The Modifying the Impact of ICU-Associated Neurological Dysfunction-USA (MIND-USA) Study

• Survival [ Time Frame: 30-day, 90-day, and 1-year ] [ Designated as safety issue: No ]
• Delirium duration [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• ICU length of stay [ Time Frame: 1 to 90 days ] [ Designated as safety issue: No ]
  Time to ICU discharge, represented by readiness for ICU discharge indicated by a physician order for transfer to a lower level of care even if a bed availability problems prevent actual discharge from the ICU.
• Hospital length of stay [ Time Frame: 1 to 90 days ] [ Designated as safety issue: No ]
• Ventilator-free days [ Time Frame: 14 days ] [ Designated as safety issue: No ]
• ICU readmission [ Time Frame: 1 to 90 days ] [ Designated as safety issue: No ]
• Hospital readmission [ Time Frame: 1 to 365 days ] [ Designated as safety issue: No ]
• Neuropsychological dysfunction [ Time Frame: 3-month, 12-month ] [ Designated as safety issue: No ]
  Assessed using a battery of cognitive tests.
• Quality of life [ Time Frame: 3-month, 12-month ] [ Designated as safety issue: No ]
• Posttraumatic stress disorder [ Time Frame: 3-month, 12-month ] [ Designated as safety issue: No ]
• QTc prolongation [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]
• Extrapyramidal symptoms [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]
• Neuroleptic malignant syndrome [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]

• Survival [ Time Frame: 30-day, 90-day, and 1-year ] [ Designated as safety issue: No ]
• ICU length of stay [ Time Frame: 1 to 90 days ] [ Designated as safety issue: No ]
  Time to ICU discharge, represented by readiness for ICU discharge indicated by a physician order for transfer to a lower level of care even if a bed availability problems prevent actual discharge from the ICU.
• Neuropsychological dysfunction [ Time Frame: 3-month, 12-month ] [ Designated as safety issue: No ]
  Assessed using a battery of cognitive tests.
• Quality of life [ Time Frame: 3-month, 12-month ] [ Designated as safety issue: No ]
• Posttraumatic stress disorder [ Time Frame: 3-month, 12-month ] [ Designated as safety issue: No ]
• QTc prolongation [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]
• Extrapyramidal symptoms [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]
• Neuroleptic malignant syndrome [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]

The long-term objective of the MIND-USA (Modifying the Impact of ICU-Induced Neurological Dysfunction-USA) Study is to define the role of antipsychotics in the management of delirium in vulnerable critically ill patients. We and others have shown that delirium is an independent predictor of more death, longer stay, higher cost, and long-term cognitive impairment often commensurate with moderate dementia. The rapidly expanding aging ICU population is especially vulnerable to develop delirium, with 7 of 10 medical and surgical ICU patients developing this organ dysfunction. Antipsychotics are the first-line pharmacological agents recommended to treat delirium, and over the past 30 years they gained widespread use in hospitalized patients globally prior to adequate testing of efficacy and safety for this indication. Haloperidol, the most commonly chosen antipsychotic, is used by over 80% of ICU doctors for delirium, while atypical antipsychotics are prescribed by 40%. Antipsychotics safety concerns include lethal cardiac arrhythmias, extrapyramidal symptoms, and the highly publicized increased mortality associated with their use in non-ICU geriatric populations. The overarching hypothesis is that administration of typical and atypical antipsychotics—haloperidol and ziprasidone, in this case—to critically ill patients with delirium will improve short- and long-term clinical outcomes, including days alive without acute brain dysfunction (referred to as delirium/coma-free days or DCFDs) over a 14-day period; 30-day, 90-day, and 1-year survival; ICU length of stay; incidence, severity, and/or duration of long-term neuropsychological dysfunction; and quality of life at 90-day and 1-year. To test these hypotheses, the MIND-USA Study will be a multi-center, double-blind, randomized, placebo-controlled investigation in 876 critically ill, delirious medical/surgical ICU patients who are (a) on mechanical ventilation or non-invasive positive pressure ventilation or (b) in shock on vasopressors. In each group (haloperidol, ziprasidone, and placebo), 292 patients will be enrolled and treated until delirium has resolved for 48 hours or to 14 days (whichever occurs first) and followed for 1 year.

The primary and secondary outcomes of the MIND-USA investigation will be analyzed both according to the individual comparisons by group of "haloperidol treated" vs. "placebo treated" and "ziprasidone treated" vs. "placebo treated" and also the combined grouping of both antipsychotics ("haloperidol plus ziprasidone treated" patients vs. "placebo treated" patients).

• Delirium
• Impaired Cognition
• Long Term Psychologic Disorders

• Drug: Haloperidol
  Haloperidol, up to 10mg q12 hours, will be administered intravenously (IV) by bolus over up to 5 minutes at concentrations of 5mg/mL. Patient will only receive IV while in the ICU.
  Other Name: Haldol
• Drug: Ziprasidone
  Ziprasidone, up to 20mg q12 hours, will be administered intravenously (IV) by bolus over up to 5 minutes at concentrations of 10mg/mL. Patient will only receive IV while in the ICU.
  Other Name: Geodon
• Drug: Placebo
  Placebo, up to 10mL q12 hours, will be administered intravenously (IV) by bolus over up to 5 minutes. Patient will only receive IV while in the ICU.
  Other Name: Placebo

• Experimental: Haloperidol
  Intervention: Drug: Haloperidol
• Experimental: Ziprasidone
  Intervention: Drug: Ziprasidone
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

1. adult patients (≥18 years old)
2. in a medical and/or surgical ICU
3. on mechanical ventilation or non-invasive positive pressure ventilation (NIPPV), and/or requiring vasopressors due to shock
4. delirious (according to the CAM-ICU)

Exclusion Criteria:

1. Rapidly resolving organ failure criteria, indicated by planned immediate discontinuation of mechanical ventilation, NIPPV, and/or vasopressors at the time of screening for study enrollment
2. Pregnancy or breastfeeding (negative pregnancy test required prior to enrollment of female patients of childbearing age)
3. Severe dementia or neurodegenerative disease, defined as either impairment that prevents the patient from living independently at baseline or IQCODE >4.5, measured using a patient's qualified surrogate, mental illness requiring long-term institutionalization, acquired or congenital mental retardation, Parkinson's disease, Huntington's disease, and/or coma or another severe deficit due to structural brain disease such as stroke, intracranial hemorrhage, cranial trauma, intracranial malignancy, anoxic brain injury, or cerebral edema.
4. History of torsades de pointes, documented baseline QT prolongation (congenital long QT syndrome), or QTc >500 ms at screening due to refractory electrolyte abnormalities, other drugs, or thyroid disease
5. Ongoing maintenance therapy with typical or atypical antipsychotics
6. History of neuroleptic malignant syndrome (NMS), haloperidol allergy, or ziprasidone allergy
7. Expected death within 24 hours of enrollment or lack of commitment to aggressive treatment by family or the medical team (e.g., likely withdrawal of life support measures within 24 hours of screening)
8. Inability to obtain informed consent from an authorized representative within 72 hours of meeting all inclusion criteria, i.e., developing qualifying organ dysfunction criteria.