A Comparison of Propofol Versus Midazolam to Sedate Critically Brain Injury; Measurement of Cytokine Response and Assessment of Function

The purpose of this research is to compare the effectiveness, length of time from cessation
of sedation till extubation, recovery time, duration of admission to the ICU, recovery of
brain function, cytokine response, and complication rate of propofol versus midazolam when
used for sedation in patients with traumatic brain injury (TBI) with or without elevated
blood alcohol levels. Since this type of trauma patient will require significant medical care
upon admission to the emergency room (ER) and the family will be concerned about the
injuries, the patient and/or family will not be approached about the research study during
this time. At the earliest possible time following neurointensive (NICU) or intensive care
(ICU) admission, an informed consent will be obtained from the patient. Depending on the
severity of the head injury, the patients may not be able to sign an informed consent. In
this case, the consent will be obtained from next-of-kin or a legal guardian. No
interventions or study research will be conducted on the patient until the consent is
obtained.

Standard blood panels are drawn for every trauma patient regardless of whether or not the
patient is a participant of the research protocol, including blood alcohol levels. During the
trauma workup in ER, it is standard of care to draw an extra vial in case additional lab
tests are needed. After consent is obtained, the research team will obtain the extra vial
from the Sparrow Lab to perform cytokine and blood cell phenotype measurements for the
research study. Typically 0.5-1.0 ml of whole blood is needed for these measurements and that
can be taken from the standardized EDTA tube that is drawn on admission. This small amount of
blood sample would otherwise be discarded. Plasma cytokines and cell phenobype IL-1, IL-3,
IL-6, IL-8, IL-10, IL-17, TNF-¦Á, TGF-¦Â, G-CSF, GM-CSF, SCF, FGF, and IGF-II will be
performed by Luminex-based mutiplex assay and ELISA. In addition to the ER analysis, left
over blood will be used from the EDTA tubes at 24 hours, day 3 and day 7 after admission.
These additional measurements will be taken from the routine morning laboratory blood draws
which are done on all intubated patients to evaluate electrolytes. No additional blood will
be drawn for the research and the study will only be using left over blood already drawn for
standard of care labs that are done on all intubated patients.

Once consented, the patients will be randomized to treatment group by random allocation
process using Research Randomizer (Urbaniak, G. C., & Plous, S. Version 3.0 Computer
software]. The patient and family will be blinded to which sedation is given. Nurses and
physicians will not be blinded as they will be administering the sedatives. Although the
patients will receive randomized sedation, these patients would be administered either
propofol or midazolam even if they were not included in this research. The only modification
for research purposes is the randomization of sedation medication by the randomizer rather
than the physician. Currently, the providers in the research team do not have a preference of
one type of sedation medication over the other.

Once randomized, patients allocated to the propofol group will be initiated with a 0.5-1
mg/kg i.v. bolus followed by repeated 10-20 mg doses at variable intervals (approximately 15
s, at the discretion of the physician/nurse) until an appropriate level of sedation will be
achieved (NICU protocol), which will be subsequently titrated to achieve a target Richmond
Agitation-Sedation Scale (+4 = combative to -5 = unarousable) (Sessler et al. The Richmond
Agitation-Sedation Scale.Am J Respir Crit Care Med 2002; 166:1338-1344). Nurses will note
pre-sedation levels based on the Richmond Agitation-Sedation Scale. While undergoing
sedation, target sedation will be defined when the Richmond Agitation-Sedation Scale meets a
score of -4 to -5. Patients randomized to the midazolam group will be initiated with 0.5-1.0
mg with incremental dosing at intervals of approximately 1-3 min until a level of sedation
will be achieved at a target Richmond Agitation-Sedation scale sedation score (per NICU
protocol).

Management of all trauma patients include a careful history taking for alcoholism with
referral for further evaluation or treatment when indicated, and determination whether other
drugs are also being used. All patients with an elevated alcohol level require a medical
social service consultation and all patients with a TBI require a neuropsychology
consultation, both consultations are standard of care. The neuropsychological testing
conducted after extubation is also standard of care. The neuropsychological evaluations will
be measured based on the following assessments: intellectual functioning, language
processing, visuospatial processing, attention, concentration, verbal learning, memory,
executive functioning, sensory, perception, motor, strength, and personal assessment. The
level of impairment will be based on a scale from zero to seven. Data will be collected until
the patient is discharged from the hospital. The clinical records from the neuropsychologist
will be reviewed to analyze the progression of the patient's outcome. Similar to all trauma
patients, the patients enrolled in this study will be offered continued care with
neuropsychology as well as the option to withdrawal all care if competent to make independent
decisions.

Throughout the study consciousness will be measured using the Glasgow Coma Score (GCS) from
the time of presentation to the ER and two times each day until the patient is discharged
from the NICU or ICU (routinely done on TBI patients). The Injury severity scores (ISS) will
be recorded from admission (done on all trauma patients). Recovery of consciousness will be
determined by measurement of the acute physiology and chronic health evaluation (APACHE) III
modification of the Glasgow coma score to allow for scoring of the verbal component in
intubated patients. Patients will be judged to be awake when the Glasgow coma score was > or
= 12.

The following will be recorded from the Sparrow medical record for each patient: gender, age,
sex, weight, primary diagnosis, significant co morbidities, blood alcohol level at admission,
intracranial pressure measurements (standard of care for TBI patients), time of starting and
finishing of the sedation, total amount of medications given, any restraint required,
additional oxygen required, resuscitative measures required, time of transfer out of the
unit, and time of discharge.

Inclusion Criteria:

- Ages 18 Years or older

- Males or Females

- Primary diagnosis of TBI, subarachnoid hemmorhage (SAH), intracranial hemmorhage
(ICH), stroke

- Requires mechanical ventilation

- Requires or is receiving continuous IV sedation

Exclusion Criteria:

- Glascow Coma Score (GCS) of 3 persisting from the scene with bilaterally fixed dilated
pupils with no appreciable chance of survival

- The inability to identify a next of kin or guardian to give consent if patient unable
to consent

- Pregnant

- Allergy or contraindication to propofol

- Allergy to contraindication to midalozam

- Status epilepticus

- Current neuromuscular blockade

- Patient with a known hypersensitivity to propofol or midalozam

- Allergies to eggs, egg products, soybeans or soy products

- Acute narrow-angle glaucoma