Study challenges notion that inhaled anesthetic is superior during open heart surgery.

The culmination of more than 20 years of research looking into the properties of intravenous anesthetic propofol by Vancouver Coastal Health Research Institute scientist Dr. David Ansley and his team of researchers is reflected in Dr. Ansley’s recently published, and controversial, paper in the Canadian Journal of Anesthesia. Central to the paper is a 10-year-long clinical study looking specifically at whether propofol offers an effective approach to protecting the heart from damage during open heart surgery, particularly amongst diabetes patients whose hearts are more vulnerable to such harm. The study was supported by the Canadian Institutes of Health Research, Canadian Anesthesia Research Foundation, and International Anesthesia Research Foundation.

In the mid-1980s, researchers began investigating whether inhaled anesthetic could – in addition to anesthetizing patients – effectively pre-condition the heart to mitigate the stress that the muscular organ experiences during open heart surgery. Their studies focused on finding strategies for inhaled anesthetic that could increase the heart’s ability to withstand damage that happens after its blood flow has been stopped (ischemia) and when its blood supply returns (reperfusion), which is called ischemia-reperfusion injury.

Today, a significant amount of data indicates that inhalational anesthetics work well for cardiac surgery because of their cardioprotective effects; however, little data exists showing that propofol offers the same benefit.

While other research groups focused on how to best to produce cardioprotective effects using inhaled anesthetic, Dr. Ansley was testing propofol’s potential for cardioprotection using a technique he and his group developed in experimental heart models, then developed for use in patients. The technique involved highly controlled, increasing doses of propofol for a very focused period of time during cardiopulmonary bypass. The ultimate goal was to administer the anesthetic to diabetic patients during open heart surgery.

He and his team found that compared to the commonly used inhaled anesthetic isoflurane, continuous systemic combined with intermittent delivery of propofol during ischemia-reperfusion was associated with better health outcomes following aortocoronary bypass surgery. Propofol may be a preemptive cardioprotectant for patients with type 2 diabetes.

Propofol paradigm shifts toward pro-oxidant rather than anti-oxidant

Propofol was thought to protect the heart because of its supposed antioxidant properties. With this in mind, Dr. Ansley and his team wanted to investigate if they could adapt propofol use during open heart surgery to take advantage of its antioxidant potential to offset cell damage.

“Our limited understanding at the time was: if you render the heart ischemic and then reperfuse it, that’s a real stimulus for free-radical biology, which basically generates these unstable, negatively charged particles of oxygen that can be very disruptive to cell membranes, proteins, DNA, and can result in injury, dysfunction, or death of organs,” Dr. Ansley, who is a clinical professor in the Department of Anesthesiology, Pharmacology and Therapeutics in the Faculty of Medicine at the University of British Columbia, explains. “This has been the operating paradigm for years: anesthesiologists are taking advantage of an antioxidant property of propofol to stop free radical insult, which ultimately is expected to translate into improved outcomes.”

However, upon examining the use of the drug in increasing concentrations to evaluate its effect on the heart, Dr. Ansley and his team began seeing otherwise in cells in vitro and in patients in surgery.

“Quite paradoxically, based on our research we think the drug actually stimulates a process that is pro-oxidant, rather than antioxidant, and the cells in the heart are responding to these pro-oxidant activities,” he explains. “Originally we thought we’re protecting the heart by soaking up free radicals, but the reality is that propofol and how we administer it is actually changing the biology of the heart to a more favourable profile that protects mitochondria, keeping cell tissue alive.”

“This is an entirely different paradigm, and different from how inhaled anaesthetics probably work. The whole biology connected to the use of propofol is different, meaning the mechanisms are different, and therefore the outcomes are different. And few people know this.”

“The good news is, yes, we’ve found a technique that doesn’t currently exist that we actually believe will be of true benefit to diabetes patients undergoing open heart surgery,” says Dr. Ansley.

The challenging news though is that propofol does not behave as researchers originally thought.

“In fact, it’s much more complex than what we thought,” he says. “But as we understand that complexity more, we can begin to identify which patients might benefit from this because we have an underlying understanding of how the biology is changed by the drug. We’re basically beginning down the road of predictive medicine.”

Dr. Ansley cautions that the study’s results should be considered more hypothesis-generating than confirmatory. And given the paradigm shifting results, he and his team are continuing researching the molecular mechanism, functional significance, and therapeutic impact of propofol cardioprotection in patients with type 2 diabetes.