Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 4, Randomized, Double-Blind, Multi-Center, Comparator Study Evaluating the Safety and Efficacy of Dexmedetomidine Compared to IV Midazolam in ICU Subjects Requiring Greater Than Twenty-Four Hours of Continuous Sedation
Brief Summary: The purpose of this study is to evaluate the safety and efficacy of dexmedetomidine in ICU subjects who are initially intubated, mechanically ventilated and require sedation for beyond 24 hours.


Options:
A: Inclusion Criteria:

* 18 years of age or older
* Hospitalized on an ICU ward
* Delirium based on the RASS and the CAM-ICU assessments at any day during ICU stay
* English speaking

Exclusion Criteria:

* Admitted directly to a regular non-ICU ward
* Previously enrolled in the study
* Not eligible for delirium assessment as determined by RASS scores
* Prior history of severe mental illness
* Alcohol-related delirium
* Pregnant or nursing
* Have had an aphasic stroke
B: Inclusion Criteria:

* 1. Systemic inflammatory response syndrome (SIRS) defined as meeting at least criteria (a) or (b)for a systemic inflammatory response:

  1. White blood cell count \>12,000 or \<4,000 or \>10% band forms
  2. Body temperature \>38 degrees Celsius (C) (any route) or \<36 degrees C (accepting core temperatures only; indwelling catheter, esophageal, rectal)
  3. Heart rate (\> 90 beats/min) or receiving medications that slow heart rate or paced rhythm 2. Suspected or proven infection: Sites of infection include thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and bacterial meningitis (Appendix A).

     3. ALI as defined by acute onset of:

  <!-- -->

  1. PaO2 / FiO2 ≤ 300 (intubated). If altitude \> 1000m, then PaO2 / FiO2 ≤ 300 x (PB/760), and
  2. Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph, and
  3. Requirement for positive pressure ventilation via an endotracheal tube, and
  4. No clinical evidence of left atrial hypertension, or if measured, a Pulmonary Arterial Wedge Pressure (PAOP) less than or equal to 18 mm Hg. If a patient has a PAOP \> 18 mmHg, then the other criteria must persist for more than 12 hours after the PAOP has declined to ≤ 18 mmHg, and still be within the 48-hour enrollment window.

"Acute onset" is defined as follows: the duration of the hypoxemia criterion (#1) and the chest radiograph criterion (#2) must be ≤ 28 days at the time of randomization. Opacities considered "consistent with pulmonary edema" include any patchy or diffuse opacities not fully explained by mass, atelectasis, or effusion or opacities known to be chronic (\> 28 days). The findings of vascular redistribution, indistinct vessels, and indistinct cardiac borders are not considered "consistent with pulmonary edema".

All ALI criteria (3a-d above) must occur within the same 24 hour period. The onset of ALI is when the last ALI criterion is met. Patients must be enrolled within 48 hours of ALI onset and no more than 7 days from the initiation of mechanical ventilation. SIRS criteria must occur within the 72 hours before or the 24 hours after ALI onset. Information for determining when these time window criteria were met may come from either the Network hospital or a referring hospital reports.

Exclusion Criteria:

1. No consent/inability to obtain consent
2. Age less than 18 years
3. More than 7 days since initiation of mechanical ventilation
4. More than 48 hours since meeting ALI inclusion criteria
5. Patient, surrogate, or physician not committed to full support ).
6. Unable to receive or unlikely to absorb enteral study drug
7. Rosuvastatin specific exclusions

   * Receiving a statin medication within 48 hours of randomization
   * Allergy or intolerance to statins
   * Physician insistence for the use or avoidance of statins during the current hospitalization
   * Creatine Kinase (CK) , alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 5 times the upper limit of normal
   * Diagnosis of hypothyroidism and not on thyroid replacement therapy
   * Pregnancy or breast feeding
   * Receiving niacin, fenofibrate or cyclosporine, gemfibrozil, atazanavir, lopinavir, ritonavir, daptomycin
8. Severe chronic liver disease
9. Moribund patient not expected to survive 24 hours
10. Chronic respiratory failure defined as PaCO2 \> 60 mm Hg in the outpatient setting
11. Home mechanical ventilation (noninvasive ventilation or via tracheotomy) except for CPAP/BIPAP (Continuous Positive Airway Pressure/BiLevel Positive Airway Pressure) used solely for sleep-disordered breathing
12. Diffuse alveolar hemorrhage from vasculitis
13. Burns \> 40% total body surface
14. Interstitial lung disease of severity sufficient to require continuous home oxygen therapy
15. Unwillingness or inability to utilize the ARDS network 6 ml/kg Predicted Body Weight (PBW) ventilation protocol
16. Cardiac disease classified as NYHA (New York Heart Association) class IV
17. Myocardial infarction within past 6 months
18. Intraparenchymal Central Nervous System (CNS) bleed within a month of randomization.
19. Temperature \>40.3 C in the 6 hours before randomization
C: Inclusion Criteria:

Patients will be eligible for the study if, in the opinion of the treating clinician, they continue to require mechanical ventilation only because their degree of agitation requires such a high dose of sedative medication (midazolam or propofol, the only commonly used specific sedatives in our unit) that extubation is not possible, AND in the opinion of their treating intensivist their agitation is so severe as to make lessening their sedation unsafe.

These criteria will be objectively quantified as follows:

* they have required either mechanical restraint and/or anti-delirium or sedative medication in the 4 hours prior to seeking consent AND
* their Confusion Assessment Method for the ICU (CAM-ICU) test is positive for delirium in the 4 hours prior to seeking consent AND
* their Motor Activity Assessment Scale (MAAS) score is 5 or more in the 4 hours prior to seeking consent, confirming psychomotor agitation AND
* their SOFA score is less than or equal to 5 in the 4 hours prior to seeking consent, predicting a mortality or around 5%.

Exclusion Criteria:

* Age less than 18 years old
* Pregnancy or breastfeeding
* Advanced dementia (in the premorbid state requiring professional nursing care)
* Open or closed head injury
* Death is deemed imminent and inevitable
* The patient has previously been enrolled in the DahLIA study
* Patients who could not be extubated, or who would be intubated within the following 48 hours, even if delirium or agitation were corrected. This will include:

  * Patients receiving high dose opioid for analgesia (not sedation) ( \> 40 mg/morphine/day)
  * Patients shortly to return to the operating theatre
  * Patients undergoing repeated invasive procedures, in whom it is desirable to maintain deep sedation
  * Patients likely to require ongoing airway protection or control, or ventilatory support (for example, spinal patients with an inadequate vital capacity)
* Known allergy to haloperidol or alpha 2 agonists
D: Inclusion Criteria:

1. Subject is ≥18 years of age.
2. If female, subject is non-lactating, and is either:

   1. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.
   2. Of childbearing potential but is not pregnant as confirmed by negative serum pregnancy test at time of screening, and is practicing one of the following methods of birth control: oral or parenteral contraceptives for three months prior to study drug administration, a vasectomized partner, or abstinence from sexual intercourse.
3. Subject is initially intubated and mechanically ventilated, or is planned for imminent intubation and mechanical ventilation, sedation is anticipated to be required during mechanical ventilation, and mechanical ventilation is anticipated to continue for at least 72 hours.
4. Subject or subject's legally authorized representative has voluntarily signed and dated an informed consent form, approved by the applicable Institutional Review Board (IRB), after the nature of the study has been explained and the subject or subject's legally authorized representative has had the opportunity to ask questions. The informed consent must be signed before any study specific procedures are performed.
5. Subject is sedated within a Richmond Agitation-Sedation Scale (RASS) range of -2 to +1 at the time of initiation of study drug

Exclusion Criteria:

1. Subject has been intubated for greater than 96 hours prior to the initiation of study drug (thus, the attainment of consent, screening evaluations, and randomization must all have been completed by the 96th hour post-intubation, so that the actual initiation of the study drug infusion may start by the end of the 96 hour window).
2. Subject has serious central nervous system pathology/trauma that, per clinical judgment of the Investigator, precludes responsiveness or survival.
3. Subject for whom opiates, benzodiazepines, or dexmedetomidine are contraindicated, or who has known or suspected serious allergy to any drug that might be administered during the course of the study.
4. Subject for whom alpha-2 agonists are contraindicated.
5. Subject requires neuromuscular blocking agents during the study for use other than intubation.
6. Subject requires epidural or spinal analgesia during the study.
7. Subject meets any of the following cardiovascular criteria:

   * Acute unstable angina (defined during current hospital stay).
   * Suspicion of acute myocardial infarction.
   * Considered to have a left ventricular ejection fraction of less than 30%. Decision to exclude is predicated on the Investigator's opinion, and may be based on any combination of acute presentations, recently performed diagnostic studies, or a history that suggests poor cardiac function. Pulmonary congestion of a non-cardiac origin or mild congestive failure primarily attributable to etiologies other than poor ventricular function are not exclusion criteria.
   * Heart rate \<50 bpm prior to infusion start.
   * Systolic blood pressure \<90 mmHg prior to infusion start.
   * Conduction abnormalities except 1st degree AV block and rate-controlled atrial fibrillation; subjects with functional pacemaker capacity may be enrolled.
8. Subject is hospitalized primarily due to trauma and/or burns, has received general anaesthesia within the 24 hours prior to the start of study drug infusion, or is anticipated to require general anaesthesia within 24 hours after the start of the infusion.
9. Subject has participated in a trial with any experimental drug within 30 days prior to enrollment in the study, or has ever been enrolled in this study.
10. Subject is unable to undergo any procedure required by the protocol.
11. Subject has laboratory results indicating the presence of liver disease consistent with a Child-Pugh score \>9 (Grade C).
12. Subject has acute hepatitis, history or presence of chronic hepatitis, and/or has had a positive result for Hepatitis B Surface Antigen Test.
13. Subject requires dialysis (eg, hemodialysis, peritoneal dialysis, Continuous Venovenous Hemodialysis \[CVVHD\]).
14. Subject has a known, uncontrolled seizure disorder.
15. Subject has, per the Investigator's judgment, a known or suspected physical or psychological dependence on an abused drug, other than alcohol.
16. Subject has a known psychiatric illness that could confound a normal response to sedative treatment.
17. Subject is incarcerated.
18. Subject is terminally ill with a life duration expectancy of ≤60 days.
19. Subject has any other condition or factor which, in the Investigator's opinion, might increase the risk to the subject.

Answer: D