The long-term objective of the proposed 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.
Aim 1 will determine whether haloperidol or ziprasidone will increase days alive without acute brain dysfunction (referred to as delirium/coma-free days or DCFDs) over a 14-day period compared with placebo and compared to one another.
Aim 2 will determine whether haloperidol or ziprasidone will improve 30-day, 90-day, and 1-year survival compared with placebo and compared to one another.
Aim 3 will determine whether haloperidol or ziprasidone will reduce ICU length of stay compared with placebo and compared to one another.
Aim 4 will determine whether haloperidol or ziprasidone will reduce the incidence, severity, and/or duration of long-term neuropsychological dysfunction and improve quality of life at 90-day and 1-year follow-up compared with placebo and compared to one another. To address these Aims, we will conduct this 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. We will monitor many safety parameters such as cardiac dysrhythmias and extrapyramidal symptoms. This study will have adequate power to detect the effect of antipsychotics in 4 important subgroups including age >65 years, severity of illness (APACHE II >25), severe sepsis at enrollment, and medical vs. surgical ICU patients, and a hypothesis generating analysis of patients with pre- existing cognitive impairment.

Public Health Relevance

Millions of critically ill patients every year develop confusion (delirium) while in Intensive Care Units (ICUs), and though a large portion of these patients go undetected and untreated, ICU teams most often use typical and atypical antipsychotics to treat such patients despite no support from placebo-controlled trials. The MIND-USA trial will be the first study ever to answer the question of whether haloperidol or an atypical antipsychotic (ziprasidone) is better or worse than a placebo as treatment for delirious medical and surgical ICU patients. This investigation will determine if either haloperidol or ziprasidone shorten delirium duration, improve survival, affect length of stay in the hospital, or improve long-term brain function and quality of life at 1-year follow-up.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG035117-03S1
Application #
8853188
Study Section
Program Officer
Wagster, Molly V
Project Start
2011-03-15
Project End
2017-02-28
Budget Start
2014-09-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hayhurst, Christina J; Pandharipande, Pratik P; Hughes, Christopher G (2016) Intensive Care Unit Delirium: A Review of Diagnosis, Prevention, and Treatment. Anesthesiology 125:1229-1241
Vasilevskis, Eduard E; Pandharipande, Pratik P; Graves, Amy J et al. (2016) Validity of a Modified Sequential Organ Failure Assessment Score Using the Richmond Agitation-Sedation Scale. Crit Care Med 44:138-46
Tomichek, Jason E; Stollings, Joanna L; Pandharipande, Pratik P et al. (2016) Antipsychotic prescribing patterns during and after critical illness: a prospective cohort study. Crit Care 20:378
Humble, Stephen S; Wilson, Laura D; Leath, Taylor C et al. (2016) ICU sedation with dexmedetomidine after severe traumatic brain injury. Brain Inj 30:1266-70
Smith, Heidi A B; Han, Jin H; Ely, E Wesley (2016) Meeting the Challenges of Delirium Assessment Across the Aging Spectrum. Crit Care Med 44:1775-7
Choi, Leena; Ferrell, Benjamin A; Vasilevskis, Eduard E et al. (2016) Population Pharmacokinetics of Fentanyl in the Critically Ill. Crit Care Med 44:64-72
Patel, Mayur B; Jackson, James C; Morandi, Alessandro et al. (2016) Incidence and Risk Factors for Intensive Care Unit-related Post-traumatic Stress Disorder in Veterans and Civilians. Am J Respir Crit Care Med 193:1373-81
Brummel, Nathan E; Balas, Michele C; Morandi, Alessandro et al. (2015) Understanding and reducing disability in older adults following critical illness. Crit Care Med 43:1265-75
Han, Jin H; Vasilevskis, Eduard E; Schnelle, John F et al. (2015) The Diagnostic Performance of the Richmond Agitation Sedation Scale for Detecting Delirium in Older Emergency Department Patients. Acad Emerg Med 22:878-82
Bassett, Rick; Adams, Kelly McCutcheon; Danesh, Valerie et al. (2015) Rethinking critical care: decreasing sedation, increasing delirium monitoring, and increasing patient mobility. Jt Comm J Qual Patient Saf 41:62-74

Showing the most recent 10 out of 48 publications