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 degrees 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.

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.

EEG burst recovery is predictive of brain injury after experimental hypothermic circulatory arrest.

OBJECTIVE: To evaluate whether electroencephalography (EEG) recovery could be considered a reliable marker of brain injury after experimental hypothermic circulatory arrest (HCA). DESIGN: Cortical electrical activity was registered before and after a 75-min period of HCA in 27 pigs that survived 7 days after the experiment. The sum of EEG bursts was counted as a percentage of the sum of artifact-free bursts and suppressions, and this percentage was used as a measure of EEG activity in the analysis. RESULTS: Brain infarction developed in 13 animals (48.1%), in 12 cases (44.4%) having involved the cortex, in 1 case the thalamus (3.7%) and in another the hippocampus (3.7%). The mean EEG burst percentage significantly correlated with the total brain histopathological score (rho = -0.588, P = 0.001). EEG burst percentage from the 2 h 20 min to the 7 h 20 min interval correlated with the total brain histopathological score and with the cortex, brainstem and cerebellum scores. The mean EEG burst percentage rate was higher, but not significantly, among the animals without brain infarction (38.5% vs 32.4%), but such a difference was significant at the 3 h 20 min postoperative interval (P = 0.02). The mean EEG burst percentage significantly correlated with brain glucose concentration at the 1 h interval (rho = 0.387; P = 0.046), brain lactate concentration at the 2 h interval (rho = -0.431; P = 0.025), and the brain lactate/glucose ratio at the 1 h 30 min interval from the start of rewarming (rho = -0.433; P = 0.024). CONCLUSION: A decreased EEG burst percentage seems to be associated with an increased risk of developing histologically evident brain ischemic injury in the cortex, brainstem and cerebellum after experimental HCA.

Topical head cooling during rewarming after experimental hypothermic circulatory arrest.

BACKGROUND: The aim of this study was to evaluate the potential neuroprotective effect of topical head cooling during the first 2 postoperative hours after experimental hypothermic circulatory arrest. METHODS: Twenty pigs underwent a 75-minute period of hypothermic circulatory arrest and were randomly assigned to rewarming to 37 degrees C or to undergo topical cooling of the head for 2 hours from the start of rewarming followed by a period of external rewarming to 37 degrees C. RESULTS: The 7-day survival rate was 70% in the control group and 60% in the topical head cooling group. Despite brain tissue oxygenation, intracranial pressures, mixed oxygen venous saturation, oxygen consumption, and extraction tended to be favorable in the topical head cooling group as a clear effect of mild hypothermia. The latter group had significantly higher postoperative brain lactate and pyruvate ratios, and lactate and glucose ratios. Furthermore, the topical head cooling group had worse fluid balance throughout the postoperative period. Brain histopathologic scores were comparable with the study groups, but among 7-days survivors these scores tended to be worse in the topical head cooling group. CONCLUSIONS: Topical cooling of the head during the first 2 postoperative hours after experimental hypothermic circulatory arrest does not appear to provide any neuroprotective effect.

Fructose-1,6-bisphosphate for improved outcome after hypothermic circulatory arrest in pigs.

OBJECTIVE: Fructose-1,6-bisphosphate is a high-energy intermediate in the anaerobic metabolism. It enhances glycolysis, preserves cellular adenosine triphosphate, and prevents the increase of intracellular calcium during ischemia. The potential neuroprotective effect of fructose-1,6-bisphosphate during hypothermic circulatory arrest was evaluated in a surviving porcine model. METHODS: Twenty-four pigs were randomly assigned to receive two intravenous infusions of either fructose-1,6-bisphosphate (500 mg/kg) or saline solution. The first infusion was given immediately before a 75-minute period of hypothermic circulatory arrest and the second was given immediately after hypothermic circulatory arrest. RESULTS: The 7-day survivals were 83.3% in the fructose-1,6-bisphosphate group and 41.7% in the control group (P =.09). The treated animals had significantly better postoperative behavioral scores. The administration of fructose-1,6-bisphosphate was associated with higher venous phosphate and sodium levels, lower venous ionized calcium levels, higher blood osmolarity, and a better fluid balance. Intracranial pressure and venous creatine kinase isoenzyme MB were significantly lower in the fructose-1,6-bisphosphate group during rewarming (P =.01 and P =.001, respectively). Among the treated animals, brain glucose, pyruvate and lactate levels tended to be higher, brain glycerol levels tended to be lower, and the histopathologic score of the brain was significantly lower (P =.04). CONCLUSIONS: Intravenous administration of fructose-1,6-bisphosphate at 500 mg/kg before and after hypothermic circulatory arrest in a surviving porcine model was associated with better survival, behavioral outcome, and histopathologic score. The observed lower blood creatine kinase isoenzyme MB and brain glycerol levels and the higher brain glucose, pyruvate, and lactate levels in the fructose-1,6-bisphosphate group suggest that this drug has supportive effects on myocardial and brain metabolisms.

Increase of intracranial pressure after hypothermic circulatory arrest in a chronic porcine model.

OBJECTIVE: An increase in intracranial pressure has been shown to threaten the outcome of patients with ischemic or traumatic brain injury. Its impact on the outcome of pigs undergoing hypothermic circulatory arrest has been evaluated in this study. DESIGN: Fifty-six pigs underwent a 75-min period of hypothermic circulatory arrest at 20 degrees C. Intracranial pressure, cerebral microdialysis, hemodynamic and metabolic parameters were monitored throughout the experiment. The animals were allowed to survive until the 7th postoperative day and, then, electively killed. RESULTS: The 7-day survival rate was 60.7%, and among survivors, 20 of them (58.8%) developed brain infarction. A significant increase in intracranial pressure as compared with the baseline level was observed since the end of cooling (p = 0.047) and the difference became larger during all the postoperative intervals (p < 0.0001). Animals that died postoperatively tended to have higher intracranial pressure levels during all the postoperative intervals, but such a difference reached significance only at the 4-h postoperative interval (p = 0.040). The same tendency was observed among animals that survived until the 7th postoperative day and that developed brain infarction or not, but the difference between these two groups did not reach statistical significance. The animals that died or developed postoperatively brain infarction had higher intracranial pressure values postoperatively as compared with those that survived without developing brain infarction and such a difference reached significance at the 2-h (p = 0.015) and 4-h postoperative intervals (p = 0.035). The peak intracranial pressure was 17.2 mmHg (IQR, 13.7-20.8) in animals that died or developed brain infarction and 14.1 mmHg (IQR, 11.8-16.4) in those that survived 7 days without developing brain infarction (p = NS). CONCLUSION: Intracranial pressure increases significantly after 75 min of experimental hypothermic circulatory arrest and such an increase is associated with a high risk of postoperative death and brain infarction.

Potential neuroprotective benefits of erythropoietin during experimental hypothermic circulatory arrest.

OBJECTIVE: Recent studies have shown that erythropoietin protects neurons from glutamate toxicity and ischemia. This study was performed to evaluate the potential neuroprotective effect of erythropoietin during experimental hypothermic circulatory arrest. METHODS: Twenty pigs were randomized to receive intravenously either 500 IU/kg recombinant human erythropoietin or saline before a 75-minute period of hypothermic circulatory arrest at an intracerebral temperature of 18 degrees C. RESULTS: After the administration of erythropoietin, its concentration in the cerebrospinal fluid increased 4.5-fold 8 hours after the start of rewarming, whereas it did not increase in control animals. The 7-day survival rate was 60% in the erythropoietin group and 70% in the control group (P = 1.0). No significant differences were observed between the study groups in terms of electroencephalography, behavioral score, and histopathologic score. The erythropoietin group had higher vascular resistance and mean arterial pressure values, lower intracerebral concentrations of glutamate and glycerol, higher brain tissue oxygen tension, and lower apoptotic index. CONCLUSIONS: Administration of 500 IU/kg erythropoietin intravenously before hypothermic circulatory arrest was followed by an increased erythropoietin concentration in the cerebrospinal fluid. Although previous studies have demonstrated neuroprotective effects of erythropoietin during brain ischemia, the present study, using a chronic porcine model, failed to show any significant benefit after administration of erythropoietin in terms of mortality or brain histopathology. Lower intracerebral concentrations of glutamate and glycerol, higher brain tissue oxygen tension, and lower apoptotic index observed in the erythropoietin group, however, suggest that a distinct neuroprotective effect of erythropoietin might be achieved at different dosages and timing of administration.

Neurotic psychopathology and alexithymia among winter swimmers and controls--a prospective study.

Random samples of 25 voluntary Finnish winter swimmers (7 males, 18 females) and 11 controls (3 males, 8 females were followed prospectively during the winter season from October 1999 to May 2000 to (determine whether winter swimming is beneficial for mental well-being, as many of its practitioners claim. The Crown-Crisp Experimental Index (CCEI) was used for measuring free-floating anxiety, phobic anxiety, obsessionality, depression, somatic anxiety and hysteria, and the 20-item version of the Toronto Alexithymia Scale (TAS-20) for measuring alexithymia. Self-reported somatic and mental health and the reasons for and the frequency of winter-swimming were asked, too. As resealed by open questions, the winter swimmers reported positive effects of winter swimming. Several of the swimmers also told that they had started winter swimming to improve their physical and mental health. Their experience was that the swimming had relieved physical symptoms and made their mood more positive. However, we found no major differences between winter swimmers and controls in any CCEI or TAS variables. The structured questionnaires do not necessarily, however, reach subjective feelings and experiences.

Prolonged mild hypothermia after experimental hypothermic circulatory arrest in a chronic porcine model.

OBJECTIVES: We sought to evaluate the potential efficacy of prolonged mild hypothermia after hypothermic circulatory arrest. METHODS: Twenty pigs, after a 75-minute period of hypothermic circulatory arrest, were randomly assigned to be rewarmed to 37 degrees C (normothermia group) or to 32 degrees C and kept at that temperature for 14 hours from the start of rewarming (hypothermia group). RESULTS: The 7-day survival was 30% in the hypothermia group and 70% in the normothermia group (P =.08). The hypothermia group had poorer postoperative behavioral scores than the normothermia group. Prolonged hypothermia was associated with lower oxygen extraction and consumption rates and higher mixed venous oxygen saturation levels during the first hours after hypothermic circulatory arrest. Decreased cardiac index, lower pH, and higher partial pressure of carbon dioxide were observed in the hypothermia group. There was a trend for beneficial effect of prolonged hypothermia in terms of lower brain lactate levels until the 4-hour interval and of intracranial pressure until the 10-hour interval. Postoperatively, total leukocyte and neutrophil counts were lower, and creatine kinase BB was significantly increased in the hypothermia group. At extubation, the hypothermia group had higher oxygen extraction rates and lower brain tissue oxygen tension. CONCLUSIONS: A 14-hour period of mild hypothermia after 75-minute hypothermic circulatory arrest seems to be associated with poor outcome. However, the results of this study suggest that mild hypothermia may preserve its efficacy when it is used for no longer than 4 hours, but the potentials of a shorter period of postoperative mild hypothermia still require further investigation.

Lamotrigine plus leukocyte filtration as a neuroprotective strategy in experimental hypothermic circulatory arrest.

BACKGROUND: Lamotrigine and leukocyte filtration seem to improve cerebral protection during experimental hypothermic circulatory arrest (HCA). This study was performed to evaluate whether their combined use may further improve cerebral protection. METHODS: Twenty-four pigs undergoing 75-minute period of HCA at 20 degrees C were randomly assigned to receive saline; lamotrigine (20 mg/kg) before HCA (L); or lamotrigine (20 mg/kg) before HCA plus leukocyte filtration before and after HCA (L + LF). RESULTS: Seven animals (87%) in the L + LF group, 4 (50%) in the L group, and 3 (37%) in the control group were alive on the seventh postoperative day. The median electroencephalogram burst recovery was 94% in the L + LF group (p = 0.024 versus control group), 81% in the L group, and 64% in the control group. Among the surviving animals, the median behavioral scores were 9, 9, and 6 at the seventh day, respectively (p = 0.005 between the L + LF group and the control group). The median histopathologic score was 14 in the L + LF group (p = 0.046 versus control group), 14.5 in the L group (p = 0.062 versus control group), and 21 in the control group. CONCLUSIONS: Lamotrigine has neuroprotective effect during HCA. The combined use of lamotrigine and LF may further improve the survival outcome.

Plasma catecholamines, serotonin and their metabolites and beta-endorphin of winter swimmers during one winter. Possible correlations to psychological traits.

OBJECTIVES: The study was a follow-up one, in which blood pressure and hormonal changes were investigated during one winter swimming season in winter swimmers (WSs) and non-swimmer controls on three occasions (autumn, winter and spring). Humoral results were compared to psychological traits recorded at the time of the three blood samplings. RESULTS: Mean systolic blood pressure of the WSs fell from 134 +/- 12 mmHg to 128 +/- 12 mmHg (p < 0.05) during the winter, and a slight but non-significant drop was also seen in the controls. Mean plasma noradrenaline concentrations diminished significantly from autumn to spring, and more so in the WS-group, but no statistically significant difference was observed between the groups. Adrenaline levels also showed a decreasing trend, and the change was significant when calculated by using the combined means of both groups. Plasma homovanillic acid and beta-endorphin values were on the same level in all seasonal samples in both groups. Plasma serotonin levels decreased in both groups by about 50 per cent by spring, but 5-HIAA did not change significantly. HVA showed correlation with blood pressure and anxiety in the autumn (r=0.367). In the winter measurement endorphin and hysteria had a negative correlation (r=0.370). In the spring 5-HIAA and obsessionality had a positive correlation (r=0.351). DISCUSSIONS: In summary, blood pressure and plasma catecholamine levels decreased during winter swimming practice over one winter, but these changes were also observed in the control persons. Plasma serotonin was lower in the spring in both groups. The changes in the humoral status speak for adaptation to the research situation, or reflect seasonal variation from autumn to spring. No clear effect of winter swimming as such was detected.