomization will be performed in blocks of 10 using a computer generated random number
assignment (odd numbers = Supraphysiologic Insulin and even numbers = Normal Insulin)

MAINTENANCE OF EUGLYCEMIA Intraoperative blood glucose levels will be maintained in the
target range of 80—110 mg/dL (euglycemia) using the randomly assigned protocol, as outline
in Appendix 1. Blood glucose levels, insulin boluses and infusion rates, and dextrose
infusion rates will be recorded on the Intraoperative Insulin & Glucose data sheet (Appendix
2).

Postoperative blood glucose levels will be maintained in the target range (80-110 mg/dL)
using the standard intensive care unit protocol (Appendix 3).

PERIOPERATIVE SYSTEMIC INFLAMMATORY RESPONSE

Blood samples for serum protein analysis will be taken from the patient at the following
times:

1. With the placement of the arterial line (baseline)

2. Every 4 hours after the surgical incision for 12 hours

3. 24 and 48 hours after surgical incision

When possible, the blood samples will be taken from an arterial line that is placed
routinely for perioperative care. One-half (approximately 1/2) tablespoon (7 mL) of blood
will be taken for plasma protein analysis at each sampling time—a total of 6 samples
(approximately 3 tablespoons or 42 mL of blood) will be collected during the first 48 hours.

POSTOPERATIVE NEUROPSYCHIATRIC & NEUROLOGIC TESTING Seven days (or on discharge from the
hospital) and ninety days (± 14 days) after surgery, all patients will undergo the same
battery of neuropsychiatric and neurologic tests that were administered preoperatively. In
addition, the SF-36 questionnaire will be administered at these times to assess the
patients' sense of functional ability. Twelve months (± 30 days) after surgery, patients
will be interviewed in the neurosurgeon's office or telephoned to assess neurologic recovery
(using the same battery of neurologic tests administered preoperatively and the SF-36).

Eligibility

GenderMinimum AgeMaximum AgeHealthy Volunteers
Both - N/A No

Inclusion Criteria:

- Unruptured intracranial aneurysm

Exclusion Criteria:

- Diabetes

- Pregnancy

- Age less than 18 years

- Inability to undergo preoperative neuropsychiatric and neurologic functional testing