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

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.

Timeline

Start

2011-12-14

Primary completion

2017-08-28

Completion

2018-07-19

Publications

• Boehm LM, Mart MF, LaNoue M, Siao SF, Pun BT, Bowton DL, Exline MC, Gong MN, Hite RD, Hough CL, Hyzy RC, Khan BA, Owens RL, Pisani MA, Rock P, Schmidt GA, Jackson JC, Ely EW, Girard TD, Brummel NE. Association between ABCDE bundle compliance and long-term outcomes: a secondary longitudinal analysis. Intensive Care Med. 2026 Mar;52(3):466-475. doi: 10.1007/s00134-026-08346-0. Epub 2026 Feb 25.
• Ahn S, LaNoue M, Su H, Moale AC, Scheunemann LP, Kiehl AL, Douglas IS, Exline MC, Gong MN, Khan BA, Owens RL, Pisani MA, Rock P, Jackson JC, Ely EW, Girard TD, Boehm LM. Post-Intensive Care Syndrome and Caregiver Burden: A Post Hoc Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2025 Apr 1;8(4):e253443. doi: 10.1001/jamanetworkopen.2025.3443.
• Mart MF, Boehm LM, Kiehl AL, Gong MN, Malhotra A, Owens RL, Khan BA, Pisani MA, Schmidt GA, Hite RD, Exline MC, Carson SS, Hough CL, Rock P, Douglas IS, Feinstein DJ, Hyzy RC, Schweickert WD, Bowton DL, Masica A, Orun OM, Raman R, Pun BT, Strength C, Rolfsen ML, Pandharipande PP, Brummel NE, Hughes CG, Patel MB, Stollings JL, Ely EW, Jackson JC, Girard TD. Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. 2024 Aug;12(8):599-607. doi: 10.1016/S2213-2600(24)00077-8. Epub 2024 Apr 30.
• Stollings JL, Boncyk CS, Birdrow CI, Chen W, Raman R, Gupta DK, Roden DM, Rivera EL, Maiga AW, Rakhit S, Pandharipande PP, Ely EW, Girard TD, Patel MB. Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2024 Jan 2;7(1):e2352034. doi: 10.1001/jamanetworkopen.2023.52034.
• Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, Douglas IS, Malhotra A, Owens RL, Feinstein DJ, Khan B, Pisani MA, Hyzy RC, Schmidt GA, Schweickert WD, Hite RD, Bowton DL, Masica AL, Thompson JL, Chandrasekhar R, Pun BT, Strength C, Boehm LM, Jackson JC, Pandharipande PP, Brummel NE, Hughes CG, Patel MB, Stollings JL, Bernard GR, Dittus RS, Ely EW; MIND-USA Investigators. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018 Dec 27;379(26):2506-2516. doi: 10.1056/NEJMoa1808217. Epub 2018 Oct 22.

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