Sebastian Dahlbacka

Acute homing of bone marrow-derived mononuclear cells in intramyocardial vs. intracoronary transplantation

Objectives. Cell homing optimisation after transplantation is critical in myocardial infarction (MI) cell therapy. Design. Eight pigs were randomized to receiving autologous purified 111indium-labeled bone marrow mononuclear cells (BMMCs) (108 cells/2 ml) by intramyocardial (IM) (n=4) or by intracoronary (IC) (n=4) transplantation after 90 minutes occlusion of the CX-coronary artery. Dual isotope SPECT imaging was performed 2 and 24 hours postoperatively. Two animals were additionally analyzed on the sixth postoperative day. Tissue samples from the major organs were analyzed. Results. In SPECT imaging revealed that BMMCs administered using IM injection remained in the injured area. In contrast, minor proportion of IC transplanted cells remained in the myocardium, as most of the cells showed homing in the lungs. Analysis of the biopsies showed a seven-fold greater number of cells in the myocardium for the IM method and a 10-fold greater number of cells in the lungs in the IC group (p < 0.001). Conclusions. In producing persistently high cell homing at the infarction site, the IM transplantation is superior to the IC transplantation. However, the IC administration might be more specific in targeting injured capillaries and epithelial cells within the infarcted myocardium.

Ph-stat versus alpha-stat perfusion strategy during experimental hypothermic circulatory arrest: a microdialysis study

BACKGROUND The superiority of the pH-stat to the alpha-stat acid-base strategy during cardiopulmonary bypass as a neuroprotective method during hypothermic circulatory arrest is still controversial. In the present study, brain metabolism and outcome have been evaluated in a surviving model of experimental hypothermic circulatory arrest. METHODS Twenty pigs undergoing 75-minutes of hypothermic circulatory arrest at a brain temperature of 18 degrees C were randomly assigned to the alpha-stat (n = 10) or pH-stat (n = 10) strategy during cardiopulmonary bypass. RESULTS The 7-day survival rate was 90% (9 of 10) in the pH-stat group and 10% (1 of 10) in the alpha-stat group. At the end of cooling, pH-stat strategy was associated with significantly lower brain lactate and pyruvate concentrations and brain lactate-glucose ratio. After reperfusion, brain concentrations of glycerol, lactate, pyruvate, and lactate-glucose ratio were significantly lower in the pH-stat group. This strategy was associated with a faster rise of brain tissue temperature and reoxygenation on reperfusion, which is likely secondary to improved cerebral perfusion. CONCLUSIONS During cardiopulmonary bypass before and after a period of hypothermic circulatory arrest, acid-base management according to the pH-stat principles seemed to be associated with less derangements in cerebral metabolism, lower intracranial pressures, and excellent behavioral recovery and survival outcome. Because there is strong evidence of the beneficial metabolic effects related to this method, further studies using an experimental model of combined HCA and embolic brain injury are required to exclude a possible increased risk of cerebral embolism associated with the pH-stat strategy.

Fructose-1,6-bisphosphate supports cerebral energy metabolism in pigs after ischemic brain injury caused by experimental particle embolization.

BACKGROUND Fructose-1,6-bisphosphate (FDP) is a high-energy intermediate that enhances glycolysis, preserves cellular adenosine triphosphate stores, and prevents the increase of intracellular calcium in ischemic tissue. Since it has been shown to provide metabolic support to the brain during ischemia, we planned this study to evaluate whether FDP is neuroprotective in the setting of combining hypothermic circulatory arrest (HCA) and irreversible embolic brain ischemic injury. METHODS Twenty pigs were randomly assigned to receive 2 intravenous infusions of either FDP (500 mg/kg) or saline. The first infusion was given just before a 25-minute period of HCA and the second infusion immediately after HCA. Immediately before HCA, the descending aorta was clamped and 200 mg of albumin-coated polystyrene microspheres (250-750 mm in diameter) were injected into the isolated aortic arch in both study groups. RESULTS There were no significant differences between the study groups in terms of neurological outcome. Brain lactate/pyruvate ratio was significantly lower (P = .015) and brain pyruvate levels (P = .013) were significantly higher in the FDP group compared with controls. Brain lactate levels were significantly higher 8 hours after HCA (P = .049). CONCLUSION The administration of FDP before and immediately after HCA combined with embolic brain ischemic injury was associated with significantly lower brain lactate/pyruvate ratio and significantly higher levels of brain pyruvate, as well as lower lactate levels 8 hours after HCA. FDP seems to protect the brain by supporting energy metabolism. The neurological outcome was not improved, most likely resulting from the irreversible nature of the microsphere occlusion.

Propofol is Associated with Impaired Brain Metabolism during Hypothermic Circulatory Arrest: An Experimental Microdialysis Study

BACKGROUND Propofol is a widely used anesthetic in cardiac surgery. It has been shown to increase cerebrovascular resistance resulting in decreased cerebral blood flow. Efficient brain perfusion and tissue oxygenation during cardiopulmonary bypass (CPB) is essential in surgery requiring hypothermic circulatory arrest (HCA). The effects of propofol on brain metabolism are reported in a surviving porcine model of HCA. METHODS Twenty female juvenile pigs undergoing 75 minutes of HCA at a brain temperature of 18 degrees C were assigned to either propofol- or isoflurane anesthesia combined with alpha-stat perfusion strategy during CPB cooling and rewarming. Brain microdialysis analysis was used for determination of brain metabolism, and tissue oxygen partial pressure and intracranial pressures were also followed-up until 8 hours postoperatively. RESULTS Brain concentrations of glutamate and glycerol were significantly higher in the propofol group throughout the experiment (P < .01 and P < .01, respectively). The lactate/pyruvate ratio was significantly higher in the propofol group at 6-, 7-, and 8-hour intervals (P < .05, P < .01, and P < .05, respectively). The intracranial pressure was significantly higher at the 8-hour postoperative interval (P < .05) in the propofol group. A trend toward higher brain oxygen concentrations was observed in the isoflurane group. CONCLUSIONS Anesthesia with propofol as compared with isoflurane is associated with impaired brain metabolism during experimental HCA.

Apotransferrin, C1‐esterase inhibitor, and alpha 1‐acid glycoprotein for cerebral protection during experimental hypothermic circulatory arrest

Background—Because of current limitations in improving metabolic support to the brain during hypothermic circulatory arrest (HCA), attenuation of ischemia‐reperfusion injury remains an area of therapeutic intervention of relevance. Apotransferrin (Apo‐Tf), alpha 1‐acid glycoprotein (AGP), and C1‐esterase inhibitor (C1‐INH) have been herein evaluated as potential beneficial agents in reducing the ischemia‐reperfusion injury in a surviving model of HCA. Methods—Apo‐Tf 100 mg/kg (n = 6), C1‐INH 50 IU/kg (n = 6), AGP 100 mg/kg (n = 6), or NaCl 0.9% 2 ml/kg (n = 6) were randomly administered to 24 juvenile pigs after a 75‐min period HCA at a brain temperature of 18°C. Results—Animals in the Apo‐Tf group had a slightly better 7‐day survival (66.7%) compared with the other study groups (50%), but such a difference was not statistically significant. Some favorable changes in the brain glucose metabolism parameters were observed in the AGP, C1‐INH, and Apo‐Tf groups, but these did not reach statistical significance. Semiquantitative analysis of the histopathological findings did not show any significant difference between the study groups. However, only two out of four surviving animals in the Apo‐Tf group developed brain infarction, whereas all three survivors of the remaining study groups developed brain infarction. Conclusions—Although the small size of the study groups may affect the present findings, none of the metabolic and hemodynamic parameters as well as outcome endpoints indicate a substantial therapeutic efficacy of Apo‐Tf, AGP, and C1‐INH as neuroprotective agents after experimental HCA.

Portal vein cytokines in the early phase of acute experimental oedematous and necrotizing porcine pancreatitis.

Abstract Objective. Cytokines initiate and modify systemic inflammatory response in early acute pancreatitis. The aim of this study was to analyze which cytokines are released from the pancreas to portal venous blood in the early phase of acute experimental necrotizing and oedematous pancreatitis and which of those cytokines are correlated with the more severe form of the disease. Material and methods. Fifteen pigs were randomized to develop mild oedematous pancreatitis (n = 5, saline infusion to pancreatic duct), severe necrotizing pancreatitis (n = 5, taurocholic acid infusion) along with a control group (n = 5). Arterial and venous blood samples were drawn and cytokine levels were measured from portal vein blood at 0, 120, 240 and 360 min after the induction of pancreatitis. Tissue samples from the pancreas were harvested at 0 and 360 min. Results. White blood cell count increased in necrotizing pancreatitis and the control group. The amount of neutrophils increased (p < 0.001) and the lymphocyte and eosinophil counts decreased in all groups (p < 0.001, p < 0.001). The monocyte count, as well as PDGF and IL-6 concentrations, increased only in necrotizing pancreatitis. IL-8 and eotaxin increased both in oedematous and necrotizing pancreatitis. MCP-1 increased in all groups. IL-9, IL-4, MIP-1α, IFN- γ concentrations did not change. Eotaxin and MCP-1 plasma levels from a previous series between portal venous and pulmonary arterial blood were not significantly different. Conclusions. The initial inflammatory process was diverse in oedematous and necrotizing pancreatitis. Increased monocyte count in combination with elevated PDGF and IL-6 are characteric of necrotizing pancreatitis in our model.

Granulation tissue is altered after intramyocardial and intracoronary bone marrow-derived cell transfer for experimental acute myocardial infarction

BACKGROUND Bone marrow-derived mononuclear cell (BMMC) treatment in acute myocardial infarction (AMI) has been shown to have a beneficial effect. Our objective was to study in detail the histopathological process after the cell therapy after intramyocardial (IM) or intracoronary (IC) administration of BMMCs following experimental AMI. METHODS Twenty-fours pigs were randomized to the IM group (n=8), the IC group (n=8), and the control group (n=8).After 90 min of transient occlusion of the circumflex coronary artery, BMMCs were injected either intramyocardially or by a transfemoral catheter into the circumflex coronary artery. Echocardiography was performed preoperatively, postoperatively, and after a 21-day recovery period. The heart biopsies were examined histopathologically. Volumetric ex vivo CT scan was performed to evaluate calcification of the infarcted myocardium. RESULTS The ejection fraction (EF) showed significant recovery in the IM group compared to the control group at Day 21 (P=.05). Despite beneficial histological changes in the infarction site in the IC group, compared to the control group, EF failed to recover. Reduction of collagen density that depicts scar formation was seen in both cell therapy groups compared to the control (P<.001). The number of mitotic cells was higher in the control group compared to the cell therapy groups (P<.001). The IC and IM groups differed significantly from each other in muscle-specific actin staining (P<.001) and smooth muscle actin staining (P<.004). The IM therapy group showed higher density for both stainings. Additionally, macrophage density was higher in the IC group compared to the IM and control groups (P<.002). Both cell therapy regimens substantially diminished tissue calcification; due to the large variation, the effect was not statistically significant. CONCLUSION BMMC therapy launches cellular changes that affect mostly the repair process in the granulation tissue. The cell transplantation method might have some effect on the magnitude of the effect.

Aprotinin to improve cerebral outcome after hypothermic circulatory arrest: a study in a surviving porcine model.

BACKGROUND Aprotinin is a serine protease inhibitor, which is usually used during cardiac surgery to reduce blood loss. There is evidence that aprotinin has neuroprotective effects during ischemia. We planned this study to evaluate its potential neuroprotective efficacy during hypothermic circulatory arrest (HCA). METHODS Twenty piglets with a median weight of 25.7 kg (interquartile range, 23.9-26.6) were randomly assigned to receive aprotinin or placebo prior to a 75-minute period of HCA at 18 degrees C. Brain microdialysis parameters and neurological and histological scores were the primary outcome measures. RESULTS Changes in brain metabolic parameters and histopathological findings were favorable in the aprotinin group. Brain lactate concentrations were significantly lower in the aprotinin group during the experiment (P = .02) along with blood lactate concentrations in the aprotinin group (P = .023). Brain glucose was significantly higher during the experiment (P = 0.02). Intracranial pressure tended to be higher in the control group. Two of 10 animals in the aprotinin group and 4 of 10 in the control group failed to reach full recovery on the seventh postoperative day. Four animals of 10 in the aprotinin group and 6 animals of 10 in the control group had brain infarction (P = .40). CONCLUSIONS The present data suggest that aprotinin mitigates cerebral damage and improves neurological outcome following a period of HCA.