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Background and Objective: Under physiological conditions, cerebral oxygen delivery is kept constant by adaptation of the regional cerebral blood flow (CBF) in relation to the oxygen content. So far, decreases of the regional CBF induced by a higher arterial oxygen content have been produced under hyperbaric or hyperviscous conditions. We tested whether local CBF is also reduced by a high haemoglobin (Hb) concentration at a normal haematocrit (Hct).Methods: Compared with controls (n=8), Hb content was increased to 19 g dl(-1) in conscious rats by isovolaemic replacement of the plasma fraction with an artificially high Hb solution (Hb-based oxygen carriers; HH group, n=8). In another group (n=8), Hct was decreased by isovolaemic exchange with an Hb-based oxygen carrier resulting in a normal Hb content (NH group). Mean and regional CBF was measured by iodo-[(14)C]-antipyrine autoradiography. Oxygen delivery was calculated from arterial oxygen content and CBF.Results: Compared with the controls (Hb 15.3 g dl(-1), Hct 0.44), mean CBF was lower in the HH (Hb 20.3 g dl(-1), Hct 0.44) group by 23% (P < or = 0.05), but remained unchanged in the NH group (Hb 15.0 g dl(-1), Hct 0.29). On a local level, hyperoxygenation reduced CBF in 22 out of 39 brain regions. In the NH group mean CBF was unchanged, whereas local CBF was higher in 10 areas. In both groups, overall cerebral oxygen delivery was unchanged compared with the control group. Locally though, high arterial Hb content decreased oxygen delivery in one-third of the brain structures.Conclusion: Whereas the overall cerebral oxygen delivery in the brain is maintained during hyperoxygenation and haemodilution, local oxygen delivery is decreased by high arterial Hb content in some brain regions. [ABSTRACT FROM AUTHOR]

Each organ possesses specific properties for controlling microvascular perfusion. Such specificity provides an opportunity to design transfusion fluids that target thrombo-embolic or vasospasm-induced ischemia in a particular organ or that optimize overall perfusion from systemic shock. The role of viscosity in the design of these fluids might be underestimated, because viscosity is rarely monitored or considered in critical care decisions. Studies linking viscosity-dependent changes of microvascular perfusion to outcome-relevant data suggest that whole blood viscosity is negligible as a determinant of microvascular perfusion under physiological conditions when autoregulation is effective. Because autoregulation is driven to maintain oxygen supply constant, the organism will compensate for changes in blood viscosity to sustain oxygen delivery. In contrast, under pathological conditions in the brain and elsewhere, increases of overall viscosity should be avoided - including all the situations where vascular autoregulatory mechanisms are inoperative due to ischemia, structural damage or physiologic dysfunction. As latter conditions are not to identify with high certainty, the risks that accompany therapeutic correction of blood viscosity are outweighing the benefits. The ability to bedside monitor blood viscosity and to link changes in viscosity to outcome parameters in various clinical conditions would provide more solid foundation for evidence-based clinical management.

Background: Recent studies showed changes in cerebral protein expression up to 3 days after desflurane anesthesia in rats. In the present study, we investigated the existence of persisting changes on the proteome level after sevoflurane anesthesia that persisted for as long as 28 days after anesthesia., Methods: Rats were anesthetized by spontaneous inhalation of 2.4% sevoflurane in air for 3 h. Animals (n = 6 for each group) were killed either directly, 72 h, or 28 days after anesthesia. Brains were removed and subjected to global protein expression profiling based on two-dimensional gel electrophoresis and mass spectrometry. Expression factors were compared to results from untreated conscious animals at each time point. Data were statistically analyzed by ANOVA (P < 0.01) and a cut of more than two-fold change in the expression factor., Results: We found 11 protein spots differentially regulated directly after anesthesia. Seventeen proteins were differentially expressed 72 h after the anesthesia. Only one spot was differentially regulated 28 days after anesthesia. The plausible targets of these differentially regulated proteins can be attributed to synaptic vesicle handling and cell-cell communication., Conclusions: Sevoflurane induced relevant changes in protein expression profiles directly and 72 h after an anesthesia with 1 MAC. Twenty-eight days after the anesthesia, all proteins except one had returned to baseline levels of abundance.

Spatial learning is known to depend on protein synthesis in the hippocampus. Whereas the role of the hippocampus in spatial memory is established, the biochemical and molecular mechanisms underlying this process are poorly understood. To comprehend the complex pattern of protein expression induced by spatial learning, we analyzed alterations in the rat hippocampus proteome after 7 days of spatial learning in the Morris water maze. Forty Wistar rats were randomized into two groups. Animals of group A learned to localize a hidden platform in the water maze. Animals of group B served as controls and spent exactly the same time in the water maze as animals of group A. However, no platform was used in this test and the rats could not learn to localize the target. After the last trial, hydrophilic proteins from the hippocampus were isolated. A proteome-wide study was performed, based on two-dimensional gel electrophoresis and mass spectrometry. Compared with non-learning animals, 53 (70%) proteins were downregulated and 23 (30%) proteins were upregulated after 7 days in rats with spatial learning. The overall changes in protein expression, as quantified by the induction factor, ranged from -1.62 (downregulation to 62%) to 2.10 (upregulation by 110%) compared with controls (100%). Most identified proteins exhibit known functions in vesicle transport, cytoskeletal architecture, and metabolism as well as neurogenesis. These findings indicate that learning in the Morris water maze has a morphological correlate on the proteome level in the hippocampus.

To examine the impact of excessive erythrocytosis on local cerebral blood flow (CBF) and cerebral glucose metabolic rate (CMR(glc)), we made use of our constitutively erythropoietin (Epo)-overexpressing transgenic mouse line (tg-6) that reach a mean hematocrit of 0.87. Compared with wild-type (wt) control siblings, CBF decreased by 44% in tg-6 mice, while upon hemodilution (tg-6-HD) to a physiologic hematocrit (e.g., 0.44) tg-6-HD mice returned the CBF to wt levels. Cerebral blood flow was determined in another transgenic mouse line that overexpresses human Epo in the brain only (tg-21): CBF increased by 17% compared with wt controls. However, oxygen delivery was similar in all four mouse groups tested (wt, tg-6, tg-6-HD and tg-21). Mean CMR(glc) was higher in tg-6 (+72%), tg-6-HD mice (+43%) and tg-21 (+22%) than in wt mice. Local CMR(glc) was higher in all 40 brain regions in tg-6 but only in 15 and 8 regions in tg-6-HD and tg-21 mice. These results show that prolonged increases in hematocrit did not alter cerebral oxygen delivery at a decreased CBF and increased CMR(glc). Hemodilution suggests that high blood viscosity is a cause of the decrease in CBF and partly of the increase in CMR(glc). Cerebral glucose metabolic rate may also be increased by a direct effect of Epo in the brain (tg-21 mice).

Objective: Acclimatization to reduced environmental oxygen includes erythropoietin-regulated increase in erythrocytes enhancing the blood's oxygen content. However, increased hematocrit levels result in elevated blood viscosity that might impair microcirculation and tissue oxygenation. To assess this oxygen supply to the skin, the authors used erythropoietin overexpressing transgenic mice (tg6) that develop excessive erythrocytosis in an oxygen-independent manner. These animals have been previously reported to elevate their blood viscosity 4-fold., Methods: The partial oxygen pressure (pO2) distribution was evaluated in microvessels as well as in subcutaneous interstitial tissue within a dorsal skinfold chamber of resting conscious mice using automated phosphorescence quenching., Results: Compared to wildtype (wt) animals, transgenic blood viscosity increased 4-fold but microvessel diameter was not altered. Despite sharing similar blood pO2 as the wt siblings, tg6 animals nearly doubled their oxygen content. Moreover, tg6 erythrocytes reduced hemoglobin's oxygen affinity by decreased 2,3-DPG levels and an increased Hill number. Transgenic arterioles and venules showed increased pO2 compared to wt controls whereas capillary and tissue pO2 were not altered., Conclusions: Excessive erythrocytosis does not elevate capillary oxygen delivery.

Background: Sepsis is still the leading cause of death in the intensive care unit. Our goal was to elucidate potential early differences in serum between survivors (SURV) and non-survivors (NON-SURV) on day 28., Methods: We applied proteomic technology to serum samples of patients with sepsis and septic shock. Serum samples from 18 patients with sepsis and septic shock were obtained during the first 12 h after diagnosis of septic shock. Patients were grouped into SURV and NON-SURV on day 28., Results: Seven patients survived and 11 patients died. Using proteome analysis, two-dimensional gel electrophoresis detected more than 200 spots per gel. A differential protein expression was discovered between SURV and NON-SURV, whereby protein alterations not yet described in sepsis were revealed., Conclusions: Our results show that proteomic profiling is a useful approach for detecting protein expression dynamics in septic patients, and may bring us closer to achieving a comprehensive molecular profiling compared with genetic studies alone.

Background: Volatile anesthetics can alter cardiac gene and protein expression. Of those underlying molecular changes in gene and protein expression in the myocardium after exposure to volatile anesthetics that have been identified, some of them have been related to cardioprotection., Methods: We used two-dimensional gel electrophoresis and mass spectrometry to identify changes in the protein expression of the left ventricle myocardium of anesthesized rats. We maintained anesthesia for 3 h using isoflurane, sevoflurane or desflurane, respectively, at 1.0 minimum alveolar concentration (MAC) and dissected the left ventricular myocardium either immediately or 72 h after the end of anesthesia., Results: We found changes of at least twofold in 106 proteins of the more than 1.600 protein spots discriminated in each gel. These differentially expressed proteins are associated with functions in glycolysis, mitochondrial respiration and stress response. No obvious difference could be observed between the patterns of differential expression of the three volatile anesthetics., Conclusion: We provide the first study of post-anesthetic protein expression profiles associated with three common volatile anesthetics. These volatile anesthetics promote a distinct change in the myocardial protein expression profile, whereby changes in the expression pattern still exist 72 h after anesthesia. These proteome changes are closely related to cardioprotection and ischemic preconditioning, indicating a common functional signaling of volatile anesthestics.

This report describes the clinical history of a patient intoxicated with methyl isocyanate (MIC), a toxic agent first receiving attention in 1984 after a mass accident in a pesticide plant in Bhopal, India, and treated with the cyanide-specific antidote 4-DMAP. The numerous clinical conditions requiring 39-day intensive care treatment included ARDS, renal and hepatic failure, haemolysis, bone marrow depression, septic encephalopathy and critical illness polyneuropathy. The most outstanding condition, however, was a methaemoglobinemia of 86.7%, which was predominantly related to the use of 4-DMAP, although uptake of MIC may have been a significant contributing factor. Since significant cyanide intoxication could be excluded clinically and by laboratory testing in the initial phase of emergency treatment, most of the clinical effects were due to the side-effects of the antidote therapy. Due to intensive therapy, the patient survived without any neurological or organ deficit. This case shows that antidotes should be used cautiously in cases where uncertainties about the nature of the underlying toxic agent exist. This may prevent severe side-effects associated with antidote therapy, e.g. 4-DMAP, if there is-as in our case-a mismatch between the toxic agent and the antidote.

Objective: Obturator nerve block is used for transurethral resection of lateral bladder wall tumors to prevent adductor muscle spasm and associated complications. Therefore, the local anesthetic applied should provide an adequate motor blockade. Ropivacaine 0.75 % was compared to prilocaine 1 % and motor blockade assessment performed by the Medical Research Council (MRC)-scale., Methods: 40 patients (20 per group) scheduled for transurethral resection were randomized to either receiving 10 ml ropivacaine 0.75 % or prilocaine 1 % for direct obturator nerve block in a controlled user-blinded study. Motor block was assessed with the MRC-scale 5 and 10 minutes after local anesthetic injection followed by an assessment 120 and 180 minutes after surgery. Surgery was performed in equally distributed spinal or general anesthesia, intraoperative adductor spasm intensity was evaluated by surgeon's ranking., Results: Motor blockade intensity was significantly higher with ropivacaine 0.75 % at all time points of assessment. Intraoperatively, severe spasm only occurred in the prilocaine 1 %-group., Conclusion: Ropivacaine 0.75 % is a more appropriate agent for direct obturator nerve block than prilocaine 1 %, providing a faster onset and a more intense and longer-lasting motor blockade. This may reduce surgical complications and facilitate early surgical re-intervention. In this study, MRC-scale was appropriate for motor blockade assessment in a peripheral nerve block.

Background: Little is known about the regional distribution of cerebral blood flow (CBF) in nonanesthetized animals during periods of lowered blood pressure. The present investigation addresses the specific reaction patterns of local cerebral blood flow (LCBF) in comparison with mean CBF during graded pressure-controlled hemorrhagic shock in conscious rats., Methods: Conscious rats were subjected to graded pressure-controlled hemorrhage (to 85, 70, 55, or 40 mm Hg) by arterial blood withdrawal. After a period of 30 minutes, blood pressure was stabilized by withdrawal or reinfusion of blood. LCBF was determined autoradiographically by the iodo(14C)antipyrine method in 34 brain structures, and mean CBF was calculated and compared with the values of nonhemorrhaged control animals., Results: Mean CBF remained unchanged except for the group with the lowest blood pressure of 40 mm Hg (decrease in CBF of 28%). Otherwise, LCBF was increased in some brain structures at an unchanged mean CBF. Congruently, at 40 mm Hg, the decrease in mean CBF did not show up in all brain structures, the local pattern of CBF varying between an unchanged and a profoundly decreased CBF. The mean coefficient of variation of CBF was increased with the severity of hemorrhagic shock, which indicates an enhanced heterogeneity of CBF., Conclusion: Because of the substantial heterogeneity in the responses of LCBF to pressure-controlled hemorrhage, autoregulation of CBF during pressure-controlled hemorrhagic shock has to be reconsidered on a regional basis.

Background: Volatile anesthetics disappear from an organism after the end of anesthesia. Whether changes of protein expression persist in the brain for a longer period is not known. This study investigates the question of whether the expression of proteins is altered in the rat brain after the end of desflurane anesthesia., Methods: Three groups (n = 12 each) of rats were anesthetized with 5.7% desflurane in air for 3 h. Brains were removed directly after anesthesia, 24 h after anesthesia, or 72 h after anesthesia. Two additional groups (n = 12 each) served as naive conscious controls, in which the brains were removed without previous anesthesia 3 or 72 h after the start of the experiment. Cytosolic proteins were isolated. A proteome-wide study was performed, based on two-dimensional gel electrophoresis and mass spectrometry., Results: Compared with conscious controls, significant (P < 0.05) increase/decrease was found: 3 h of anesthesia, 5/2 proteins; 24 h after anesthesia, 13/1 proteins; 72 h after anesthesia, 6/4 proteins. The overall changes in protein expression as quantified by the induction factor ranged from -1.67 (decrease to 60%) to 1.79 (increase by 79%) compared with the controls (100%). Some of these regulated proteins play a role in vesicle transport and metabolism., Conclusion: Desflurane anesthesia produces changes in cytosolic protein expression up to 72 h after anesthesia in the rat brain, indicating yet unknown persisting effects.

Background: This single-blind randomized study in general surgery evaluated the efficacy of perflubron emulsion (PFC) as an artificial oxygen carrier being used to augment preoperative acute normovolemic hemodilution to reduce and avoid transfusion of both allogeneic erythrocytes and erythrocytes from preoperative autologous donation compared with standard of care., Methods: Subjects (N = 492) with hemoglobin concentrations of 12-15 g/dl undergoing noncardiac surgical procedures with 20 ml/kg or greater expected blood loss were randomized into two groups. Control patients were transfused intraoperatively at a hemoglobin concentration less than 8.0 +/- 0.5 g/dl or at protocol-defined, physiologic triggers. PFC-treated patients first underwent acute normovolemic hemodilution to hemoglobin of 8.0 +/- 0.5 g/dl, followed by dosing with perflubron emulsion (1.8 g/kg). When hemoglobin reached less than 6.5 +/- 0.5 g/dl, an additional 0.9-g/kg dose was given. PFC patients were transfused at hemoglobin less than 5.5 +/- 0.5 g/dl or at predefined physiologic triggers. After surgery, hemoglobin was maintained at 8.5 +/- 0.5 g/dl or greater in all patients until discharge. Efficacy endpoints included the number of allogeneic and preoperative autologous donation units transfused and the percentage of subjects avoiding transfusion., Results: Both groups had similar hemoglobin concentrations at screening (13.5 +/- 1.0 g/dl) and at discharge: 10.8 +/- 1.2 g/dl (PFC) and 11.1 +/- 1.3 g/dl (control). At 24 h, more patients in the PFC group avoided allogeneic and preoperative autologous donation erythrocyte transfusions (53% vs. 43%, < 0.05), and fewer erythrocytes were transfused (1.5 +/- 4.8 vs. 2.1 +/- 3.9 units; median, 0 vs. 1 unit; P = 0.013). By day of discharge, these differences were not significant in the intent-to-treat population, but overall there were less allogeneic and preoperative autologous donation erythrocyte transfusions in the PFC group (696 vs. 846 units). In the protocol-defined target population (n = 330 subjects with blood loss > or = 20 ml/kg), significantly greater avoidance of any erythrocyte transfusion was maintained through day of hospital discharge (26% vs. 16% in the PFC and control groups, respectively; P < 0.05), and there was also a significant reduction in the number of erythrocyte units transfused (3.4 +/- 2.9 vs. 4.9 +/- 2.4 units; median 2 vs. 4 units; P < 0.001). Adverse events rates were similar in the PFC (86%) and control (81%) groups; however, more serious adverse events were reported in the PFC group (32%) than in controls (21%; P < 0.05). Overall mortality was 3%, and the difference between groups (PFC, 4% vs. controls, 2%) was not statistically significant., Conclusions: Augmented acute normovolemic hemodilution with PFC reduces transfusion needs in patients undergoing noncardiac surgical procedures with blood loss 20 ml/kg or greater.

Background: Although the frequency for the use of moderate hypothermia in acute ischemic stroke is increasing, the optimal acid-base management during hypothermia remains unclear. This study investigates the effect of pH- and alpha-stat acid-base management on cerebral blood flow (CBF), infarct volume, and cerebral edema in a model of transient focal cerebral ischemia in rats., Methods: Twenty Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h during normothermic conditions followed by 5 h of reperfusion during hypothermia (33 degrees C). Animals were artificially ventilated with either alpha- (n = 10) or pH-stat management (n = 10). CBF was analyzed 7 h after induction of MCAO by iodo[(14)C]antipyrine autoradiography. Cerebral infarct volume and cerebral edema were measured by high-contrast silver infarct staining (SIS)., Results: Compared with the alpha-stat regimen, pH-stat management reduced cerebral infarct volume (98.3 +/- 33.2 mm(3) vs. 53.6 +/- 21.6 mm(3); P > or = 0.05 mean +/- SD) and cerebral edema (10.6 +/- 4.0% vs. 3.1 +/- 2.4%; P > or = 0.05). Global CBF during pH-stat management exceeded that of alpha-stat animals (69.5 +/- 12.3 ml x 100 g(-1) x min(-1) vs. 54.7 +/- 13.3 ml x 100 g(-1) x min; P > or = 0.05). The regional CBF of the ischemic hemisphere was 62.1 +/- 11.2 ml x 100 g(-1) x min(-1) in the pH-stat group versus 48.2 +/- 7.2 ml x 100 g(-1) x min(-1) in the alpha-stat group ( P> or = 0.05)., Conclusions: In the very early reperfusion period (5 h), pH-stat management significantly decreases cerebral infarct volume and edema as compared with alpha-stat during moderate hypothermia, probably by increasing CBF.

Erythropoietin (EPO) and its receptor are expressed in the brain, and one of its roles appears to be neuroprotection. This study investigates whether chronic overexpression of EPO changes brain mRNA expression in the brains of transgenic mice. Therefore, cerebral mRNA expression was investigated in transgenic mice overexpressing EPO. Microarray analysis revealed an upregulation (2.8- to 3.6-fold) of N-acetylglucosamine-6-O-sulfotransferase (prolongation of the EPO effect), a translocase of the inner mitochondrial membrane (mitochondrial matrix import of nuclear encoded proteins), a mitochondrial ribosomal protein (mitochondrial protein translation), and a peroxisomal biogenesis factor (formation of peroxisomes). In conclusion, components of oxidative metabolism pathways were activated at the level of transcription which could be related to neuroprotective effects of EPO or could indicate compromised tissue.

Background and Purpose: We tested whether volatile anesthetics induce neuroprotection that is maintained for a prolonged time., Methods: Rats were pretreated for 3 hours with 1 minimal anesthetic concentration of isoflurane or halothane in normal air (anesthetic preconditioning [AP]). The animals were subjected to permanent middle cerebral artery occlusion (MCAO) at 0, 12, 24, or 48 hours after AP. Halothane-pretreated animals were subjected to MCAO 24 hours after AP. Histological evaluation of infarct volumes was performed 4 days after MCAO. Cerebral glucose utilization was measured 24 hours after AP with isoflurane. Primary cortical neuronal cultures were exposed to 1.4% isoflurane for 3 hours. Oxygen-glucose deprivation (OGD) was performed 24 hours after AP. Injury was assessed 24 hours later by measuring the release of lactate dehydrogenase into the medium 24 hours after OGD., Results: Isoflurane anesthesia at 0, 12, and 24 hours before MCAO or halothane anesthesia 24 hours before MCAO significantly reduced infarct volumes (125+/-42 mm3, P=0.024; 118+/-51 mm3, P=0.008; 120+/-49 mm3, P=0.009; and 121+/-48 mm3, P=0.018, respectively) compared with control volumes (180+/-51 mm3). Three hours of isoflurane anesthesia in rats did not have any effect on local or mean cerebral glucose utilization measured 24 hours later. Western blot analysis from cortical extracts of AP-treated animals revealed an increase of the inducible NO synthase (iNOS) protein beginning 6 hours after AP. The iNOS inhibitor aminoguanidine (200 mg/kg IP) eliminated the infarct-sparing effect of AP. In cultured cortical neurons, isoflurane exposure 24 hours before OGD decreased the OGD-induced release of lactate dehydrogenase by 49% (P=0.002)., Conclusions: Pretreatment with volatile anesthetics induces prolonged neuroprotection in vitro and in vivo, a process in which iNOS seems to be critically involved.

Background: The hypothesis of a compensatory dilation of cerebral vessels to maintain cerebral blood flow at a high blood viscosity was tested during hypercapnia in the study after replacement of blood by hemoglobin solutions of defined viscosities. If compensatory vasodilation exists at normocapnia at a high blood viscosity, vasodilatory mechanisms may be exhausted when hypercapnia is added, resulting in a lack of increase in cerebral blood flow at hypercapnia., Methods: In conscious rats, blood was replaced by ultrapurified cross-linked hemoglobin solutions that had defined and shear rate-independent low or high viscosities (low- and high-viscosity groups). Blood viscosity differed threefold between both groups (1.2 vs. 3.6 mP x s). Thereafter, rats inhaled either a normal or an increased concentration of carbon dioxide in air. Cerebral blood flow was determined by the iodo[14C]antipyrine method., Results: During normocapnia, global and local cerebral blood flows did not differ between both groups. With increasing degrees of hypercapnia, global and local cerebral blood flows were gradually elevated in the low-viscosity group (2.8 ml x mmHg(-1) CO2 x 100 g(-1) x min(-1)), whereas they remained unchanged in the high-viscosity group., Conclusions: Changes in blood viscosity do not result in changes of cerebral blood flow as long as cerebral vessels can compensate for these changes by vasodilation or vasoconstriction. However, such vascular compensatory adjustments may be exhausted in their response to further pathophysiologic conditions in blood vessels that have already been dilated or constricted as a result of changes in blood viscosity.

We addressed the question to which extent cerebral blood flow (CBF) is maintained when, in addition to a high blood viscosity (Bvis) arterial oxygen content (CaO2) is gradually decreased. CaO2) was decreased by hemodilution to hematocrits (Hct) of 30, 22, 19, and 15% in two groups. One group received blood replacement (BR) only and served as the control. The second group received an additional high viscosity solution of polyvinylpyrrolidone (BR/PVP). Bvis was reduced in the BR group and was doubled in the BR/PVP. Despite different Bvis, CBF did not differ between BR and BR/PVP rats at Hct values of 30 and 22%, indicating a complete vascular compensation of the increased Bvis at decreased CaO2. At an Hct of 19%, local cerebral blood flow (LCBF) in some brain structures was lower in BR/PVP rats than in BR rats. At the lowest Hct of 15%, LCBF of 15 brain structures and mean CBF were reduced in BR/PVP. The resulting decrease in cerebral oxygen delivery in the BR/PVP group indicates a global loss of vascular compensation. We concluded that vasodilating mechanisms compensated for Bvis increases thereby maintaining constant cerebral oxygen delivery. Compensatory mechanisms were exhausted at a Hct of 19% and lower as indicated by the reduction of CBF and cerebral oxygen delivery.

Snoring is a characteristic feature of habitual snorers and patients with sleep apnoea syndrome. However, unlike snorers, sleep apnoea patients have an increased peri-operative morbidity. Presently available methods to differentiate between these two groups are either expensive, invasive or time consuming. As cardiac reflexes are impaired in sleep apnoea syndrome, we tested whether heart rate variability could discriminate between snorers and patients with sleep apnoea syndrome. Heart rate variability measurement detects cardiac autonomic dysfunction non-invasively in an ambulatory setting. We studied 32 male patients undergoing polysomnography for suspected sleep apnoea. Total, low- and high-frequency power were measured using a Holter electrocardiogram. Differences in night- and daytime variability were then calculated. Differences between day and night values were more pronounced in the sleep apnoea group and related to the apnoea-hypopnoea-index and low oxygen saturation. Higher values in sleep apnoea patients resulted from increasing variability at night. Heart rate variability might thus help to differentiate between snorers and patients with severe sleep apnoea syndrome.

Background: Storage of blood as packed RBCs and FFP is standard practice in allogeneic transfusion. Separation into components has been proposed for autologous transfusion, as well, but beneficial effects have not yet been shown., Study Design and Methods: Twenty-four healthy male volunteers were randomly assigned to receive 1 unit of either autologous RBCs and FFP (RCP group) or WB (WB group) after 49 or 35 days of storage, respectively. The immune response was analyzed by ELISA for IL-6, C3a, terminal complement complex SC5b-9, TNF-alpha, and neopterin. Differential WBC counts and the phagocytosis of neutrophils and monocytes were measured by flow cytometry., Results: Cell counts of monocytes (0.85 x 10(3) ng/microL) [corrected] and neutrophils (6.9 x 10(3) ng/microL) [corrected] increased 30 minutes after WB transfusion and then returned to close to the baseline values seen in the RCP group (0.47 and 2.9 x 10(3) ng/microL [corrected], respectively) throughout the monitored period (p<0.05). C3a (169 vs. 116 ng/microL) [corrected] and IL-6 (29 vs. 6 pg/mL) reached higher plasma concentrations in the WB group (n = 11) than in the RCP group (n = 10). Phagocytosis of opsonized Escherichia coli was increased in neutrophils and monocytes and lasted up to 7 days after the transfusion of whole blood., Conclusion: Autologous WB induces a modest immunomodulation, but this effect is not observed upon transfusion of autologous blood components.

Despite the high frequency of sickle cell disease in Europe, the disease is poorly managed. Critical periods are the hospital stays during which the anaesthesiologist plays an important role. Understanding the molecular basis of polymerization processes of haemoglobin S can help to avoid triggering a crisis. Differentiation of the various haemoglobin phenotypes helps to estimate the individual perioperative risk. Knowledge of the patient's history and the actual haemoglobin S level facilitates general anaesthesia, surgery and postoperative care. Damage to liver, spleen, eyes, bones, lung and central nervous system increases the perioperative risk. Preoperative preparation includes early admission, intravenous volume substitution, continuing pain therapy and prophylactic antibiotic medication. General anaesthesia seems to be better for patients with a high-risk profile rather than regional anaesthesia. Careful perioperative and postoperative monitoring should allow hypoxaemia, hypovolaemia, hypothermia, acidosis and overtransfusion to be avoided. Effective pain therapy includes a combination of opioids with peripherally acting analgesia.

Background: The effects of xenon inhalation on mean and local cerebral blood flow (CBF) and mean and local cerebral glucose utilization (CGU) were investigated using iodo-[14C]antipyrine and [14C]deoxyglucose autoradiography., Methods: Rats were randomly assigned to the following groups: conscious controls (n = 12); 30% (n = 12) or 70% xenon (n = 12) for 45 min for the measurement of local CBF and CGU; or 70% xenon for 2 min (n = 6) or 5 min (n = 6) for the measurement of local CBF only., Results: Compared with conscious controls, steady state inhalation of 30 or 70% xenon did not result in changes of either local or mean CBF. However, mean CBF increased by 48 and 37% after 2 and 5 min of 70% xenon short inhalation, which was entirely caused by an increased local CBF in cortical brain regions. Mean CGU determined during steady state 30 or 70% xenon inhalation remained unchanged, although local CGU decreased in 7 (30% xenon) and 18 (70% xenon) of the 40 examined brain regions. The correlation between CBF and CGU in 40 local brain structures was maintained during steady state inhalation of both 30 and 70% xenon inhalation, although at an increased slope at 70% xenon., Conclusion: Effects of 70% xenon inhalation on CBF in rats are time-dependent. During steady state xenon inhalation (45 min), mean values of CBF and CGU do not differ from control values, and the relation of regional CBF to CGU is maintained, although reset at a higher level.

That cerebral blood flow remains unchanged at an increased blood viscosity, as long as the vascular supply is not compromised, was tested. To induce a reduced blood supply of some parts of the brain and to keep the supply unchanged in others both carotid arteries were occluded in anesthetized, ventilated rats. By this procedure, blood supply to the rostral brain, but not to the brainstem and cerebellum, was compromised. Blood viscosity was increased by intravenous infusion of 20% polyvinylpyrrolidone (high viscosity group) or decreased by infusion of 5% albumin (low viscosity group). Cerebral blood flow was measured by the [14C]iodoantipyrine method in 50 complete coronal sections of the rostral brain and 22 complete coronal sections of the brainstem and cerebellum in each rat. In the high viscosity group, mean cerebral blood flow of the rostral brain was significantly lower (46 +/- 7 mL/100 g(-1) x min(-1)) than in the low viscosity group (82 +/- 18 mL/100 g(-1) x min(-1)). No differences could be observed in brainstem and cerebellum between both groups (162 +/- 29 mL/100 g(-1) x min(-1) vs. 156 +/- 18 mL/100 g(-1) x min(-1)). Local analysis of cerebral blood flow in different brain structures of the coronal sections showed the same identical results; i.e., in 29 of the 31 brain structures analyzed in rostral brain, local cerebral blood flow was lower in the high viscosity group, whereas no differences could be observed in the 11 brain structures analyzed in the brainstem and cerebellum. It is concluded that under normal conditions cerebral blood flow can be maintained at an increased blood viscosity by a compensatory vasodilation. When the capacity for vasodilation is exhausted by occlusion of supplying arteries, an increased blood viscosity results in a decrease of cerebral blood flow.

Background and Purpose: The effects of hypothermia on global cerebral blood flow (CBF) and glucose utilization (CGU) have been extensively studied, but less information exists on a local cerebral level. We investigated the effects of normothermic and hypothermic anesthesia on local CBF (LCBF) and local CGU (LCGU)., Methods: Thirty-six rats were anesthetized with isoflurane (1 MAC) and artificially ventilated to maintain normal PaCO(2) (alpha-stat). Pericranial temperature was maintained normothermic (37.5 degrees C, n=12) or was reduced to 35 degrees C (n=12) or 32 degrees C (n=12). Pericranial temperature was maintained constant for 60 min until LCBF and LCGU were measured with autoradiography. Twelve conscious rats served as normothermic control animals., Results: Normothermic anesthesia significantly increased mean CBF compared with conscious control animals (29%, P<0.05). Mean CBF was reduced to control values with mild hypothermia and to 30% below control animals with moderate hypothermia (P<0.05). Normothermic anesthesia reduced mean CGU by 44%. No additional effects were observed during mild hypothermia. Moderate hypothermia resulted in a further reduction in mean CGU (41%, P<0.05). Local analysis showed linear relationships between LCBF and LCGU in normothermic conscious (r=0.93), anesthetized (r=0.92), and both hypothermic groups (35 degrees C r=0. 96, 32 degrees C r=0.96, P<0.05). The LCBF-to-LCGU ratio increased from 1.5 to 2.5 mL/micromol during anesthesia (P<0.05), remained at 2.4 mL/micromol during mild hypothermia, and decreased during moderate hypothermia (2.1 mL/micromol, P<0.05)., Conclusions: Anesthesia and hypothermia induce divergent changes in mean CBF and CGU. However, local analysis demonstrates a well-maintained linear relationship between LCBF and LCGU during normothermic and hypothermic anesthesia.

Background: Hypothermia may interfere with the relationship between cerebral blood flow (CBF) and metabolism. Because this conclusion was based on the analysis of global values, the question remains whether hypothermic CBF/metabolism uncoupling exists on a local cerebral level. This study investigated the effects of hypothermic anesthesia on local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU)., Methods: Thirty-six rats were anesthetized with isoflurane (1 minimum alveolar concentration) and artificially ventilated to maintain normal arterial carbon dioxide partial pressure (pH-stat). Pericranial temperature was maintained as normothermic (37.5 degrees C, n = 12) or was reduced to 35 degrees C (n = 12) or 32 degrees C (n = 12). Pericranial temperature was maintained constant for 60 min until LCBF or LCGU were measured by autoradiography. Twelve conscious rats served as normothermic controls., Results: Compared with conscious animals, mean CBF remained unchanged during normothermic anesthesia. Mean CBF significantly increased during mild hypothermia but was unchanged during moderate hypothermia. During normothermic anesthesia, mean CGU was 45% lower than in conscious controls (P < 0.05). No further CGU reduction was found during mild hypothermia, whereas CGU further decreased during moderate hypothermia (48%; P < 0.05). Local analysis showed a linear LCBF/LCGU relationship in conscious (r = 0.94) and anesthetized (r = 0.94) normothermic animals, as well as in both hypothermic groups (35 degrees C: r = 0.92; 32 degrees C: r = 0.95; P < 0.05). The LCBF-to-LCGU ratio increased from 1.4 (conscious controls) to 2.4 (normothermic isoflurane) and 3.6 ml/micromol (mild and moderate hypothermia, P < 0.05)., Conclusions: Decrease of mean CGU at unchanged or increased mean CBF during hypothermic anesthesia may not indicate uncoupling. Local analysis shows a maintained linear relationship that is reset to a higher CBF/CGU ratio.

Background: It is not known whether the effects of desflurane on local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) are different from those of other volatile anesthetics., Methods: Using the autoradiographic iodoantipyrine and deoxyglucose methods, LCGU, LCBF, and their overall means were measured in 60 Sprague-Dawley rats (10 groups, n = 6 each) during desflurane and isoflurane anesthesia and in conscious controls., Results: During anesthesia, mean cerebral glucose utilization was decreased compared with conscious controls: 1 minimum alveolar concentration (MAC) desflurane: -52%; 1 MAC isoflurane: -44%; 2 MAC desflurane: -62%; and 2 MAC isoflurane: -60%. Local analysis showed a reduction of LCGU in the majority of the 40 brain regions analyzed. Mean cerebral blood flow was increased: 1 MAC desflurane: +40%; 1 MAC isoflurane: +43%; 2 MAC desflurane and 2 MAC isoflurane: +70%. LCBF was increased in all brain structures investigated except in the auditory cortex. No significant differences (P < 0.05) could be observed between both anesthetics for mean values of cerebral glucose use and blood flow. Correlation coefficients obtained for the relation between LCGU and LCBF were as follows: controls: 0.95; 1 MAC desflurane: 0.89; 2 MAC desflurane: 0.60; 1 MAC isoflurane: 0.87; and 2 MAC isoflurane: 0.68., Conclusion: Differences in the physicochemical properties of desflurane compared with isoflurane are not associated with major differences in the effects of both volatile anesthetics on cerebral glucose utilization, blood flow, and the coupling between LCBF and LCGU.

For the usage as blood substitutes perfluorocarbons (PFC) have been developed as artificial oxygen carriers. In addition they may have potency for protective use in ischemic tissue. Formulation improvement achieved higher oxygen carrying capacity and better compatibility than the first generation of PFC. Preclinical studies have been performed in animal heart and brain. Former and progressed emulsification for intravascular use have been investigated for infarction and reperfusion injury. This investigations are reviewed and the potencies for the use of PFC in neurology, neurosurgery, diagnostics today and in the future are emphasized.

Systemic and microcirculatory effects of autologous whole blood resuscitation after 4-h hemorrhagic shock with a mean arterial pressure (MAP) level of 40 mmHg were investigated in 63 conscious Syrian golden hamsters. Microcirculation of skeletal skin muscle and subcutaneous connective tissue was visualized in a dorsal skinfold. Shed blood was retransfused within 30 min after 4 h. Animals were grouped into survivors in good (SG) and poor condition (SP) and nonsurvivors (NS) according to 24-h outcome after resuscitation and studied before shock, during shock (60, 120, and 240 min), and 30 min and 24 h after resuscitation. Microvascular and interstitial PO2 values were determined by phosphorescence decay. Shock caused a significant increase of arterial PO2 and decrease of PCO2, pH, and base excess. In the microcirculation, there was a significant decrease in blood flow (QB), functional capillary density (FCD; capillaries with red blood cell flow), and interstitial PO2 [1.8 +/- 0.8 mmHg (SG), 1.3 +/- 1.3 mmHg (SP), and 0.9 +/- 1.1 mmHg (NS) vs. 23.0 +/- 6.1 mmHg at control]. Blood resuscitation caused immediate MAP recompensation in all animals, whereas metabolic acidosis, hyperventilation, and a significant interstitial PO2 decrease (40-60% of control) persisted. In NS (44.4% of the animals), systemic and microcirculatory alterations were significantly more severe both in shock and after resuscitation than in survivors. Whereas in SG (31.8% of the animals) there was only a slight (15-30%) but still significant impairment of microscopic tissue perfusion (QB, FCD) and oxygenation at 24 h, SP (23.8% of the animals) showed severe metabolic acidosis and substantial decreases (>/=50%) of FCD and interstitial PO2. FCD, interstitial PO2, and metabolic state were the main determinants of shock outcome.

After decades of research activities and product improvements in the field of artificial oxygen carriers based on either haemoglobin modifications or perfluorocarbon emulsions, these products have reached a critical stage of their development. Varieties of haemoglobin-based oxygen carriers and perfluorocarbon emulsions are under current clinical investigation. Although the clinical availability of artificial oxygen carriers may result in profound changes of fluid resuscitation from haemorrhage, the transfusion of human blood components as an integral part of medical trauma management will not be replaced. However, a rapid and effective restoration of tissue oxygenation by the use of artificial oxygen carriers in the treatment of severe haemorrhage may bridge time delays until stored and cross-matched human packed red cells are available. Whether artificial oxygen carriers could provide additional clinical benefits by sustaining tissue oxygenation even under conditions of a disturbed macro- or microcirculation is the subject of current investigations. Therefore, the application of safe and effective artificial oxygen carriers would not only be restricted to the treatment of severe haemorrhage, but additional therapeutic indications of artificial oxygen carriers in emergency medicine, trauma anaesthesia and other medical specialities would emerge.

Background: Compared to isoflurane, knowledge of local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) during sevoflurane anesthesia is limited., Methods: LCGU, LCBF, and their overall means were measured in Sprague-Dawley rats (8 groups, n=6 each) during sevoflurane and isoflurane anesthesia, 1 and 2 MAC, and in conscious control animals (2 groups, n=6 each) using the autoradiographic 2-[14C]deoxy-D-glucose and 4-iodo-N-methyl-[14C]antipyrine methods., Results: During anesthesia, mean cerebral glucose utilization was decreased: control, 56+/-5 micronmol x 100 g(-1) x min(-1); 1 MAC isoflurane, 32+/-4 micromol x 100 g(-1) x min(-1) (-43%); 1 MAC sevoflurane, 37+/-5 micromol x 100 g(-1) x min(-1) (-34%); 2 MAC isoflurane, 23+/-3 micromol x 100 g(-1) x min(-1) (-58%); 2 MAC sevoflurane, 23+/-5 micromol x 100 g(-1) x min(-1) (-59%). Local analysis showed a reduction in LCGU in the majority of the 40 brain regions analyzed. Mean cerebral blood flow was increased as follows: control 93+/-8 ml x 100 g(-1) x min(-1); 1 MAC isofurane, 119+/-19 ml x 100 g(-1) x min(-1) (+28%); 1 MAC sevoflurane, 104+/-15 ml x 100 g(-1) x min(-1) (+12%); 2 MAC isoflurane, 149+/-17 ml x 100 g(-1) x min(-1) (+60%); 2 MAC sevoflurane, 118+/-21 ml x 100 g(-1) min(-1) (+27%). LCBF was increased in most brain structures investigated. Correlation coefficients obtained for the relationship between LCGU and LCBF were as follows: control 0.93; 1 MAC isoflurane, 0.89; 2 MAC isoflurane, 0.71; 1 MAC sevoflurane, 0.83; 2 MAC sevoflurane, 0.59)., Conclusion: Mean and local cerebral blood flows were lower during sevoflurane than during isoflurane anesthesia. This difference cannot be explained by differing changes in glucose utilization because glucose utilization was decreased to the same extent in both groups.

The clinical availability of artificial oxygen carriers (AOCs) would result in profound alterations in transfusion medical practice. Rapid progress in the scientific and technological development of AOCs has advanced to a critical stage at which safe and effective alternatives to the transfusion of red blood cells are emerging. Haemoglobin- and perfluorocarbon-based oxygen carriers are under current clinical investigation. Artificial oxygen-carrying solutions, by virtue of their acellular structure, can be used to transport oxygen to ischaemic tissues that cannot otherwise be reached by cellular blood components. Organs awaiting transplantation can be preserved for a long time after perfusion with AOCs and tumour susceptibility to chemo- and radiotherapy is increased. The use of AOCs is therefore not confined to their use as red blood cell substitutes, but may find a wide spectrum of interdisciplinary applications.

Partial liquid ventilation (PLV) is a relatively new therapeutic approach to acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). The idea of combining the intrapulmonary application of an oxygen-carrying substance and positive pressure ventilation was introduced by Fuhrman in 1991 and originally called perfluorocarbon-associated gas exchange (PAGE). Nowadays, the technique is mostly known as partial liquid ventilation (PLV). The efficacy of PVL treatment has been demonstrated in numerous animal studies in different models of lung injury. The results of those studies led to multicenter phase I-II studies in patients of all age groups in the United States and Canada. Recently, the first randomized, controlled study in 90 adult patients suffering from ALI and ARDS was completed and first results have been published. Comparison of overall mortality and number of ventilator-free days (VFD's) in a 28-day period showed no differences between PLV and conventionally treated patients. A post-hoc stratification by age (< 55 years) demonstrated a tendency to lower mortality (PLV 25.6%; CMV 36.8%) and a significant increase of VFD (PLV 8.95 days; CMV 4.11 days; p = 0.03) in PLV when compared to conventionally treated patients. Perfluorocarbons (PFCs) are chemically stable and inert. They are mostly eliminated via exhalation (> 99%). The unique physicochemical properties of PFCs permit access to atelectatic, non-ventilated lung areas, enhance gas exchange and decrease inflammation. The dense PFCs prevent the endexpiratory collapse of alveoli and reestablish functional residual capacity (FRC). Comparable to positive endexpiratory pressure (PEEP), these effects have been described as "liquid or fluid PEEP". These properties offer a new approach to the underlying pathophysiology of ALI and ARDS. In addition, the combination with other therapeutic approaches to ALI and ARDS like high-frequency oscillations (HFO), inhaled nitric oxide (NO) therapy, and surfactant replacement can be considered and is already the subject of recent publications. However, combination therapy is still experimental and further investigation is necessary to evaluate efficacy and potential risks. Many questions still exist which need to be answered by experimental as well as human pilot studies. Based on these studies, the results of ongoing human trials can be assessed properly and new multicenter trials can be planned effectively.

Previous studies from our group have indicated a heterogeneity of plasma transit times in brain capillaries. The heterogeneity was decreased with increasing cerebral blood flow during hypercapnia. In the present study, the hypothesis was tested that these apparent changes in microvascular plasma perfusion heterogeneity depend on the existence of red blood cells (RBC). To this end, the blood of anesthetized and paralyzed rats was replaced by a shear rate-independent oxygen-carrying substitute, ultrapurified polymerized bovine hemoglobin (UPBHB). Cerebral blood flow ([14C]iodoantipyrine technique) or microvascular perfusion pattern (intravenous bolus injection of Evans blue and decapitation 3-4 s later) was measured. After exchange transfusion with UPBHB, cerebral blood flow still varied with arterial PCO2, whereas in contrast to the unexchanged condition, the heterogeneity of the intracapillary Evans blue concentration remained unchanged. Compared with the unexchanged normocapnic condition, the heterogeneity of intracapillary dye concentration was decreased by one-quarter. It is concluded that RBC contribute to the microvascular perfusion heterogeneity in the brain.

Objective: Stroma-free hemoglobin solutions have been shown to maintain oxygen transport in the absence of red blood cells. This study was designed to investigate the impact of such solutions on hemodynamics and oxygen transport during progressive isovolemic hemodilution within and even beyond a clinically relevant range of hematocrit values., Design: Prospective, randomized experimental study comparing a bovine hemoglobin-based oxygen carrier (bHBOC) with a conventional nonoxygen-carrying volume substitute (hydroxyethyl starch [HES])., Setting: Animal laboratory of a university cardiovascular research center., Participants: Splenectomized full-grown foxhounds, anesthetized with pentobarbital and piritramid., Interventions: Twelve splenectomized foxhounds were anesthetized and mechanically ventilated. Catheters were placed for hemodilution, arterial and venous blood sampling, and hemodynamic measurements. The baseline hematocrit (Hct) value was adjusted to 0.35 by an initial isovolemic exchange of blood for identical volumes of HES (10% HES 200/0.5). Thereafter, the hematocrit was progressively reduced by isovolemic hemodilution using either HES (n = 6) or bHBOC (n = 6)., Measurements and Main Results: Hemodynamic and laboratory parameters of oxygen transport were measured at Hct values of 0.30, 0.20, and 0.10. Oxygen content was directly estimated using an oxygen-specific fuel cell. Arterial oxygen content at an Hct value of 0.10 nearly doubled in bHBOC-treated dogs as compared with HES-diluted animals (p < 0.001). This gain in oxygen-carrying capacity was completely negated by a decrease in cardiac output (-32% Hct 0.35 v Hct 0.30; p < 0.001) immediately on the first infusion of bovine hemoglobin. Thus, oxygen delivery was significantly lower as compared with HES-treated dogs at Hct 0.30 and 0.20, but remained stable at a level of 60% of baseline until Hct was 0.10. Both the pulmonary and the systemic vascular resistances increased., Conclusions: Isovolemic hemodilution with bHBOC did not improve systemic oxygen delivery in comparison with a nonoxygen-carrying diluent (HES) in a range of Hct values down to 0.10. Unchanged mixed venous lactate levels and stable oxygen consumption indicate sufficiently maintained oxygen delivery. This might become advantageous in patients who are unable to adequately increase cardiac output during hemodilution.

Clark and Gollan demonstrated impressively in 1966 the ability of perfluorchemicals (PFCs) to transport oxygen and to provide gas exchange across the alveolar capillary membrane. PFCs are used for two major medical indications: as artificial blood substitutes and as a medium for liquid ventilation. The PFC perflubron is additionally used as a contrast medium for diagnostic radiologic procedures. For the intravenous application perfluorocarbons have to be emulgated in phospholipids for the intrapulmonary application the sterile pure solution is used. Liquid ventilation can either be performed by a method known as total liquid ventilation (TLV), in which a device is utilised to ventilate with perfluorocarbon the previously perfluorocarbon-filled lung, or as partial liquid ventilation (PLV) in which a conventional mechanical gas ventilator is used to gas ventilate the partially perfluorocarbon-filled lung. A number of studies have demonstrated the efficacy of perfluorocarbon liquid ventilation in improving gas exchange and pulmonary function in a number of animal species in the setting of acute respiratory failure. In 1989 Greenspan reported on the first human liquid ventilation experience in a neonate. More recently human experiences for neonatal, paediatric and adult patients with acute lung injury have been reported. Since 1995 an FDA-approved study to examine the efficacy of PLV in severe respiratory failure in patients of all ages has been undertaken in the United States. The number of PLV-treated patients is still small; if PLV demonstrates its efficacy even in the ongoing human studies, it might be a very effective additional tool for treating severe acute lung injury.

Objective: Of the animal models of human hemorrhagic shock, the volume-controlled hemorrhage model appears to come closer to the clinical situation than the commonly used pressure-controlled model, since the volume-controlled model allows regulatory adjustment of blood pressure. The effects of volume-controlled hemorrhage on local cerebral blood flow (LCBF) of conscious animals are not known. The present study investigates specific reaction patterns of LCBF in comparison to mean cerebral blood flow (CBF) during graded volume-controlled hemorrhagic shock in conscious rats., Methods: Conscious, spontaneously breathing, and minimally restrained rats were subjected to different degrees of volume-controlled hemorrhage (taking either 25, 30, 35, or 40 ml arterial blood/kg body weight (b.w.). Thirty minutes after the completion of blood taking, LCBF was determined during hemorrhagic hypovolemia using the autoradiographic iodo (14C) antipyrine method. A group of untreated rats (no hemorrhage) served as controls. LCBF was determined in 34 defined brain structures and mean CBF was calculated., Results: During less severe hemorrhage (25 and 30 ml/kg b.w.) mean CBF was significantly higher than in the control group (+19% and +25%). During severe hemorrhage (35 and 40 ml/kg b.w.) mean CBF remained unchanged compared to the control values, although significant increases in LCBF could be detected in many of the brain structures analyzed (maximum +44%). The mean coefficient of variation of CBF was increased, indicating a larger heterogeneity of LCBF values at shed blood volumes of 35 and 40 ml/kg b.w., Conclusions: A comprehensive and novel description of the local distribution of CBF during graded volume-controlled hemorrhage in conscious rats shows unexpected increases in LCBF and mean CBF. This "hypovolemic cerebral hyperemia" might be caused by endogenous hemodilution, thus maintaining the blood supply to the brain during hypovolemic shock.

Permanent occlusion of the middle cerebral artery in rats was used to assess the effects of focal ischemia on the expression of members of the bcl-2 family which have been implicated in the regulation of programmed cell death. Intraluminal occlusion of one middle cerebral artery for 6 h resulted in histologically detectable brain damage within the ipsilateral caudate putamen, basolateral cortex and parts of the thalamus. In the infarcted basolateral cortex and thalamus fragmentation of DNA was detected in many nuclei using in-situ end-labeling of DNA breaks by terminal transferase, whereas only scattered labeled nuclei were visible in the infarcted caudate putamen. Immunohistochemical analysis revealed activation of c-Fos in the infarcted cortex and thalamus and in the non-infarcted cingulate cortex as has been shown by others. A decrease in immunoreactivity for Bcl-2, and Bcl-X and an increase in immunostaining for Bax was observed exclusively in neurons within the ischemic cortex and thalamus. Within the infarcted caudate putamen, however, protein levels of all bcl-2 family members declined and c-Fos remained absent. By reverse transcription and polymerase chain reaction it was demonstrated that levels of bcl-2 mRNA markedly decreased in the ipsilateral hemisphere, whereas the amount of bax mRNA was elevated. These findings suggest that a shift in the ratio of cell death repressor Bcl-2 to cell death effector Bax and a concomitant activation of c-Fos may contribute to neuronal apoptosis in the infarcted thalamus and cortex.

The effects of small volume hypertonic/hyperoncotic fluid resuscitation from hemorrhage on brain metabolism and blood flow were evaluated by autoradiographic techniques with high spatial resolution. The data were compared to fluid resuscitation with a volume equal to shed blood of isotonic 6% hydroxyethyl starch solution (HES) and a control group without hemorrhage and fluid resuscitation (n = 6 in each group). In conscious rats, volume-controlled hemorrhage for 30 min (30 mL/kg body weight, resulting in a blood loss of approximately 50% of the circulating blood volume) was followed by intravenous infusion of a hypertonic/hyperoncotic saline hydroxyethyl starch solution (HTHO; 7.5% saline/10% hydroxyethyl starch, 4.0 mL/kg body weight). Local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) were measured in 34 brain structures 2 h after fluid resuscitation by means of the quantitative autoradiographic iodo [14C]antipyrine and 2-[14C]-deoxy-D-glucose methods. Compared to the untreated control group, LCBF increased significantly in all brain regions analyzed after fluid resuscitation with HTHO (mean, +63%) or HES (mean, +56%). The increases in LCBF after fluid resuscitation were sufficient to restore cerebral oxygen delivery to the level calculated for the untreated control group. LCGU was unchanged after fluid resuscitation. The close relationship between LCGU and LCBF observed in the control group (r = 0.95) was preserved after hemorrhage and fluid resuscitation with HTHO (r = 0.97) and HES (r = 0.96), although the LCBF-to-LCGU ratio was reset to a higher level (1.5 mL/mumol in the control group and 2.7 mL/mumol after fluid resuscitation with HTHO and HES, P < 0.05). We conclude that the increase in LCBF compensates for the reduction of arterial oxygen content to maintain cerebral oxygen delivery. Therefore, "small volume resuscitation" appears to be as effective as resuscitation with large volumes of isotonic HES in meeting the circulatory and metabolic demands of the brain tissue within the first 2 h after fluid resuscitation from hemorrhage.

Although the attempts to develop an oxygen-carrying alternative to red blood cells (RBC) have spanned the last 100 years, it has proven difficult to develop a clinically useful haemoglobin-based oxygen carrier. Four major problems have been shown to compromise the use of haemoglobin outside the RBC as an oxygen carrier: (1) the increased oxygen affinity due to the loss of 2,3-diphosphoglycerate; (2) dissociation into dimers and monomers with consequent renal and capillary loss of hemoglobin; (3) insufficient concentrations of prepared solutions under iso-oncotic conditions, and thereby reduced oxygen-carrying capacity; and (4) toxicity. Most of these limitations have been overcome by different modifications of haemoglobin, including pyridoxylation, intra- and intermolecular cross-linking, polymerisation, liposome encapsulation, conjugation to inert macromolecules, and genetic engineering. Questions of toxicity are not completely answered at present, especially with regard to renal toxicity, interactions with the nitric oxide system, and antigenicity. Therefore, the issues preventing clinical application are those of safety and not of efficacy of haemoglobin-based RBC substitutes. Potential clinical applications include fluid resuscitation, treatment of anaemia and ischaemia, support in extracorporeal circulation, and organ preservation. Based on promising and reproducible results obtained from animal studies, clinical phase I and II trials with newer haemoglobin solutions have been started in the United States. Substantial knowledge has been gained in the development, production, and evaluation of haemoglobin-based oxygen carriers during the past years. It will probably not take another century before oxygen-carrying RBC substitutes will become available for clinical use.

Regional cerebral blood flow and metabolism were investigated after addition of a small volume of perfluorocarbon (PFC) emulsion to the resuscitation fluid after hemorrhage. Severe volume-controlled hemorrhage (40 mL/kg body weight (bw) withdrawn over 30 min followed by hypovolemia of 30 min duration) was induced in conscious rats. While breathing 100% oxygen, the intravascular volume was repleted by the infusion of either 6% hydroxyethyl starch (mean mol wt 200,000/0.5; HES) or 6% hydroxyethyl starch plus perflubron (90% wt/vol emulsion of perfluoroctylbromide, 3 mL/kg bw; HES-PFOB). Two hours after fluid resuscitation either iodo[14C]antipyrine or 2[14C]deoxy-D-glucose were infused. Local cerebral blood flow (LCBF) or local cerebral glucose utilization (LCGU) were determined in 34 brain structures using quantitative autoradiography. Local cerebral metabolism was not disturbed in the HES and the HES-PFOB groups after fluid resuscitation, although slight reductions (mean -14%) were measured (HES-PFOB vs HES; P < 0.05). The HES-PFOB group showed LCBF values that were higher in the different brain structures than those of the HES group (mean +30%). A close correlation was found between LCGU and LCBF of the 34 brain structures in both groups (HES: r = 0.96, P < 0.01; HES-PFOB: r = 0.98, P < 0.01), whereas the LCBF-to-LCGU ratio was reset from 2.2 mL/mumol in the HES group to 3.4 mL/mumol in the HES-PFOB group (P < 0.05). The higher blood flows in the HES-PFOB group were sufficient to restore cerebral oxygen delivery to normal levels at a reduced arterial oxygen content.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of resuscitation fluids on the brain have been investigated in previous studies by global measurements of cerebral blood flow and metabolism. In this study we have examined the effects of a novel haemoglobin-based oxygen carrier on local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) after resuscitation from a volume-controlled haemorrhage of 30 min (3.0 ml/100 g body weight) with ultrapurified, polymerized, bovine haemoglobin (UPBHB). LCBF and LCGU were measured in 34 brain structures of conscious rats 2 h after resuscitation using quantitative iodo(14C)antipyrine and 2-(14C)-deoxy-D-glucose methods. The data were compared with a control group without haemorrhage and fluid resuscitation. In the haemorrhage group, LCBF increased after resuscitation by 12-56% in the different brain structures (mean 36%). LCGU changed less (0 to +18%, mean +9%). In the control group there was a close relationship between LCGU and LCBF (r = 0.95). After fluid resuscitation the relationship was preserved (r = 0.95), although it was reset at a higher ratio of LCBF to LCGU (P < 0.05). We conclude that fluid resuscitation of a 30 min volume-controlled haemorrhage using the haemoglobin-based oxygen carrier, UPBHB, induced a moderate degree of heterogeneity in the resulting changes of LCGU and LCBF. Local disturbances of cerebral blood flow or metabolism were not observed.

Whether the increase in cerebral blood flow measured after hemodilution is mediated by a decrease in blood viscosity or in oxygen delivery to the brain is debated. In the present study, blood was replaced by an oxygen-carrying blood substitute, ultrapurified, polymerized, bovine hemoglobin (UPBHB). In contrast to normal blood, UPBHB yields a constant and defined viscosity in the brain circulation, since its viscosity is not dependent on the shear rate. CBF was determined after blood exchange with UPBHB in one group of conscious rats (UPBHB group) and in another group of blood-exchanged conscious rats in which viscosity was increased fourfold by the addition of 2% polyvinylpyrrolidone (PVP), mw 750,000 (UPBHB-PVP group). Local CBF (LCBF) was measured in 34 brain structures by means of the quantitative iodo(14C)antipyrine method. After blood replacement, systemic parameters such as cardiac index, arterial blood pressure, blood gases, and acid-base status were not different between the UPBHB and the UPBHB-PVP groups. In particular, arterial oxygen content was similar in both groups. Compared with a control group without blood exchange, LCBF was increased after blood exchange in the different brain structures by 60-102% (UPBHB group) and by 33-101% (UPBHB-PVP group). Mean CBF was increased by 77% in the UPBHB group and by 69% in the UPBHB-PVP group. No significant differences were observed in the values of LCBF or mean CBF between the UPBHB group and the UPBHB-PVP group. The results show that a fourfold variation in the viscosity of a Newtonian blood substitute does not result in differences in CBF values.(ABSTRACT TRUNCATED AT 250 WORDS)