About the MINDDS II Study
The MINDDS II study is a pragmatic phase III, randomized, blinded, double placebo-controlled, three-arm trial of elderly patients following cardiac surgery to assess the relationship between nighttime intravenous and sublingual dexmedetomidine on postoperative delirium and functional outcomes after surgery. Using this robust infrastructure, MINDDS II also provides a biorepository of plasma, ribonucleic, and deoxyribonucleic samples to enable future insights into postoperative delirium.
What is the rationale for this study?
Postoperative delirium (POD) is an acute state of confusion marked by inattention and global cognitive dysfunction that occurs shortly after surgery, and can occur in up to 30% of the approximately 400,000 patients who undergo major cardiac surgery annually in the United States. Disturbingly, the cognitive decline observed in patients who develop POD appears to accelerate Alzheimer’s disease and related dementia (ADRD). Recent studies have shown an association between increased systemic markers of neurodegeneration, such as neurofilament light chain and tau, and the incidence and severity of POD, both in non-cardiac and cardiac surgery. Hence, there is a possibility that major cardiac surgery exacerbates underlying vulnerabilities related to ADRD, leading to POD. Recent studies have suggested that approximately 30% to 40% of POD may be preventable. However, multicomponent nonpharmacological POD prevention strategies are resource intensive and increasingly challenging to implement. At present, there are no definitive guidelines or large clinical trials supporting the use of any medication to prevent postoperative delirium.
Why is IV and sublingual dexmedetomidine being proposed?
Dexmedetomidine, an alpha-2 adrenergic agonist, possesses sleep-promoting, anti-inflammatory, and brain toxin clearance properties. In a single-center, explanatory trial involving elderly patients (aged ≥ 60 years) undergoing cardiac surgery, we found that a short (40-minute infusion) nighttime intravenous (IV) dexmedetomidine infusion reduced the next-day incidence of POD. Preliminary studies from this cohort demonstrate that nighttime dexmedetomidine also modified the relationship between pre-surgical levels of neurofilament light chain and POD. These data provide biological plausibility for using nighttime IV dexmedetomidine to prevent POD and suggest that non-IV formulations may also be suitable for POD prevention.
What will happen during the study?
In this study patients will be will be assessed before surgery to evaluate their baseline cognitive performance and functional status. Enrolled patients will then be randomized to one of three groups including intravenous dexmedetomidine (1 μg/kg over 40 minutes, a maximal dose of 80 μg), sublingual dexmedetomidine (120 μg), or placebo (saline over 40 minutes and/or inert sublingual film) which will be initially administered and subsequently every night throughout the ICU stay for up to three days postoperatively. All three groups will include an intravenous and/or sublingual placebo, as appropriate, to maintain the study blinding. Participants will then be assessed twice daily for the first three days after surgery for delirium and changes in neurocognitive function after surgery. Blood will be collected at three different timepoints, including before surgery, intraoperatively and on postoperative day one. Throughout their hospital stay data will be abstracted from the electronic medical record to maintain a robust clinical database for research. Following discharge, patients will be contacted at 1, 3 and 12 months after surgery to evaluate overall cognition and functional status after surgery.
Who can participate in the MINDDS II study?
This study will enroll 1,800 patients aged 60 or greater who are planning to undergo cardiac surgery with cardiopulmonary bypass at one of the 12 participating centers. Exclusions are designed to protect patient safety and maximize scientific integrity. Patients will be excluded if they are unable to tolerate the study procedures (e.g. hypersensitivity of the study medication) or meet one of the predefined study exclusion criteria.
What study outcomes are being evaluated?
The primary outcome of this study is postoperative delirium occurring on the day after surgery. We will also be evaluating secondary outcomes including delirium and delirium severity within the first three days after surgery, changes in cognition, changes in health and physical function up to a year after surgery, as well as characteristics of the in-hospital stay (e.g. pain, opioid use, length of stay, mortality).
Is this study funded?
This study is funded by the National Institutes of Health (NIH) National Institute on Aging (NIA) as grant 1R01AG083777. To find out more, please click here.
What is the current status?
This study is actively open to enrollment. As of January 2025, 0.6% of the 1800 subjects have been enrolled.