**6. Strategies for brain protection during DHCA**

#### **6.1 Hypothermia – reduction of metabolism**

Hypothermia is the most efficient measure to prevent or reduce ischemic damage to the central nervous system when blood circulation is reduced. The central nervous system has a high metabolic rate and limited energy stores, which make it extremely vulnerable to ischemia (Elrich et al, 2002). Hypothermia acts by reducing the metabolic rate of the brain and improving the balance between energy supply and demand, and thus lengthens the period of tolerated ischemia. Hypothermia reduces cerebral blood flow (CBF) in a linear manner, but the decrease in cerebral metabolic rate of oxygen (CMRO2) is not exactly linear. On average, the reduction in CMRO2 is about 7%/1°C. Between 37°C and 22°C, CMRO2 is reduced by about 5%/1°C, and then the reduction accelerates when CMRO2 reaches 20% at 20°C and 17% at 18°C, at which point about 60% of patients achieve electrical silence on electroencephalography (EEG) (McCullough et al, 1999).

#### **6.2 Techniques and perfusion strategies**

Although reduction of cerebral metabolism and swift surgery are the two fundamental measures that can prevent or reduce brain damage during circulatory arrest, there are adjunctive protective measures that can be considered. The basic established techniques and perfusion strategies during aortic arch replacement number three: hypothermic circulatory arrest (HCA), antegrade cerebral perfusion (ACP), and retrograde cerebral perfusion (RCP).

Neurologic Injury Following Hypothermic Circulatory Arrest 249

relatively high at 18°C in traditional HCA protocols (McCullough et al., 1999). In light of evidence suggesting that the apoptotic pathway may be reversible in their earlier stages (McCullough et al., 1999), studies from our team were undertaken to assess whether cooling to 10°C can reduce neurological injury during 75 minutes of HCA in an acute porcine model compared to less profoundly cooled (18°C) animals, as assessed by DNA fragmentation, anti-apoptotic protein Bcl-2 expression, and ultrastructural changes in the sensory cortex. Sixteen male juvenile pigs from a commercial farm, 2-3 months of age and weighing 25-35 Kg were used for this study. The animals were divided into three groups: Group A (*n*=6) underwent hypothermic circulatory arrest at 18oC for 75 min, Group B (*n*=6) underwent hypothermic circulatory arrest at 10oC for 75 min and Group C (*n*=4)

Preparation and surgery were performed as previously described (Ananiadou et al 2005). Briefly, catheters were inserted in an ear vein and the left femoral artery for monitoring purposes and withdrawal of blood samples. Anesthesia was induced with intramuscularly ketamine hydrochloride (15 mg/kg), atropine (0.05 mg/kg), and dormicum (0.1 mg/kg) and was maintained with intravenous fentanyl (50-200 μg/kg), dormicum and 1% to 2% isoflurane. Paralysis was achieved with a bolus intravenous rocuronium (0.6 mg/kg) and

Animals were ventilated mechanically with 100% oxygen, after endotracheal intubation. Ventilator rate and tidal volume were adjusted to maintain the arterial carbon dioxide tension at 40 mmHg. Hematocrit values during cardiopulmonary bypass (CPB) were maintained between 13%-23%. A temperature probe was placed in the rectum, while brain temperature was determined with bilateral tympanic membrane probes. Urine output was collected through a bladder catheter (Foley 8-10 F). Arterial pressure, end-expired carbon dioxide, electrocardiogram, and blood gases (ABL Radiometer Medical A/S DK-2700,

As previously described, the chest was opened via a right thoracotomy in the fourth intercostal space (Ananiadou et al., 2005). After administration of intravenous heparin (300 IU/kg), cannulas were advanced to the ascending aorta (16 F arterial cannula) and to the right atrium (single 26 F cannula). Non-pulsatile CPB, was initiated at a flow rate of 100 ml/kg per min and then adjusted to maintain a minimum arterial pressure of 50 mmHg. To avoid distension of the left ventricle during CPB, a 10 F vent catheter was inserted via the superior pulmonary vein. The lungs were allowed to collapse after CPB was initiated. The CPB circuit was primed with a bloodless solution consisting of 1000cc lactated Ringer's, 50 ml mannitol, and 5000 IU heparin. Sodium bicarbonate was added to adjust the pH to 7.4, as

CPB was continued for an average 58 or 106 minutes, to reach a deep brain temperature of 18oC or 10oC, respectively. Myocardial protection was afforded by applying iced saline (4oC) topically during the 75-minute interval of hypothermic circulatory arrest. When the tympanic membrane temperature reached 18oC or 10oC, bypass was discontinued, the blood was drained into the oxygenator reservoir, and circulatory arrest was maintained for 75 minutes. Ice bags were positioned around the head to maintain the brain temperature during HCA. At the end of the arrest, bypass was initiated again with gradual rewarming to a rectal temperature of approximately 35oC to 36oC. A temperature gradient exceeding 10oC between the perfusate and the core temperature was avoided. A temperature of 36oC was reached after an average of 83 or 104 minutes of reperfusion for animals treated with 18 oC

served as normal controls.

was maintained with 20% of the total dose every 30 min.

Copenhagen, Denmark) were monitored.

necessary.
