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:

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.
B: Inclusion Criteria:

* Age 18 years and over
* Clinical need for sedation of an initially intubated (or tracheotomised) and ventilated (with inspiratory assistance) patient
* Prescribed light to moderate sedation (target RASS = 0 to -3) using midazolam infusion
* Patients should be randomised within 72 hours from ICU admission and within 48 hours of commencing continuous sedation in the ICU
* Patients should have an expected requirement for sedation of at least 24 hours from time of randomisation
* Written informed consent must be obtained according to local regulations before starting any study procedures other than pre-screening.

Exclusion Criteria:

* Acute severe intracranial or spinal neurological disorder due to vascular causes, infection, intracranial expansion or injury
* Uncompensated acute circulatory failure at time of randomisation (severe hypotension with MAP \< 55 mmHg despite volume and pressors)
* Severe bradycardia (HR \< 50 beats/min)
* AV-conduction block II-III (unless pacemaker installed)
* Severe hepatic impairment (bilirubin \> 101 µmol/L)
* Need for muscle relaxation at the time of randomisation (may only be used for intubation and initial stabilization)
* Loss of hearing or vision, or any other condition which would significantly interfere with the collection of study data
* Burn injuries requiring regular anaesthesia or surgery
* Use of centrally acting α2 agonists or antagonists at the time of randomisation, notably clonidine (see section 5.7 for prior and concomitant treatments)
* Known allergy to any of the study drugs or any excipients of the study drugs
* Patients who have or are expected to have treatment withdrawn or withheld due to poor prognosis
* Patients receiving sedation for therapeutic indications rather than to tolerate the ventilator (e.g. epilepsy)
* Patients unlikely to require continuous sedation during mechanical ventilation (e.g. Guillain-Barré syndrome)
* Patients who are unlikely to be weaned from mechanical ventilation; e.g. diseases/injuries primarily affecting the neuromuscular function of the respiratory apparatus such as clearly irreversible disease requiring prolonged ventilatory support (e.g. high spinal cord injury or advanced amyotrophic lateral sclerosis)
* Distal paraplegia
* Positive pregnancy test or currently lactating
* Received any investigational drug within the preceding 30 days
* Concurrent participation in any other interventional study (any study in which patients are allocated to different treatment groups and/or non-routine diagnostic or monitoring procedures are performed)
* Previous participation in this study
* Any other condition which, in the investigator's opinion, would make it detrimental for the subject to participate in the study
C: Inclusion Criteria:

* Recently on mechanical ventilation (less than 2 weeks prior to enrollment)
* Require mechanical ventilation for more than 12 hours
* Over 18 years old
* Under the services of medicine, cardiology, and neurology

Exclusion Criteria:

* Admission after cardiopulmonary arrest
* Inability to obtain informed consent
* Existence of an extubation order at the time of the evaluation
* Dependence upon mechanical ventilation for 2 weeks prior to enrollment
D: Inclusion Criteria:

* Male or female adult patients admitted to the medical and surgical ICU for critical illnesses requiring mechanical ventilation with expectation of being mechanically ventilated for greater than 24 hours

Exclusion Criteria:

* Subjects who are less than 18 years of age
* Subjects who are pregnant (a pregnancy test will be performed on all women of child bearing age)
* Inability to obtain informed consent from the patient or his/her surrogate
* Subjects in the ICU due to a lack of beds elsewhere in the hospital, triage issues, or withdrawal of care decisions rather than severity of illness
* Subjects admitted with alcohol or drug overdoses, suicide attempts, or alcohol/delirium tremens
* Subjects who are physiologically benzodiazepine dependent, and at risk for withdrawal syndromes
* Subjects with chronic pain syndromes on maintenance narcotics
* Subjects treated within the last 30 days with a drug or device that has not received regulatory approval as of study entry
* Subjects with a psychiatric history for which they are on neuroleptic treatment
* Subjects with documented moderate to severe dementia
* Subjects with anoxic brain injuries, strokes, neurotrauma, or neuromuscular disorders such as myasthenia gravis or Guillain Barre syndrome
* Medical team following patient unwilling to use the sedation regimens
* Subjects whose family and/or physician have not committed to aggressive support for 72 hours or who are likely to withdraw within 72 hours
* Subjects who are moribund and not expected to survive 24 hours
* Subjects not expected to survive hospital discharge due to preexisting uncorrectable medical condition
* Documented allergy to study medications
* Subjects who have either Child-Pugh Class B or C cirrhosis
* Subjects with active coronary artery disease at time of screening as defined by any recent evidence of ischemia, documented myocardial infarction, or coronary intervention within the past 6 months.
* Subjects with advanced heart block at time of screening

Answer: A