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

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

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

Study Overview

• Status: Withdrawn
• Conditions: Intracranial Aneurysm
• Intervention / Treatment: Drug: Insulin

Detailed 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).

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Unruptured intracranial aneurysm

Exclusion Criteria:

• Diabetes
• Pregnancy
• Age less than 18 years
• Inability to undergo preoperative neuropsychiatric and neurologic functional testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Normal insulin; Maintenance of intraoperative euglycemia (blood glucose 80--110 mg/dL) using normal intensive insulin infusion rates (0-10 U/hr).	Drug: 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); Other Names: Novolin R (Human Recombinant Insulin)
Experimental: Supraphysiologic insulin; Maintenance of intraoperative euglycemia (blood glucose 80--110 mg/dL) using supraphysiologic insulin infusion doses (0.3 U/kg/hr) and exogenous dextrose to provide stable blood glucose levels .	Drug: 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); Other Names: Novolin R (Human Recombinant Insulin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Time Frame
Neuropsychiatric outcomes	Postoperative day 7, 90+/- 14 days, and 365+/-30 days
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
Amount of time blood glucose concentration is outside the target glucose concentration range (80-120 mg/dL)	Perioperative Period (Induction of anesthesia + 24 hrs)
Biomarkers of the Perioperative Inflammatory Response	Perioperative Period (Induction of anesthesia + 48 hrs)

Collaborators and Investigators

• Sponsor: Northwestern University
• Investigators: Principal Investigator: Dhanesh K. Gupta, M.D., Northwestern University Feinberg School of Medicine

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: January 21, 2008
• First Submitted That Met QC Criteria: February 1, 2008
• First Posted (Estimate): February 14, 2008

Study Record Updates

• Last Update Posted (Estimate): April 23, 2015
• Last Update Submitted That Met QC Criteria: April 21, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: Insulin; Neuropsychology; Craniotomy; Intracranial Aneurysm, Unruptured
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Arterial Diseases; Aneurysm; Intracranial Aneurysm; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: DKG 2498-002