Rodent models of cardiopulmonary bypass: utility in improving perioperative outcomes

Abstract

Despite advances in surgical and anesthesia techniques, subtle neurologic injury still remains an important complication after cardiac surgery. Because the causes are multifactorial and complex, research in an appropriate small animal model for cardiopulmonary bypass (CPB) is warranted. This thesis describes several applications and adaptations of a rat model of cardiopulmonary bypass, all aimed to improve perioperative outcomes. First an appropriately sized oxygenator was implemented in the model. We then subjected old rats and diabetic rats to 90 min of CPB, and found that if CPB causes cognitive deficits, these are only subtle. Further, we investigated whether different temperature strategies would improve outcome. We concluded that mild hypothermia during CPB and continued into the postoperative period may have a beneficial effect. In the model we also tested a RNA molecule (aptamer) that inhibits Factor IX and thus is a very effective anticoagulant and a possible replacement for heparin. Anticoagulation during CPB and reversal with the aptamer were non-inferior compared to heparin, but 3 hr postoperative cardiac function was improved in the aptamer group when compared to the heparin/protamine group. Because hypoperfusion is thought to contribute to the observed deficits in humans, we tested an artificial oxygen carrier, able to dissolve large quantities of oxygen and deliver it in the microvasculature, in our rat CPB model. Administration of the oxygen carrier led to increased inflammation an mortality in the experimental group. In addition, we adapted the model to better mimic specific clinical situations and related research questions. We improved the model by induction of cardioplegic cardiac arrest while on CPB. Due to the closed-chest approach, survivability is warranted and longterm functional (ultrasound), enzymatic or histological outcomes can be assessed. To mimic embolic showers as can occur during cardiac surgery, we injected holmium microspheres. Due to the paramagnetic properties of holmium, the microspheres cause artifacts on MRI and can thus be easily located and quantified. We also changed the current delivery and injection technique and found the delivery reproducible in location and delivered load. We believe that the models described in this thesis will continue to help research aimed to improve perioperative outcomes.