Acute Neurological ICU Sedation Trial (ANIST)
Condition: Sedation
Study type: Interventional
Phase: Phase 2

Summary: 
      Dexmedetomidine (Precedex, Hospira) is a "super" selective alpha2-agonist - 8-10x more avid
      binding to alpha2 receptors than clonidine - and may have particularly favorable
      characteristics as a continuous i.v. infusion sedative for critically ill neuroscience
      patients. Its combination of anxiolysis, analgesia, without undue lethargy may make it an
      ideal agent where frequent neurological examinations are important. Unclear, however, is
      whether Precedex is superior to current common i.v. sedation protocols, and if there are any
      undue concerns of this agent on cerebral physiology and cortical stimulation.
    

Detailed description: 
      Dexmedetomidine has shown promise in small case series to be an efficacious sedative agent in
      the intensive care unit (ICU) setting, in both post-surgical and medical patients. A recent
      publication reported on the efficacy in a small series of medical patients (n=12), but as
      part of the exclusion criteria were any serious nervous system trauma or direct central
      nervous system (CNS) pathology.

      A potential advantage of dexmedetomidine as a sedative agent compared to current popular
      classes of drugs, particularly propofol, benzodiazepines, and narcotics, is the nominal
      effect on reduction of level of arousal. Experience suggests that this agent may induce
      effective degrees of sedation without concomitant loss of attentive behavior and cognition
      following low levels of auditory or tactile stimulation. Thus, neurological assessment may be
      preserved while achieving the goal of a non-agitated or anxious patient. Additionally, the
      combination of both sedative/anxiolytic and analgesic action of dexmedetomidine may permit
      single drug use for both sedation and pain control during the post-operative and medical ICU
      period.

      The cerebral effects of alpha2-agonists have been modestly studied in the clinical
      environment, and only in normal volunteers. As expected, cerebral blood flow decreased
      following initiation of the sedative, coincident with the expected diminishment of global
      cerebral metabolism. No studies have evaluated dexmedetomidine in patients suffering from
      neurological injury, the very population that may most benefit from the agent's sedative
      characteristics. Thus, it is imperative that a safety & efficacy study be carried out in a
      population of both medical and post-operative neuroscience patients. From an intraoperative
      perspective, dexmedetomidine has been effectively used as a sedative for both awake and
      sedation cases. Some evidence suggests prolonged cognitive deficits may persist beyond the
      sedative action of the drug.

      One concern in the neuroscience patient population is laboratory evidence that
      alpha2-agonists may lower the seizure threshold. Such data has been shown for both clonidine
      and dexmedetomidine.

      Therefore, to provide a comprehensive evaluation leading to successful safety and efficacy
      data for this sedative, it will be important to perform the following three studies. All
      three studies will be done concurrently but enrollment between the three studies will be
      mutually exclusive.

      Objective 1: Evaluation of Quality of Sedation: Does dexmedetomidine provide superior
      sedative characteristics relative to current standard agents in patients with neurological
      dysfunction? The metrics for such a study will include -

        1. Pharmacodynamic ease of sedation: time to goal, required nursing interventions to goal;

        2. Quality & consistency of sedation: ability to examine the patient, number of required
           titration interventions;

        3. Rapid weaning: time to off and no residual effect both hemodynamic and neurologic;

        4. Systemic hemodynamic alterations requiring drug infusion adjustment or medical
           intervention;

        5. Side effect and toxicity of sedative infusion: neurological dysfunction - cognitive,
           motor, sensory; electrolyte/hematological/metabolic disturbances, alteration of drug
           levels.

      Objective 2: Alteration of Cerebral Physiology: Does Dexmedetomidine alter intracranial
      physiology either in a favorable or unfavorable manner? The metrics for such a study will
      include -

        1. Measures of intracranial pressure (ICP), mean arterial pressure (MAP), cerebral
           perfusion pressure (CPP);

        2. Cognitive neurological state;

        3. Cerebral saturation (venous) or direct cerebral oximetry (oxygen tissue level) in a
           subset population with specific intracranial device.
    

Intervention name(s): Fentanyl/Dexmedetomidine; Fentanyl/Propofol; Fentanyl
Intervention type(s): Drug; Drug; Drug
Other intervention name(s): Precedex; Diprivan
Intervention MeSH terms: Fentanyl; Dexmedetomidine; Propofol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment