Potent, Selective Sedative May Reduce or Prevent Cognitive Impairment after Open Heart Surgery

Stephen Choi, M.D., M. Sc.

University of Toronto

Grant Program:

Clinical Neuroscience Research

Funded in:

September 2018, for 3 years

Funding Amount:


Lay Summary

Potent, selective sedative may reduce or prevent cognitive impairment after open heart surgery

This study will assess a treatment that may minimize cognitive impairment in patients following cardiac surgery. Up to 60 percent of cardiac surgery patients show persistent cognitive impairments for weeks or months following surgery. McKhann and colleagues found that patients undergoing CABG (coronary artery bypass grafting) whether on or off a bypass pump showed long-term cognitive decline that was associated with patients’ coronary artery disease prior to surgery and not to the surgery itself. Clinicians consider that contributive factors also might include interactive surgical and anesthetic factors, medications used proximal to surgery, and inflammation related to pre-existing conditions or the surgical procedure. Finding effective ways to prevent or minimize risks of post-surgical cognitive impairments risks remains a high priority.

This anesthetic investigative team suggests that Dexmedetomidine (DEX) may confer beneficial effects in preventing cognitive impairment following cardiac surgery. DEX is a highly potent and selective sedative. Recent patient studies indicate that DEX may have beneficial effects on cognitive changes by reducing post-surgical delirium. Animal studies suggest that DEX may help prevent and/or restore impaired memory functions following anesthesia.

DEX appears to have both an indirect and direct effect on reducing cognitive impairment following cardiac surgery, investigators note. It may act indirectly through its sedating function to reduce the amount of anesthesia needed during surgery; and it may act directly by reducing brain inflammation, which could explain its beneficial effects regarding delirium. These DEX effects may potentially be sustained weeks to months following cardiac surgery. The investigators hypothesize that postoperative sedation using dexmedetomidine versus standard sedation protocols reduces the incidence of cognitive dysfunction three months after open cardiac surgery.

Surgical teams at three participating hospitals will conduct a randomized controlled study comparing DEX to standard sedation protocols (infused sedative anesthetic or antipsychotic-type pill) in ICU patients following open cardiac surgery using either valve replacement via sternotomy/thoracotomy or CABG, including off-pump. They will assess whether DEX has an effect on cognitive dysfunction months after surgery and whether it accelerates cognitive recovery following anesthesia and cardiac surgery. Blinded randomization assures that neither assessors nor patients will know which treatment was provided. They will assess in-hospital outcomes, including delirium, depression, cognitive dysfunction; and will conduct periodic post-discharge outcomes over the year to assess mild cognitive impairment and cognitive dysfunction.

Investigator Biographies

Stephen Choi, M.D., M. Sc.

Dr. Stephen Choi is an Associate Professor of Anesthesiology at the University of Toronto. He was appointed as a staff anesthesiologist at Sunnybrook Health Sciences Centre in 2011 and an affiliate scientist at Sunnybrook Research Institute. He was than appointed the director of the Clinical Research Unit in the Department of Anesthesia in 2014. After obtaining his MD from the University of Western Ontario (2005), he completed anesthesiology residency at the University of Toronto (2010), subspecialty training in regional anesthesia (2011), and an MSc in Health Research Methodology at McMaster University (2014). His research interests include examining optimal methods of providing superior post-operative analgesia with regional techniques and examining cognitive changes after major surgery. In addition to his own research program, he collaborates on multi-centre trials with internationally recognized investigators. Dr. Choi has been awarded over $350,000 in competitive, peer reviewed grants as a principal investigator. He is a co-investigator on several major, international peer-reviewed grants totalling $14 million. He has also authored/co-authored 20 peer reviewed manuscripts and is a consultant reviewer for Regional Anesthesia and Pain Medicine, Anesthesia and Analgesia, the British Journal of Anaesthesia, and the Canadian Journal of Anesthesia.


Dexmedetomidine to reduce the incidence of persistent cognitive dysfunction after open cardiac surgery: A multicentre randomized trial

Hypothesis: Postoperative sedation using dexmedetomidine versus standard sedation protocols reduces the incidence of cognitive dysfunction 3 months after open cardiac surgery. Background and Rationale: Postoperative Cognitive Dysfunction (POCD) is associated with significant morbidity, mortality and increased health care costs. Morbidity includes prolonged hospital length of stay (increased cost), premature retirement, and loss of independence (increased caregiver burden). Cardiac surgery appears to carry the highest risk of POCD, with the incidence ranging from 30- 80% of patients three weeks after surgery, and 10- 60% three to six months after surgery. Postulated etiologies include perioperative medications (such as GABA-ergic drugs), inflammation (underlying disease burden or surgical procedure), in the context of those with CAD an advancing CVD burden. Dexmedetomidine (DEX) is a highly potent and selective α2 receptor (α2R) agonist that has been used in clinical practice as a sedative, analgesic and anxiolytic. More recent studies suggest that DEX may have beneficial effects on early cognitive changes by reducing delirium in humans. It also has attenuating effects on memory deficits secondary to GABA-ergic medication including inhalational anesthetics, etomidate, propofol and benzodiazepines in murine models. Therefore, our goal is to investigate whether DEX has an effect on cognitive dysfunction months after surgery and whether it accelerates cognitive recovery from anesthesia and surgery.

Methods: Pragmatic, assessor/participant blinded, randomized controlled trial of consenting individuals ≥60 years scheduled CABG (including off-pump) or valve replacement (+/- CABG) via sternotomy/thoracotomy, with initial recovery in the Cardiovascular Intensive Care Unit (CVICU) without contraindications to DEX. Consenting participants will be randomized to one of the following protocols: 1. DEX group (Intervention): Dexmedetomidine will be loaded by the anesthesiologist in the operating room at the completion of surgery (at the time of sternal closure) prior to transfer to the CVICU. This will be followed by a titrated infusion in the CVICU. The infusion rate can be adjusted higher or lower at the discretion of the intensive care physician for clinical indications .The infusion will be stopped when the patient is ready for discharge from the CVICU or 24 hours of infusion (whichever is earlier). 2. Standard group: Standard sedation protocols. This includes, at the discretion of the attending physician in the CVICU, infusions of fentanyl, midazolam, or propofol while intubated. In extubated patients still in CVICU this could also include anti-psychotics such as quetiapine and haloperidol. Clinicians will not be blinded to group allocation. Study participants will effectively be blinded to group allocation, as the intervention is initiated when the participant is emerging from anesthesia. Data collectors and those administering postoperative cognitive tests will also be blinded to group allocation.

Primary Outcome: Presence of POCD 3 months after surgery. Secondary Outcomes: POCD at 6/12 months, in-hospital delirium death, hemodynamic instability (MAP< 60), time to extubation, re-intubation, length of stay (ICU/total), depression (3/6/12 months), in hospital opioid consumption, chronic surgical site pain Sample size calculation: Estimating a 25% incidence of POCD at 3 months with standard care, α= 0.05, β= 0.2, and effect size of DEX (40%), a sample size of 248 per group (496 total). To account for loss to follow-up (estimated at approximately 10%), 275 participants per group (550 total) will be recruited. Statistical analysis: Data will be analyzed on an intention-to-treat basis. Demographic data will be summarized and expressed using appropriate measures of central tendency and dispersion for continuous data, and frequency for categorical data. Inferential testing will be 2-sided. www.clinicaltrials.gov Identifier: NCT03480061