[MODERN TECHNOLOGIES OF THE SAVING OF PATIENT'S BLOOD AND REDUCTION OF THE USE OF DONOR BLOOD DURING OPERATIONS ON THE ASCENDING AORTA AND AORTIC ARCH].

Questions of saving of the patient's blood and limitation of the use of donated blood in the aortic surgery remain relevant in contrast with interventions on the valves of the heart and coronary arteries. In this regard, the aim of the study was to develop and introduce ofcomplex of technologies for saving the patient's blood in order to minimize transfusion of donor blood components during operations on the ascending aorta and aortic arch under hypothermic arrest. The study included 37 patients operated on the ascending aorta and aortic arch under cardiopulmonary bypass (CPB) and hypothermic cardiac arrest (CA) in 2013-2014 (Group 1). 2nd group consisted of 65 patients who at the same time performed reconstructive surgery on the ascending aorta with CBP without stopping the blood circulation. The comparative aspect studied the following parameters: duration of the CBP, CA, temperature, volume of intraoperative and postoperative blood loss, frequency of use of donor blood components autoplasma, washed red blood cells, autologous blood, hemostatic agents, the frequency resternotomy, hematocrit dynamics, glucose, and blood lactate. Comparative studies have shown that the amount of intraoperative blood loss during operations on the aortic arch under the CA was 1294 ± 303 mL, 20% higher than the blood loss during operations on the ascending aorta without CA. Program of saving of the blood of patients with aortic disease included preoperative preparation of autoplasma in 60% of patients, intraoperative collection and laundering of autoerythrocytes in 40-70% of patients and autotransfusion modified method, the improvement of surgical and pharmacological hemostasis and monitoring. Design and implementation of these methods reduced the patients need for donor red blood cells (from 76 to 47%), fresh frozen plasma (from 65 to 35%) during the operation at the aortic arch and the ascending aorta and to completely avoid the use of donor blood in 25% of patients. Proof of the adequacy of the developed strategy of conservation and limitation of the patient's blood was allogeneic blood conservation targets hemoglobin, hematocrit levels and metabolism at the end of the operation.

Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.

Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer-drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems.

Perioperative moxifloxacin treatment in rats subjected to deep hypothermic circulatory arrest: reduction in cerebral inflammation but without improvement in cognitive performance.

OBJECTIVE: Moxifloxacin reduces infectious complications after cerebral damage, such as ischemia and stroke. This study investigated whether moxifloxacin treatment influences cerebral inflammation and improves cognitive outcome after cardiopulmonary bypass with deep hypothermic circulatory arrest in rats. METHODS: Rats were randomly assigned to deep hypothermic circulatory arrest (n = 40), sham operation (n = 40), and untreated control (n = 20) groups. Deep hypothermic circulatory arrest and sham groups were equally subdivided into moxifloxacin and placebo subgroups, receiving 6 × 100 mg/kg moxifloxacin or saline solution every 2 hours intraperitoneally. Hippocampal tumor necrosis factor α, nuclear factor κB, cyclooxygenase 2, and macrophages were assessed immunohistochemically. Histologic outcome was determined with hematoxylin and eosin. Neurologic outcome was assessed preoperatively and postoperatively. Cognitive performance was tested with the modified hole board test for 14 postoperative days. RESULTS: On postoperative day 14, deep hypothermic circulatory arrest moxifloxacin group was lower than deep hypothermic circulatory arrest placebo group in hippocampal neurons positive for tumor necrosis factor α (1.33, 0.73-2.37, vs 4.10, 2.42-18.67), nuclear factor κB (3.03, 1.33-5.20, vs 9.32, 2.53-24.14), and cyclooxygenase 2 (3.16, 0.68-6.04, vs 8.07, 3.27-19.91) and also had fewer macrophages than all other groups (72, 60-90, vs deep hypothermic circulatory arrest placebo 128, 76-203, sham moxifloxacin 89, 48-96, and sham placebo 81, 47-87). On postoperative day 14, both deep hypothermic circulatory arrest groups showed impaired motor, cognitive, and histologic outcomes relative to sham-operated groups, with no difference between deep hypothermic circulatory arrest subgroups. CONCLUSIONS: Moxifloxacin transiently reduces cerebral inflammatory reaction, but without impact on neurologic function, histologic outcome, or long-term cognitive performance.

Low hematocrit worsens cerebral injury after prolonged hypothermic circulatory arrest in rats.

PURPOSE: This study tests the hypothesis that low hematocrit (Hct) worsens cerebral injury after prolonged hypothermic circulatory arrest (HCA) in rats, and the mechanism involves variable expression of the genes C-Fos, Bcl-2 and Bax. METHODS: A rat HCA model was developed, and 40 animals were randomly assigned to four groups: Sham (sham) group, or Hct groups of Hct 10%, Hct 20% and Hct 30%. After 90 min of HCA at 18 degrees C, physiologic variables were recorded and brain morphological changes were evaluated with light and electron microscopy. Expressions of C-Fos, Bcl-2, Bax in various brain areas were measured by the reverse transcriptase polymerase chain reaction and standard immunohistochemistry techniques. RESULTS: The number of injured neurons in the hippocampus CA1 and parietal cortex in the Hct 10% group (CA1: 11.44 +/- 2.52; cortex: 13.65 +/- 2.31) exceeded the mean number of injured neurons in the Hct 20% group (CA1: 8.29 +/- 1.31; cortex: 10.68 +/- 1.24; P < 0.05) and the Hct 30% group. Mean mitochondrial injury scores were greatest at lower Hct levels, while the expression of C-Fos and Bax were highest in the Hct 10% group and lowest in the Hct30% group (P < 0.05). In contrast, the expression of the Bcl-2 mRNA was greatest in the Hct 30% group (P < 0.05). CONCLUSION: Low Hct worsens cerebral injury after prolonged HCA and CPB in rats, which may relate in part to the variable expression of the genes C-Fos, Bcl-2 and Bax.

Valproic acid prevents brain injury in a canine model of hypothermic circulatory arrest: a promising new approach to neuroprotection during cardiac surgery.

BACKGROUND: The anticonvulsant valproic acid (sodium valproate, Depacon) acts as a neuroprotectant in rodents, but has never been tested in larger animals. We used valproate in our canine model of hypothermic circulatory arrest to evaluate its neuroprotective benefit in complex cardiac surgical cases. METHODS: Thirteen dogs pretreated with valproate before 2 hours of hypothermic circulatory arrest survived for 24 hours (n = 7) or 72 hours (n = 6). Thirteen control animals (placebo only) also survived for 24 hours (n = 7) or 72 hours (n = 6) after hypothermic circulatory arrest. Blinded clinical neurologic evaluation was performed daily until sacrifice using the Pittsburgh Canine Neurologic Scoring System. Brains were harvested for blinded histopathologic analysis by a neuropathologist to determine the extent of apoptosis and necrosis in 11 brain regions (Total Brain Cell Death Score: 0 = normal, 99 = extensive neuronal death in all regions). Quantification of N-acetyl-aspartate, an established marker for brain injury, was performed with mass spectrometry. RESULTS: Valproate dogs scored significantly better than control animals on clinical neurologic evaluation. Histopathologic examination revealed that valproate animals demonstrated less neuronal damage (by Total Brain Cell Death Score) than control animals at both 24 hours (16.4 versus 11.4; p = 0.03) and 72 hours (21.7 versus 17.7; p = 0.07). At 72 hours, the entorhinal cortex, an area involved with learning and memory, was significantly protected in valproate dogs (p < 0.05). Furthermore, the cortex, hippocampus, and cerebellum demonstrated preservation of near-normal N-acetyl-aspartate levels after valproate pretreatment. CONCLUSIONS: These data demonstrate clinical, histologic, and biochemical improvements in dogs pretreated with valproate before hypothermic circulatory arrest. This commonly used drug may offer a promising new approach to neuroprotection during cardiac surgery.

Hypertonic saline dextran improves outcome after hypothermic circulatory arrest: a study in a surviving porcine model.

BACKGROUND: Hypertonic saline dextran (HSD) has been shown to have neuroprotective properties. In the present study we have assessed its potential neuroprotective efficacy in the setting of hypothermic circulatory arrest in a surviving porcine model. METHODS: Twenty-four pigs were randomized to receive two 5-minute intravenous infusions (4 mL/kg) of either HSD (7.5 % saline, 6% dextran 70) or normal saline immediately after and 4 hours after a 75-minute period of hypothermic circulatory arrest at a brain temperature of 18 degrees C. RESULTS: The 7-day survival was 75% in the HSD group and 66% in the control group (p > 0.9). Brain total histopathologic score was lower in the HSD group (p = 0.01). Postoperative behavioral scores were higher in the HSD group on the second day after surgery (p = 0.03). Intracranial pressure was lower in the HSD group from 45 minutes to 8 hours after hypothermic circulatory arrest (p = 0.03). Cerebral perfusion pressure was higher in the HSD group from 45 minutes to 3 hours after hypothermic circulatory arrest (p = 0.06). Brain lactate concentration was lower in the HSD group when compared with controls (p = 0.05). Furthermore, brain glucose levels tended to be higher and brain lactate-pyruvate ratio and lactate-glucose ratio were lower in the HSD group. Brain tissue oxygen partial pressures were somewhat higher in the HSD group (p = 0.08). CONCLUSIONS: The use of HSD in experimental hypothermic circulatory arrest is associated with significantly better neurologic recovery, better histopathology, lower intracranial pressure, higher cerebral perfusion pressure, and better preservation of brain metabolism.

S-nitroso human serum albumin attenuates ischemia/reperfusion injury after cardioplegic arrest in isolated rabbit hearts.

BACKGROUND: Depletion of nitric oxide (NO) is associated with ischemia/reperfusion injury. The novel NO donor, S-nitroso human serum albumin (S-NO-HSA), could bridge NO depletion during reperfusion in cardiac transplantation and minimize ischemia/reperfusion injury. METHODS: In an isolated erythrocyte-perfused working heart model, rabbit hearts were randomly assigned after assessment of hemodynamic baseline values to receive S-NO-HSA (0.2 micromol/100 ml, n = 8), L-arginine (10 mmol/100 ml, n = 8) or albumin (control) (0.2 micromol/100 ml, n = 8). After 20 minutes of infusion, the hearts were arrested and stored in Celsior (4 degrees C) enriched with respective drugs for 6 hours, followed by 75 minutes of reperfusion. Hemodynamic values were assessed and biopsy specimens were taken to determine calcium-ionophore stimulated release of NO and superoxide. RESULTS: During early reperfusion, recovery of cardiac output (75% +/- 6% vs 49% +/- 5%, p < 0.05) and coronary flow (99% +/- 8% vs 70% +/- 5%, p < 0.05) were higher, and myocardial oxygen consumption was reduced in the S-NO-HSA Group compared with Control (4.08 +/- 0.46 ml/min/0.1 kg vs 6.78 +/- 0.38 ml/min/0.1 kg, p < 0.01). At the end of the experiment cardiac output (53% +/- 5% vs 27% +/- 5%, p < 0.01) was higher and left atrial pressure (115% +/- 9% vs 150% +/- 8%, p < 0.05) was lower in the S-NO-HSA Group compared with Control. NO release was increased (1,040 +/- 50 nmol/liter and 1,070 +/- 60 nmol/liter vs 860 +/- 10 nmol/liter, p < 0.01) and superoxide release diminished (31 +/- 5 nmol/liter and 38 +/- 5 nmol/liter vs 64 +/- 5 nmol/liter, p < .01) in the S-NO-HSA and L-arginine Groups compared with Control. CONCLUSION: S-NO-HSA improved hemodynamic functions after prolonged hypothermic cardiac arrest by supplementing NO and thereby decreasing ischemia/reperfusion injury.