Please select the eligibility criteria that correspond to the clinical trial below.
Title: Delirium in the ICU: a Prospective, Randomized, Trial of Placebo vs. Haloperidol vs. Ziprasidone
Brief Summary: Delirium is associated with increased risk of death, prolonged stay, higher cost of care, and likely long-term brain deficits in survivors. This form of brain dysfunction occurs in intensive care unit (ICU) patients in epidemic proportions, and the scope of this problem is likely to worsen in upcoming years due to the aging of our population and increased utilization of the ICU. Currently, delirium goes unrecognized and untreated in the vast majority of circumstances in the ICU unless the patient presents with hyperactive delirium and agitation. In the latter circumstance, a commonly used typical antipsychotic called haloperidol is considered the principal agent for treating delirium based largely on anecdotal evidence to support its usefulness, though no placebo controlled trials exist. There are no FDA approved medications for delirium. The atypical antipsychotics provide a promising alternative for the treatment of delirium due to their enhanced beneficial effects on positive (agitated) and negative (quiet) symptoms proven in mania and schizophrenia, reduced risk for side effects common to haloperidol such as extrapyramidal symptomatology, and less potentially lethal heart rhythm disturbances. It is imperative that well-designed phase II studies to determine proof of principle be conducted. A pilot study of feasibility to begin assessing the role of antipsychotics in the management of ICU delirium.


Options:
A: Inclusion Criteria:

* 18 years or older
* Positive CAM-ICU

Exclusion Criteria:

* Known allergy to rivastigmine
* Unable to receive enteric medication
* Pregnant or lactating
* Renal replacement therapy
* Hepatic encephalopathy
* Second or third degree atrioventricular block
* Uncertainty about diagnosis delirium and no confirmation by neurologist, psychiatrist or geriatrician
* Parkinson's disease.
* Lewy body dementia.
* ECG QT interval above 500 msec.
* No informed consent
B: Inclusion Criteria:

* Medical or surgical ICU patients on mechanical ventilation who are receiving sedatives or analgesics or displaying an abnormal level of consciousness (delirium or coma).

Exclusion Criteria:

* Subjects expected to have a short time on mechanical ventilation. That is, those in whom the likelihood for the need for mechanical ventilation is less than 24 hours.
* Subjects who have been on mechanical ventilation for more than 72 hours.
* Subjects in whom gastric access is not available (i.e., no enteral feeding tube or NG/OG tube)and is not anticipated to be available for 48 hours.
* Subjects younger than 18 years old.
* Subjects who are pregnant (a pregnancy test will be performed on all women of child bearing age) or breastfeeding.
* Inability to obtain informed consent from the subject or the subject's authorized representative.
* Documented history of allergic reaction to ziprasidone or haloperidol.
* Subjects admitted to the ICU for drug/alcohol overdose, suicide attempts, alcohol withdrawal/delirium tremens.
* Subjects with active seizures or cerebrovascular accident within the last 2 weeks.
* Subjects who are benzodiazepine dependent at the time of index hospitalization (i.e., patients on benzodiazepines as outpatient and whose attending judges it unsafe to withhold these medications due to risk for withdrawal syndrome).
* Subjects with chronic pain syndromes or who are on maintenance narcotics.
* Subjects with a history of torsades de pointes, known history of QT prolongation (e.g., congenital long QT syndrome), a QTc at baseline of 500 ms or over in the absence of bundle branch block, documented myocardial infarction within the previous 2 weeks, or uncompensated NYHA IV heart failure (dyspnea or anginal syndrome present at rest due to CHF). \[NOTE: ICU patients who have an incidental rise in troponin in the absence of definitive ischemic ECG changes remain eligible\]
* Subjects who are on neuroleptic therapy as an outpatient maintenance drug (e.g., haloperidol, mesoridazine, thorazine, chlorpromazine, trifluoperazine, droperidol, risperidone, quetiapine, olanzapine, or ziprasidone).
* Subjects who are receiving and will continue to receive other drugs that prolong the QT interval such as sotalol, quinidine, other Class Ia or III anti-arrhythmics, dofetilide (Tikosyn for arrhythmias), pimozide (for Tourette's), gatifloxacin, moxifloxacin (levofloxacin permissible), pentamidine, tacrolimus (Prograf), dolasetron (Anzemet). Azithromycin is an acceptable medication for study patients, and anyone slated to receive (or receiving) either clarithromycin or erythromycin can be switched to azithromycin by their primary team and be enrolled into the study the following day. Patients receiving clindamycin or clotrimazole will be excluded from the study.
* Subjects who have a history of neuroleptic malignant syndrome.
* Subjects with potassium levels below 3.0 mg/dl or magnesium levels below 1.8 mg/dl. NOTE: If the patient is receiving replacement of K+ or Mg+, then he/she would be eligible unless there is reason to suspect that these electrolyte abnormalities will be refractory.
* Subjects with moderate/severe dementia (e.g., Alzheimer's type, vascular origin, or HIV-related) as documented by medical history or modified Blessed dementia rating scale (mBDRS) 4 or more or Informant Questionnaire of Cognitive Dysfunction in the Elderly (IQCODE) over 3.6.
* Subjects who have suspected anoxic brain injury or documented cerebral edema at the time of screening.
* Subjects who are moribund and not expected to survive 24 hours from the time of study enrollment, or who have a "Do Not Resuscitate" order, or whose family or medical team have not committed to aggressive support (e.g., not going to use vasopressors or mechanical ventilation or likely to have withdrawal of support within 24 hours).
C: Inclusion Criteria:

* Adult patients (age 18 years or older) in a state of delirium (hyperactive ore mixed type) upon detection in the ICU (i.e., ICDSC \>3).

Exclusion Criteria:

* Hypersensitivity to the active substance
* Advanced heart block (grade 2 or 3) unless implanted pacemaker
* Uncontrolled hypotension
* Severe cardiac dysfunction
* Bradycardia
* Egg allergy
* Soybean/soy allergy
* Age below 18 years
* Terminal state
* Pregnancy
* Active psychosis (of non organic origin = functional disturbances)
* Status epilepticus or postictal states following seizures on EEG
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: B