Supraphysiologic Insulin to Improve Outcomes After Surgical Treatment of Unruptured Cerebral Aneurysms
Supraphysiologic Insulin to Improve Outcomes After Surgical Treatment of Unruptured Cerebral Aneurysms
We hypothesize that in patients undergoing surgical treatment of unruptured intracranial
 aneurysms, the increase in blood sugar as a result of surgical stress is detrimental to
 outcome, as measured by blood levels of proteins associated with systemic inflammation and 7
 day, 90 day, and 1 year postoperative neurologic and neuropsychiatric outcomes. Because
 insulin itself is an anti-inflammatory agent, we anticipate that normalizing blood sugar
 levels with insulin doses higher than normally produced by the body (i.e., "supraphysiologic"
 insulin doses) will have a greater benefit on these outcomes than equally normalizing blood
 sugar levels using normal insulin doses. Based on the results of this study, we will be able
 to determine if a more laborious strategy to normalize blood sugar levels (i.e.,
 "supraphysiologic" insulin therapy) offers any additional benefits to normal insulin dosing
 strategies. In addition, we will obtain a robust assessment of postoperative neuropsychiatric
 and neurologic outcomes of surgically repaired unruptured intracranial aneurysms that will
 serve as the basis for future studies to decrease morbidity of these patients
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).
Inclusion Criteria:

 -  Unruptured intracranial aneurysm

 Exclusion Criteria:

 -  Diabetes

 -  Pregnancy

 -  Age less than 18 years

 -  Inability to undergo preoperative neuropsychiatric and neurologic functional testing