The Modifying the Impact of ICU-Associated Neurological Dysfunction-USA (MIND-USA) Study
Condition: Delirium; Impaired Cognition; Long Term Psychologic Disorders
MeSH terms: Delirium; Cognitive Dysfunction
Intervention: Haloperidol; Ziprasidone; Placebo
Intervention description: 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.; 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.; 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.
Intervention MeSH terms: Haloperidol; Haloperidol decanoate; Ziprasidone
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double blind, placebo controlled
Enrollment: 566.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Delirium; Intensive care; Mechanical ventilation; Antipsychotic; Haloperidol; Ziprasidone; Randomized; Placebo; Sepsis; Sedation; Long-term cognitive impairment

Summary:

      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 561 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), 187 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.
    

Eligibility criteria:

        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.