Perflubron emulsion in prolonged hemorrhagic shock: influence on hepatocellular energy metabolism and oxygen-dependent gene expression

BACKGROUND: Liver dysfunction as a result of impaired oxygen availability frequently occurs following hemorrhage and contributes to delayed mortality. Artificial oxygen carriers may improve oxygen supply to vital organs while avoiding the need for allogeneic transfusion. METHODS: Rats were subjected to hemorrhagic hypotension (mean arterial pressure = 35-40 mmHg for 120 min) and were subsequently resuscitated with (1) stored whole rat blood, (2) pentastarch, or (3) pentastarch combined with perflubron emulsion (PFE; 2.7 or 5.4 g/kg body weight), a second-generation artificial oxygen carrier. Recovery of liver adenosine triphosphate, hepatocellular injury, and expression of glutamine synthetase 1, a gene that is induced by exposure of hepatocytes to low partial pressure of oxygen, were studied at 4 h of resuscitation. RESULTS: Stored whole blood or pentastarch failed to restore liver adenosine triphosphate concentrations after prolonged shock as compared to sham controls and resulted in increased gene expression of glutamine synthetase 1. Addition of 2.7 g PFE/kg restored liver adenosine triphosphate to control, whereas 5.4 g PFE/kg resulted in adenosine triphosphate concentrations significantly above control. Improved hepatocellular oxygen supply was also confirmed by restoration of the physiologic expression pattern of glutamine synthetase 1. Serum enzyme concentrations were highest after resuscitation with stored blood, whereas addition of PFE failed to further decrease enzyme concentrations as compared to pentastarch alone. CONCLUSIONS: Resuscitation with PFE is superior to stored blood or asanguineous resuscitation with respect to restoration of hepatocellular energy metabolism. The improved hepatocellular oxygen availability is reflected in normalization of oxygen-dependent gene expression. However, improved oxygen availability failed to affect early hepatocellular injury.     

Hemodynamic and oxygen transport effects of pentastarch in burn resuscitation.

If nonprotein colloid plasma expanders could be demonstrated to be safe and efficacious in burn resuscitation, a significant cost benefit would result. This study was a randomized cross-over comparison of 500 ml of 5% albumin and 500 ml of 10% pentastarch, a new hydroxyethyl starch, in acute burn resuscitation. Pentastarch was an effective plasma expander, resulting in increases of preload, cardiac output, oxygen delivery, and oxygen consumption; the hemodynamic effects of pentastarch infusion were equal or superior to those of albumin. Both albumin and pentastarch infusions resulted in increased bleeding and clotting times; these effects were most likely dilutional. Pentastarch is a promising plasma substitute for burn resuscitation; the effects of a 500 ml infusion are equal or superior to those of albumin. Further study is necessary to assess the safety of larger infusion volumes.     

Successful 40-hour preservation of the canine small intestine with the cavitary 2-layer method with glutamine supplementation

BACKGROUND: We recently reported that the cavitary 2-layer method (cTLM) allowed stable 24-hour preservation of canine intestine. The aim of this study was to examine the possibility of the 40-hour preservation by cTLM that is supplemented with glutamine. METHODS: Canine jejunal segments (40 cm) were allotransplanted heterotopically without storage (group 1), after 40-hour cold storage with University of Wisconsin solution (group 2), cTLM (group 3), UW with 2% glutamine (group 4), or cTLM with 2% glutamine (group 5). Mucosal glutamine, histidine, tryptophan, glutathione, and adenosine triphosphate concentrations were determined immediately after preservation. At day 7 after the transplantation, maltose absorption test and histopathologic analysis were performed. RESULTS: Mucosal glutamine concentrations increased significantly with glutamine supplementation during preservation in groups 4 and 5 (P < .01). Mucosal adenosine triphosphate levels in cTLM groups (groups 3 and 5) were similar to those in group 1; group 4 showed very low levels after preservation, despite glutamine supplementation. Mucosal glutathione did not differ among groups 2, 3, 4, and 5 and were significantly lower than in group 1. In the absorption test, serum glucose curves showed a peak level by 30 minutes in groups 1 and 5; delayed peaks were seen in groups 2, 3, and 4 compared with group 1. The villous heights were 879, 555, 685, 688, and 773 microm in groups 1, 2, 3, 4, and 5, respectively (group 1 vs group 2, 3, and 4: P < .05). CONCLUSION: cTLM that was supplemented with glutamine extended a safe preservation period up to 40 hours in canine segmental small intestinal transplantation, although this study failed to elucidate a precise mechanism of the glutamine beneficial effect on the graft mucosa.     

Hemodynamic actions of acute ethanol after resuscitation from traumatic brain injury

BACKGROUND: The purposes of this study were to determine how clinically relevant levels of acute ethanol (EtOH) influence cerebral perfusion pressure (CPP), cerebral venous O saturation (Scvo ), and systemic hemodynamics after fluid resuscitation from traumatic brain injury (TBI); and to test the hypothesis that the actions of EtOH on these variables are mediated by adenosine. METHODS: Anesthetized swine were ventilated (Fio = 0.4) and instrumented. In protocol 1, EtOH (3.5 g/kg, n = 11) or its vehicle (n = 17) was administered orally before TBI + 40% hemorrhage. At 90 minutes post-TBI, resuscitation consisted of shed blood + saline. In protocol 2, either saline (n = 15) or an adenosine-regulating agent (5-amino-4-imidazolecarboxamide riboside) in saline (1 mg/kg bolus + 12 mg/kg/h intravenously [i.v.]) (n = 5), was administered i.v. before TBI + 45% hemorrhage. At 90 minutes post-TBI, resuscitation consisted of saline only (three times shed blood volume). In protocol 3, EtOH was administered i.v. (1 g/kg; 20% vol/vol in saline) followed by either an adenosine receptor antagonist (theophylline, 10 mg/kg) or an adenosine uptake inhibitor (dipyridamole, 0.25 mg/kg). RESULTS: In protocol 1, with no EtOH, 11 of 17 (65%) survived post-TBI hypotension. Mean arterial blood pressure, cardiac index, and mixed venous oxygen saturation were stable for 1 hour at 40% to 60% below their respective baselines, whereas lactate increased three- to fourfold (all p < 0.05). After fluid resuscitation, most variables rapidly corrected, but intracranial pressure was increased 10 to 15 mm Hg (p < 0.05). With EtOH, 9 of 11 (82%) survived post-TBI hypotension (p = 0.42 vs. no EtOH). After resuscitation from TBI, there were significant effects of EtOH on systemic hemodynamics (mean arterial pressure, cardiac index, mixed venous oxygen saturation), on CPP, on lactate, and on Scvo at normo- and hypercapnia (all p < 0.05). The data from protocol 2 showed that essentially none of these changes were duplicated with an adenosine-regulating agent. In protocol 3, i.v EtOH produced small but significant changes in Scvo, intracranial pressure, and lactate, at normo-, hyper-, and hypocapnia. Dipyridamole and theophylline tended to have opposite, albeit small and not statistically significant, effects on these variables relative to EtOH alone.(2) (2)CONCLUSION: Acute EtOH (200-300 mg/dL) did not increase mortality after TBI + secondary hypotension, as long as cardiopulmonary support was provided. With EtOH, CPP was maintained and cerebral blood flow appeared to be adequate, if not excessive, with respect to cerebral metabolic demand, as judged by changes in Scvo at normo-, hyper-, and hypocapnia. These changes were probably not mediated, but might have been modulated, by increases in endogenous adenosine.     

A comparison of the hemoglobin-based oxygen carrier HBOC-201 to other low-volume resuscitation fluids in a model of controlled hemorrhagic shock

BACKGROUND: The ideal resuscitation fluid for military applications would be effective at low volumes, thereby reducing logistical constraints. We have previously shown that the bovine hemoglobin-based oxygen carrier HBOC-201 is an effective low-volume resuscitation fluid. The goal of this experiment was to evaluate the effectiveness of HBOC-201 in comparison with other low-volume resuscitation fluids in a swine model of controlled hemorrhagic shock. METHODS: Forty-two immature female Yorkshire swine (55-70 kg) were divided into seven groups of six. Animals were hemorrhaged to a mean arterial pressure of 30 mm Hg. After 45 minutes, animals were resuscitated to a mean arterial pressure of 60 mm Hg with one of the following agents: hypertonic saline 7.5% (HTS), hypertonic saline 7.5%/Dextran-70 6% (HSD), pentastarch 6%, hetastarch 6%, or HBOC-201. Lactated Ringer's (LR) solution was used as a standard resuscitation control. Another group of animals received no resuscitation. Resuscitation was continued for 4 hours. Hemodynamic variables and oxygen consumption were measured continuously. Arterial and mixed venous blood gases and serum lactate levels were measured at intervals throughout the experiment. Data were analyzed using analysis of variance with Tukey's post hoc test when appropriate. Significance was defined as p < 0.05. RESULTS: Five of six animals in the no-resuscitation control group, six of six in the HTS group, and one animal in the HSD group died before completion of the study. All other animals survived to completion. Animals receiving resuscitation with HBOC-201 had significantly lower cardiac output, mixed venous oxygen saturation levels, and urinary output throughout the resuscitation period; however, there were no differences with regard to lactate, base excess, or oxygen consumption. Animals receiving HBOC-201 required significantly less fluid than any other group. CONCLUSION: In this model, hypotensive resuscitation with HBOC-201 restores tissue oxygenation and reverses anaerobic metabolism at significantly lower volumes when compared with HTS, HSD, pentastarch, or hetastarch solutions. These data suggest that HBOC-201 would be an effective primary resuscitation fluid for far-forward military or rural trauma settings where logistic constraints and prolonged transport times are common. However, when HBOC-201 is administered as a primary resuscitation fluid in hypotensive protocols, common clinical markers for determining adequacy of resuscitation may not be useful.     

Selective enhancement of intratumoural blood flow in malignant gliomas: Experimental study in rats by intracarotid administration of adenosine or adenosine triphosphate

Summary We studied the effect of intravenous and intracarotid infusion of adenosine and adenosine triphosphate (ATP) on the regional blood flow of intracerebrally transplanted RG-C 6 tumours in rats, using the hydrogen clearance method. The intracarotid administration of adenosine or ATP selectively increased blood flow in the tumour, but did not produce any significant change either in the regional cerebral blood flow of the extratumoural ipsilateral hemisphere or in the ipsilateral hemisphere without tumour. The intracarotid administration of ATP at a dose of 10 g/kg/min produced the most effective increase in the tumour blood flow (+51.5± 16.8%). In contrast, both the intravenous administration of adenosine and that of ATP failed to increase tumour blood flow. These results may possibly indicate that intracarotid administration of the adenosine or ATP might contribute in selectively enhancing the delivery of anti-cancer agents to malignant brain tumours.     

The effect of adenosine triphosphate on vecuronium-induced neuromuscular block

Continuous IV adenosine triphosphate administration has been used during surgery in the expectation of analgesic and vasodilative effects. Because adenosine triphosphate inhibits neuromuscular transmission, we investigated whether the neuromuscular effect of vecuronium was enhanced by IV adenosine triphosphate in 29 patients randomly given either continuous IV adenosine triphosphate 0.1 mg.kg(-1).min(-1) or 0.9% NaCl when undergoing elective minor surgery. Anesthesia was induced and maintained with propofol. Neuromuscular monitoring was recorded from the adductor pollicis muscle using electromyography with train-of-four stimulation of the ulnar nerve. Vecuronium 25, 30, or 40 microg/kg was given and lag time, onset time, and maximum block were recorded. ED50 and ED95 values for each group were derived from least squares linear regression analysis. ED50 and ED95 values were 29 microg/kg and 44 microg/kg, respectively, for the adenosine triphosphate group and 26 microg/kg and 46 microg/kg, respectively, for the controls. Differences in lag time, onset time, and neuromuscular responses between the two groups were not statistically significant. A significantly larger number of patients in the adenosine triphosphate group showed hypotension (systolic blood pressure <80 mm Hg). Our results demonstrated that adenosine triphosphate 0.1 mg.kg(-1).min(-1) did not enhance the neuromuscular block induced by vecuronium.     

Cerebral hemodynamic effects of fluid resuscitation in the presence of an experimental intracranial mass

We addressed the impact on intracranial pressure (ICP) of posthemorrhage fluid resuscitation with a protocol in which additional fluid was infused to maintain a stable cardiac output after an initial bolus of fluid was infused. Anesthetized, mechanically ventilated mongrel dogs (n = 27) underwent a 30-minute interval of hemorrhagic shock (mean arterial pressure = 55 mm Hg) during which inflation of a subdural balloon maintained ICP at 15 mm Hg. After shock, animals were resuscitated with one of four randomly assigned fluids: (1) slightly hypotonic crystalloid (Na+, 125 mEq.L-1; designated Na-125); (2) hypertonic crystalloid (Na+, 250 mEq.L-1; designated Na-250); (3) slightly hypotonic crystalloid plus 10% pentastarch (Na-125P); or (4) hypertonic crystalloid plus 10% pentastarch (Na-250P). Supplemental fluid was administered as needed to maintain cardiac output comparable to baseline values. ICP increased progressively in all fluid groups during resuscitation. Cerebral blood flow, measured by the cerebral venous outflow method, increased immediately after resuscitation and then declined steadily over time in all groups. Fluids containing pentastarch maintained hemodynamic stability with minimal supplementation throughout most of the postresuscitation period, compared with crystalloid alone, which required substantial additional volume. If decreased intracranial compliance and hemorrhage are combined, ongoing resuscitation is associated with significantly increased ICP and significantly decreased cerebral blood flow, independent of the tonicity and oncotic pressure of the infused fluid.     

A new free radical scavenger,edaravone, ameliorates oxidative liver damage due to ischemia-reperfusion in vitro and in vivo

Ischemia-reperfusion injury causes oxidative stress producing reactive oxygen species, which is a serious problem linked to morbidity and mortality in liver surgery. We investigated the effects of edaravone, a new free radical scavenger, on liver oxidative stress in vitro and in vivo. We employed a hypoxiareoxygenation model of primary cultured hepatocytes using an AnaeroPack (Mitsubishi Gas Chemical Co., Tokyo, Japan). Hepatocytes were exposed to 3 or 4 hours of hypoxia and then returned to oxygenation. We analyzed the time course changes of aspartate aminotransferase (AST), phosphatidylcholine hydroperoxide (PCOOH), and adenosine triphosphate (ATP) content in hepatocytes of edaravone-treated groups or nontreated groups after reoxygenation. Edaravone significantly attenuated the elevation of the AST level of the medium and hepatocellular PCOOH and preserved the hepatocellular ATP level. In vivo, male Sprague-Dawley rats were subjected to 45 minutes of hepatic ischemia and 120 minutes of reperfusion. The rats were intravenously injected with vehicle or edaravone (3 mg/kg or 10 mg/kg) before reperfusion and 1 hour after reperfusion. Serum AST levels and hepatic PCOOH and energy charge were significantly improved in both edaravone groups compared with control. In conclusion, edaravone has the ability to eliminate intra-hepatocellular superoxide species and attenuate oxidative liver damage in liver surgery. This work was supported in part by research grants from the Ministry of Education, Science, and Culture of Japan and the Yamanouchi Foundation.     

Storage of strain-specific rat blood limits cerebral tissue oxygen delivery during acute fluid resuscitation

BACKGROUND: The effect of blood storage on tissue oxygen delivery has not been clearly defined. Some studies demonstrate reduced microvascular oxygen delivery, whereas others do not. We hypothesize that storage of rat blood will limit its ability to deliver oxygen to cerebral tissue. METHODS: Anaesthetized rats underwent haemorrhage (18 ml kg(-1)) and resuscitation with an equivalent amount of fresh or 7 day stored strain-specific whole blood. Arterial blood gases, co-oximetry, red cell counts and indices, and blood smears were performed. Hippocampal tissue oxygen tension (PBr(O2)), regional cerebral blood flow (rCBF), and mean arterial pressure (MAP) were measured before and for 60 min after resuscitation (n=6). Data [mean (SD)] were analysed by anova. RESULTS: After 7 days, there was a significant reduction in pH, Pa(O2), an increase in Pa(CO2), but no detectable plasma haemoglobin in stored rat blood. Stored red blood cell morphology demonstrated marked echinocytosis, but no haemolysis in vitro. MAP and PBr(O2) in both groups decreased after haemorrhage. Resuscitation with stored blood returned MAP [92 (SD 16) mm Hg] and PBr(O2) [3.2 (0.7) kPa] to baseline, whereas rCBF remained stable [1.2 (0.1)]. Resuscitation with fresh blood returned MAP to baseline [105 (16) mm Hg] whereas both PBr(O2) [5.6 (1.5) kPa] and rCBF [1.9 (0.4)] increased significantly (P<0.05 for both, relative to baseline and stored blood group). There was no evidence of haemolysis in vivo. CONCLUSIONS: Although resuscitation with stored blood restored cerebral oxygen delivery to baseline, fresh blood produced a greater increase in both PBr(O2) and rCBF. These data support the hypothesis that storage limits the ability of RBC to deliver oxygen to brain tissue.     

Effects of resuscitation from hemorrhagic shock on cerebral hemodynamics in the presence of an intracranial mass

This study compares intracranial pressure, cerebral blood flow, and cerebral oxygen transport during hemorrhagic shock and following fluid resuscitation with crystalloid or colloid solution in a canine model with an epidural mass lesion. After placement of an epidural balloon, intracranial pressure was increased to 30 mm Hg for 5 minutes and then permitted to vary without further manipulation. Hemorrhagic shock was produced by the rapid removal of blood to achieve a mean arterial pressure of 55 mm Hg for 30 minutes. Resuscitation then was performed with intravenous lactated Ringer's solution, 60 ml/kg, or with 6.0% hetastarch, 20 ml/kg. Following both solutions mean arterial pressure and cardiac output were increased and hemoglobin concentration was reduced. Intracranial pressure was significantly lower immediately after resuscitation in the hetastarch group; it then gradually increased so that the difference was much less 1 hour later. Cerebral blood flow decreased during shock and was not restored by either fluid; cerebral oxygen transport fell further with resuscitation in both groups due to hemodilutional reductions in hemoglobin. Although colloid resuscitation improved systemic hemodynamics and maintained lower intracranial pressure, it failed, as did crystalloid resuscitation, to restore cerebral oxygen transport to prehemorrhagic shock levels.     

Starch-deferoxamine conjugate inhibits hepatocyte Ca2+ uptake during hemorrhagic shock and resuscitation

BACKGROUND: This study investigated whether hepatocyte Ca2+ dysregulation after hemorrhagic shock and resuscitation could be modulated by the iron chelator hydroxyethyl starch-conjugated deferoxamine (HES-DFO). METHODS: In a randomized experimental study, anesthetized rats (n = 7) were bled for 60 minutes to maintain mean arterial blood pressure at 40 mm Hg. They were then resuscitated with 60% of shed blood and threefold the shed-blood volume as lactated Ringer's solution, 1 mL of pentastarch solution (hydroxyethyl starch 10%) per mL of shed blood, or 1 mL of HES-DFO solution (10%) per mL of shed blood. In isolated hepatocytes, the rate of Ca2+ influx (Ca2+ in), total Ca2+ uptake (Ca2+ up), and membrane Ca2+ flux (Ca2+ flux) were determined by 45Ca incubation. Reduced or oxidized glutathione and malondialdehyde concentrations were assessed fluorometrically. RESULTS: Significant increases of hepatocellular Ca2+ in, Ca2+ up, and Ca2+ flux were observed in rats resuscitated with lactated Ringer's solution compared with control groups (p < 0.05). Although hydroxyethyl starch decreased Ca2+ in but not Ca2+ up, HES-DFO not only prevented the increase of Ca2+ in and Ca2+ up but also inhibited hepatocyte oxidative injury. CONCLUSION: Iron-catalyzed oxyradical production and membrane peroxidation seem to alter hepatocyte Ca2+ homeostasis after hemorrhagic shock and resuscitation.     

Oxygen requirements of the isolated rat heart during hypothermic cardioplegia. Effect of oxygenation on metabolic and functional recovery after five hours of arrest

Previous studies from this laboratory demonstrated that the use of an oxygenated cardioplegic solution in the hypothermic arrested rat heart resulted in improved preservation of high-energy phosphate stores (adenosine triphosphate and creatine phosphate), mechanical recovery during reperfusion, and preservation of myocardial ultrastructure. In the current study the effect of cardioplegic solutions oxygenated with 30%, 60%, and 95% oxygen was evaluated in the isolated rat heart with reference to the maintenance of adenosine triphosphate, creatine phosphate, oxygen consumption, functional recovery, and mitochondrial oxidative phosphorylation in vitro. Results indicate that the hearts receiving cardioplegic solutions supplemented with 95% oxygen and 5% carbon dioxide maintained adenosine triphosphate and creatine phosphate at control values for at least 5 hours. The oxygen consumption during elective cardiac arrest, mechanical performance during reperfusion, and in vitro mitochondrial oxygen uptake and phosphorylation rate were highest in the hearts receiving cardioplegic solutions supplemented with 95% oxygen when compared to solutions with 30% and 60% oxygen. Addition of glucose and insulin to the cardioplegic solution (95% oxygen) increased the adenosine triphosphate levels but failed to improve function after reperfusion. Although myocardial adenosine triphosphate and creatine phosphate were well preserved by the oxygenated cardioplegic solution, there was a discrepancy between the adenosine triphosphate levels at the end of the arrest period, which represents the potential for mechanical function, and the actual function of the hearts after 5 hours.     

Perflubron emulsion reduces inflammation during extracorporeal circulation.

The recovery from cardiac surgery and cardiopulmonary bypass can be complicated by an acute inflammatory response. Circulating blood through an extracorporeal circuit (ECC) contributes to this complication. Perfluorocarbon-based blood substitutes (PFCs) are under investigation for use as a component of the ECC "prime" solution, because PFCs increase the oxygen-carrying capacity of the diluted blood. Some PFCs may provide the additional benefit of attenuating the ECC-induced inflammatory response. Earlier, we reported that perflubron emulsion (PFE, Alliance Pharmaceutical Corp.) reduced neutrophil (PMN) activation in vivo. However, the potential of PFE to reduce ECC-induced PMN activation has not been investigated. In this study, we used a small-scale ECC model to quantify the extent of PMN activation during circulation and to examine if PFE treatment attenuated PMN activation. ECC circuits were filled with a mixture of blood and Plasmalyte. Two groups were studied: an untreated group containing blood plus PlasmaLyte and a treated group in which some of the Plasmalyte was substituted with PFE (4.5 g/100 ml). Hematology and measures of whole blood PMN activation were made from blood samples taken periodically throughout the 120-min ECC circulation period. We found, for the untreated group, a significant decrease in the number of circulating PMNs and an increase in PMN activation with time. PMN activation was demonstrated as a significant increase in the expression of the PMN adhesion protein CD11b (P < 0.05) and an increase in PMN oxygen free radical production (reactive oxygen species (ROS)). After 120 min of circulation, the PMNs remained capable of a significant response to a second inflammatory stimulus, but PFE treatment significantly attenuated the fMLP-induced increase in PMN ROS at t = 120 min (P < 0.05). These results suggest that PFE may have dual utility in cardiac surgery, to increase oxygen delivery and to serve as an antiinflammatory agent.     

Influence of progressive tumor growth on glutamine metabolism in skeletal muscle and kidney.

OBJECTIVE: The effects of progressive malignant growth on glutamine metabolism in skeletal muscle and in kidney were investigated. SUMMARY BACKGROUND DATA: Fast-growing tumors consume considerable quantities of glutamine and lead to a decrease in circulating glutamine concentrations. METHODS: Experiments were performed at various stages of tumor growth in rats implanted subcutaneously with the non-metastasizing methylcholanthrene-induced (MCA) fibrosarcoma and in pair-fed non tumor-bearing controls. RESULTS: Tumor growth stimulated a twofold increase in hindquarter (muscle) glutamine release, which was not due to an increase in blood flow, but rather to a doubling in the fractional release rate. Consequently, a progressive decrease in skeletal muscle glutamine concentrations was observed over time. Simultaneously, the activity of glutamine synthetase (GS), the principal enzyme of de novo glutamine biosynthesis, increased more than twofold. This increase in muscle GS activity was accompanied by an increase in GS mRNA but the augmentation in GS expression apparently could not match the increased rate of efflux since muscle depletion developed. In rats with large tumors and severe glutamine depletion, GS activity was not elevated. Glutamine feeding increased muscle glutamine concentrations and glutamine synthetase specific activity. Although tumor growth led to the development of mild systemic acidemia, the classic renal adaptations normally observed, i.e., elevated glutaminase activity and accelerated renal glutamine utilization, were not present in acidotic tumor-bearing rats. Instead, renal GS activity was increased in tumor-bearing animals and ammoniagenesis was enhanced, in spite of a reduction in net renal glutamine uptake. CONCLUSIONS: These data suggest that marked alterations in muscle and renal glutamine handling occur in the host with cancer; the enhanced muscle glutamine release in conjunction with no increase in renal consumption is consistent with increased glutamine uptake in other organs, most likely the tumor itself and the liver.     

Beneficial effects of cyclosporine on postischemic liver injury in rats.

The discovery of cyclosporine has had a significant impact on preventing the rejection of transplanted organs in humans. In this study, we present another positive aspect of cyclosporine. Rats were pretreated with cyclosporine (10 mg/kg, i.v.), or untreated. After 2-hr ischemia or 1 hr of reperfusion following 2-hr ischemia, livers were isolated and liver adenine nucleotide concentrations were determined. Liver mitochondria were prepared and their function was estimated polarographically. Leakage of AST, ALT, LDH, and adenine nucleotides into the hepatic vein just after reperfusion was also measured. Cyclosporine treatment did not affect ischemia-induced mitochondrial dysfunction, nor did it prevent the associated decrease in adenosine triphosphate concentration. However, treatment with cyclosporine accelerated the recovery of mitochondrial function and of tissue adenosine triphosphate concentrations. Cyclosporine treatment also mitigated leakage of AST, ALT, LDH, and adenine nucleotides after reperfusion. These results indicate that cyclosporine shows a potent protective effect on ischemia-reperfusion-related liver injury.     

Increased cerebral tissue oxygen tension after extensive hemodilution with a hemoglobin-based oxygen carrier

Transfusion of anemic patients with hemoglobin-based oxygen carriers (HBOCs) may improve cerebral oxygen delivery. Conversely, cerebral vasoconstriction, associated with HBOC transfusion, could limit optimal cerebral tissue oxygenation. We hypothesized that hemodilution with a HBOC would maintain cerebral tissue oxygenation, despite the occurrence of cerebral vasoconstriction. Isoflurane-anesthetized rats (100% oxygen) underwent direct measurement of mean arterial blood pressure (MAP), caudate tissue oxygen tension (P(Br)o(2)), and regional cortical cerebral blood flow (rCBF) before and after 50% of the estimated blood volume (30 mL/kg) was exchanged with either an HBOC (hemoglobin raffimer; Hemolink) or pentastarch (n = 6). Hemodilution with hemoglobin raffimer caused a transient increase in P(Br)o(2) from 24.9 +/- 13.3 mm Hg to 32.2 +/- 19.1 mm Hg (P < 0.05), a sustained increase in MAP, and no change in rCBF. Arterial blood oxygen content was maintained despite an increase in methemoglobin and reduced oxygen saturation. Hemodilution with pentastarch caused a transient increase in MAP, no change in P(Br)o(2), and a sustained increase in rCBF (P < 0.05), whereas the hemoglobin concentration and oxygen content were significantly reduced. Hemodilution with hemoglobin raffimer augmented P(Br)o(2) and prevented the increase in rCBF observed after similar hemodilution with pentastarch. These data suggest that transfusion with hemoglobin raffimer may help to maintain cerebral oxygenation during severe anemia.     

Protection of the hypertrophied pig myocardium. A comparison of crystalloid, blood, and Fluosol-DA cardioplegia during prolonged aortic clamping

The myocardial protective effects of crystalloid, blood, and Fluosol-DA-20% cardioplegia were compared by subjecting hypertrophied pig hearts to 3 hours of hypothermic (10 degrees to 15 degrees C), hyperkalemic (20 mEq/L) cardioplegic arrest and 1 hour of normothermic reperfusion. Left ventricular hypertrophy was created in piglets by banding of the ascending aorta, with increase of the left ventricular weight-body weight ratio from 3.01 +/- 0.2 gm/kg (control adult pigs) to 5.50 +/- 0.2 gm/kg (p less than 0.001). An in vivo isolated heart preparation was established in 39 grown banded pigs, which were divided into three groups to receive aerated crystalloid (oxygen tension 141 +/- 4 mm Hg), oxygenated blood (oxygen tension 584 +/- 41 mm Hg), or oxygenated Fluosol-DA-20% (oxygen tension 586 +/- 25 mm Hg) cardioplegic solutions. The use of crystalloid cardioplegia was associated with the following: a low cardioplegia-coronary sinus oxygen content difference (0.6 +/- 0.1 vol%), progressive depletion of myocardial creatine phosphate and adenosine triphosphate during cardioplegic arrest, minimal recovery of developed pressure (16% +/- 8%) and its first derivative (12% +/- 7%), and marked structural deterioration during reperfusion. Enhanced oxygen uptake during cardioplegic infusions was observed with blood cardioplegia (5.0 +/- 0.3 vol%), along with excellent preservation of high-energy phosphate stores and significantly improved postischemic left ventricular performance (developed pressure, 54% +/- 4%; first derivative of left ventricular pressure, 50% +/- 5%). The best results were obtained with Fluosol-DA-20% cardioplegia. This produced a high cardioplegia-coronary sinus oxygen content difference (5.8 +/- 0.1 vol%), effectively sustained myocardial creatine phosphate and adenosine triphosphate concentrations during the extended interval of arrest, and ensured the greatest hemodynamic recovery (developed pressure, 81% +/- 6%, first derivative of left ventricular pressure, 80% +/- 10%) and the least adverse morphologic alterations during reperfusion. It is concluded that oxygenated Fluosol-DA-20% cardioplegia is superior to oxygenated blood and especially aerated crystalloid cardioplegia in protecting the hypertrophied pig myocardium during prolonged aortic clamping.     

Experimental study in a rabbit model of ischemia-reperfusion lung injury during cardiopulmonary bypass.

Adult white rabbits were subjected to 2 hours of partial cardiopulmonary bypass (flow rate 90 ml/min/kg) at 32 degrees C, and unilateral pulmonary artery occlusion was used to simulate total cardiopulmonary bypass in the lung subjected to arterial occlusion, with the other side used as the control lung. The lung subjected to arterial occlusion was reperfused by one of the following methods: (1) by whole blood (WB group), (2) by leukocyte-depleted blood (LD group), and (3) by whole blood with protease inhibitor (nafamostat mesilate, FUT group), expecting its anticomplement action. In the fourth group, the lung was inflated with oxygen during pulmonary artery occlusion followed by whole blood reperfusion (OXY group). As a result, lungs subjected to pulmonary artery occlusion showed significant decreases in tissue concentrations of adenosine triphosphate and regional tissue blood flow during cardiopulmonary bypass. Furthermore, recovery of adenosine triphosphate was depressed in the WB group and recovery of regional tissue blood flow in the WB and OXY groups. Ultrastructural findings in alveolar epithelial cells and capillary endothelial cells showed worsening at reperfusion in only the WB group. Transpulmonary gradients of C5a and leukocyte showed significant increases at reperfusion in the WB and OXY groups. Alveolar-arterial oxygen difference was significantly higher in the WB group than in the others. Results indicate that complete cessation of pulmonary artery flow in normothermic cardiopulmonary bypass may cause ischemia of the lung followed by reperfusion injuries with the no-reflow phenomenon, with possible involvement of activation of leukocytes and complement.