Priming fluids for cardiopulmonary bypass have been extremely varied, with resultant hemodilution. Furthermore, major surgeries utilizing cardiopulmonary bypass require multiple postoperative transfusions of blood and blood products. The appeal of having a readily available blood substitute for major cardiovascular and neurosurgical operations could prove to be a life saver, while also eliminating the risk of diseases transmitted by transfusion. Blood substitutes could also lessen the reported complications resulting from blood damage due to prolonged circulation of the blood by the extracorporeal pump. A technique was examined in 15 dogs using hypothermia for maximum metabolic suppression, incorporating an aqueous blood substitute (Cryomedical Sciences, Inc., Rockville, MD). The anesthetized animals were cannulated for extracorporeal pump oxygenation. As temperature was lowered the dogs were exsanguinated and volume replaced with blood substitute to lower the hematocrit to <1 %. After 3 hours of cardiac arrest and continuous perfusion at a core temperature < 10°C, rewarming began. When temperature reached ≥ 10°C, the blood substitute was drained and the animals were autotransfused. The heart was started at l5°C and spontaneous respiration resumed at 29°C. Using the first generation blood substitute the survival rate was maximal (100%) at 2.5 hrs under 10°C and 3 hours of cardiac arrest. Research is underway on a new blood substitute, which is to serve as a universal hypothermic preservation solution (in situ organ preservation). When perfected, combining total blood substitution and cooling to ultraprofound (< 10°C) levels may prove beneficial in sustaining cerebral ischemia for prolonged time periods, without incurring major metabolic debt. This may provide significant benefits for neurovascular surgery by prolonging the safe limits of cardiac arrest for several hours, rendering currently inoperable tumors and aneurysms more approachable, as well as a multitude of cardiovascular applications. In addition, this technique could find application in other interventional techniques, including systemic trauma resuscitation and transplantation cases.