Quantification of [(18)F]FDG uptake in the normal liver using dynamic PET: impact and modeling of the dual hepatic blood supply.

UNLABELLED: For quantification of hepatic [(18)F]FDG uptake, the dual blood supply to the liver must be considered. In contrast to the arterial input, however, the portal venous blood supply to the liver cannot be monitored directly by PET because of the inaccessibility of the portal vein on PET scans. In this study, we investigated whether the dual hepatic input can be predicted from the measurable arterial input. Moreover, we assessed the effect of different input models on the rate constants of the standard 3-compartment model describing regional uptake of FDG. METHODS: Dynamic FDG PET scanning was performed on 5 foxhounds. Activity concentrations in blood from the aorta and the portal vein were measured simultaneously using external circuits. After image reconstruction, time--activity courses were determined from the aorta and the liver. The venous input was approximated by convolving the arterial input with a notional system function describing the dispersion of the arterial input on its way through the gastrointestinal tract. On the basis of these data, 5 different hepatic input models, which pertain to a single-input as well as a dual-input scenario, were statistically compared with regard to the adequacy of the model fits to liver data and to differences in the estimated rate constants. RESULTS: Portal venous input to the liver could be approximated by convolving the arterial input function with a system function. From this function, a mean transit time of 25 s was computed for FDG to pass through the gastrointestinal tract. According to the statistical analysis, dual-input models were superior to their single-input counterparts. However, differences in the rate constants estimated for the 5 input models were in the same order as interindividual variations within the different model groups. For the dephosphorylation rate constant, a consistent value of 0.05 +/- 0.01 min(-1) was found. CONCLUSION: Dual-input models proved to be superior to single-input models with respect to the adequacy of FDG model fits to normal liver data. However, the hepatic blood supply may be approximated by the arterial input function as well, especially for the evaluation of liver lesions mainly fed by the hepatic artery.

Hypertonic-hyperoncotic solutions decrease cardiac troponin I concentrations in peripheral blood in a porcine ischemia-reperfusion model.

In this study we addressed the question of whether the measurement of cardiac Troponin I (cTnI) is able to reflect beneficial effects of hypertonic-hyperoncotic solutions after transient cardiac arrest. Ten pigs were anaesthetized and cardiac arrest was induced by electric fibrillation. After 5 minutes of global ischemia, cardiac arrest was reversed by electric defibrillation. Upon return of spontaneous circulation 5 animals received hypertonic-hyperoncotic solutions (10% Hydroxyethylstarch 200/0.5 and 7.2% NaCl). The other animals received equivalent volumes of physiological saline. We observed that cTnI serum levels of animals treated with hypertonic-hyperoncotic solutions were significantly lower than those treated with saline. We conclude that hypertonic-hyperoncotic solutions may have cardioprotective effects.

Oxygen delivery at high blood viscosity and decreased arterial oxygen content to brains of conscious rats.

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.

Cardiac troponin I and cardiac troponin T increases in pigs during ischemia-reperfusion damage.

In this study we addressed the question of whether the measurement of cardiac Troponin T (cTnT) and cardiac Troponin I (cTnI) is able to detect myocardial cell damage in an ischemia-reperfusion model in pigs. To answer the question 3 pigs were anaesthesized and a cardiac arrest was induced by electric fibrillation. After 5 minutes of global ischemia the cardiac arrest was reversed by electric defibrillation until normal perfusion was restored. We could clearly demonstrate an increase of cTnT and cTnI 30 minutes after reperfusion indicating myocardial injury during ischemia and subsequent reperfusion. The cTnT as well as the cTnI serum levels increased till 180 minutes after reperfusion. This ischemia-reperfusion injury is likely induced by oxygen radicals generated during hypoxia and subsequent reperfusion We conclude from our first results that troponin measurements with commercial available test kits may also reflect myocardial cell damage in pigs as it was recently demonstrated in rats. Further studies are needed for correlation of troponin serum levels and histopathological damage in this model especially if it is used to test beneficial or toxicological effects of radical neutralizing drugs.

Isovolemic hemodilution with a bovine hemoglobin-based oxygen carrier: effects on hemodynamics and oxygen transport in comparison with a nonoxygen-carrying volume substitute.

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.

Measurement of liver blood flow using oxygen-15 labelled water and dynamic positron emission tomography: limitations of model description.

To date no satisfactory method has been available for the quantitative in vivo measurement of the complex hepatic blood flow. In this study two modelling approaches are proposed for the analysis of liver blood flow using positron emission tomography (PET). Five experiments were performed on three foxhounds. The anaesthetised dogs were each given an intravenous bolus injection of oxygen-15 labelled water, and their livers were then scanned using PET. Radioactivity in the blood from the aorta and portal vein was measured directly and simultaneously using closed external circuits. Time-activity curves were constructed from sequential PET data. Data analysis was performed by assuming that water behaves as a freely diffusible tracer and adapting the standard one-compartment blood flow model to describe the dual blood supply of the liver. Two particular modelling approaches were investigated: the dual-input model used both directly measured input functions (i.e. using the hepatic artery and the portal vein input, determined from the radioactivity detected in the aorta and portal vein respectively) whereas the single-input model used only the measured arterial curve and predicted the corresponding portal input function. Hepatic arterial flow, portal flow and blood volume were fitted from the PET data in several regions of the liver. The resulting estimates were then compared with reference blood flow measurements, obtained using a standard microsphere technique. The microspheres were injected in a separate experiment on the same dogs immediately prior to PET scanning. Whilst neither the single- nor the dual-input models accurately reproduced the arterial reference flow values, the flow values from the single-input model were closer to the microsphere flow values. The proposed single-input model would be a good approximation for liver blood flow measurements in man. The observed discrepancies between the PET and microsphere flow values may be due to the inherent temporal and spatial heterogeneity of liver blood flow. The results presented suggest that adaptation of the standard one-compartment blood flow model to describe the dual blood supply of the liver is limited and other flow tracers have to be considered for quantitative PET measurements in the liver.

Effect of cyclooxygenase inhibition in a canine model of unilateral pulmonary occlusion and reperfusion.

OBJECTIVE: To assess the effects of the cyclooxygenase inhibitor diclofenac in a canine model of pulmonary occlusion and reperfusion of the left lower lobe (LLL). DESIGN: Twelve adult beagle dogs (13-17 kg) were randomly assigned to a control group (n = 6) and a diclofenac-treated group (n = 6). Animals in the treatment group received 20 mg diclofenac sodium/kg as a single dose both before the experiment and at the end of surgical preparation; six animals served as controls. INTERVENTIONS: In the anesthetized animals, the left upper and middle lobes were resected. Circulation and ventilation of the LLL were selectively blocked by clamping. Complete occlusion of the LLL (30 min) was followed by periods of selective reperfusion (10 min, RP) and combined reperfusion and reventilation (120 min, RP/RV). MEASUREMENTS AND RESULTS: Reperfusion of the LLL resulted in a significant increase in pulmonary arterial pressure (Ppa) in the early RP/RV period as compared to baseline values (25.3 +/- 4.7 vs 15.8 +/- 1.9 mmHg, p < 0.05, paired t-test). This increase was significantly inhibited in the diclofenac-treated animals (17.0 +/- 2.0 mmHg, p < 0.01 vs controls, ANOVA). Gravimetrically determined extravascular lung water (EVLW) showed no significant difference in the continuously ventilated lobes of the right lung between diclofenac-treated animals (3.8 ml/g dry weight) and controls (3.9 +/- 0.9 ml/g dry weight) at the end of the experiment. EVLW, however, increased significantly in the LLL of control animals after 2 h of combined reperfusion and reventilation, whereas this increase was significantly inhibited in the diclofenac-treated animals (4.5 +/- 0.7 ml/g dry weight in the diclofenac group vs 6.5 +/- 1.3 ml/g dry weight in the control group, p < 0.05). CONCLUSIONS: Diclofenac inhibits the increase in both pulmonary arterial pressure and EVLW during reperfusion and reventilation of LLL. Thus, these changes appear to be mediated by cyclooxygenase metabolites.

Does colloid-induced plasma hyperviscosity in haemodilution jeopardize perfusion and oxygenation of vital organs?

BACKGROUND AND METHODS: The infusion of dextran solutions is associated with haemodilution and, under some conditions, with a slight increase in plasma viscosity. To clarify the compound effects of simultaneous haemodilution and plasma viscosity increases on macro- and microhaemodynamics, we investigated the changes in arterial perfusion (radiolabelled microspheres, 15 microns ø) and oxygenation (tissue Po2) of vital organs using an animal model of plasma hyperviscosity. In nine splenectomized beagles plasma viscosity was increased step by step from 1.06 (baseline) to 2.14, and 2.99 mPa.s by infusion of small amounts (4% of total blood volume) of an ultra-high-molecular-weight dextran (50% w/v, mw: 500,000). RESULTS: Despite the significant increase in plasma viscosity, cardiac output as well as specific organ blood flows in heart, brain, liver, and muscle rose steadily with each step of viscosity, while the haematocrit declined from 0.31 to 0.24 and 0.20, respectively. Medians of tissue Po2 in liver peaked at a viscosity of 2 mPa.s and returned to baseline values at 3 mPa.s, whereas in non-working skeletal muscle Po2 values were maximal at 3 mPa.s. CONCLUSION: These results indicate that the impact of plasma viscosity on the rheological properties of whole blood is completely offset by the concomitant reduction of haematocrit. Thus, the comparatively minor changes in plasma viscosity observed after prolonged use of clinical dextrans and other colloids in no way compromise the perfusion and oxygenation of vital organs.

Lack of dependence of cerebral blood flow on blood viscosity after blood exchange with a Newtonian O2 carrier.

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)

Infusion of oxidized glutathione enhances postischemic segment-shortening in dog hearts.

Oxidized glutathione (GSSG) but not its reduced form (GSH) is taken up by intact myocardial cells, and is rapidly converted into GSH. Reduced glutathione is an important intracellular defense against oxygen-derived free radicals and has been found to enhance calcium sensitivity in skinned cardiac fibers. We have investigated the effects of intravenous GSSG on left ventricular systolic pressure, maximal rate of rise of pressure and regional segment-shortening in dogs subjected to occlusion of the left anterior descending artery for 30 minutes, followed by 45 minutes reperfusion. Starting 10 minutes before reperfusion, the dogs were randomly treated with either GSSG (100 mM, 5 ml/min, n = 5) or Ringer's solution (5 ml/min, n = 5) until 30 minutes of reperfusion. Myocardial blood flow was measured by radioactive microspheres. Infusion of GSSG increased total glutathione content in both ischemic (47 +/- 16 mumol/g protein) and nonischemic myocardium (71 +/- 17 mumol/g protein) as compared to controls (23 +/- 2 mumol/g protein, p < 0.05). In both groups paradoxical wall motion occurred in the ischemic region during occlusion. On reperfusion, regional dyskinesia persisted in controls; while, in glutathione-treated dogs, systolic segment-shortening reached half the baseline values (p < 0.05, treated vs controls, at 15, 30, 45 minutes reperfusion). During ischemia the area of pressure-length loops, obtained from simultaneous recordings of left ventricular pressure and regional segment length, decreased to 30 +/- 7% of baseline in controls and to 40 +/- 18% of baseline in GSSG-treated animals. After 45 minutes reperfusion it was restored to 78 +/- 22% baseline in treated hearts but was still 36 +/- 16 of baseline in controls (p < 0.05). We conclude that infusion of GSSG increases the intracellular stores of glutathione and improves the contractile state of postischemic myocardium.

Organ blood supply and tissue oxygenation after limited normovolemic hemodilution with 3% versus 6% Dextran-60.

BACKGROUND: The use of dextran solutions (DX) for hemodilution (HD) is considered being detrimental due to their effects on plasma viscosity. METHODS: 14 splenectomized beagles (12.7 +/- 1.3 kg) were anesthetized and randomly assigned to HD to 20 vol% hematocrit (hct) with either 3 or 6% DX-60. The effects of HD upon nutritional organ blood flow (radioisotope-labelled microspheres, phi 15 microns), local tissue oxygenation (pO2 multiwire surface electrode), plasma and blood volume (131I-labelled dog albumin distribution), and macrohemodynamics were evaluated with regard to actual changes in hct and plasma viscosity, respectively. RESULTS: Normovolemic HD with either solution resulted in equivalent changes in macrohemodynamics, and plasma and blood volume. Despite the increase in plasma viscosity associated with HD using 6% DX-60 (up to 1.45 +/- 0.10 mPa.s), blood flow rose in all organs studied (p < 0.05). After HD by means of 3% DX-60, plasma viscosity remained unchanged (1.09 +/- 0.04 mPa.s) but was not associated with higher organ blood flow as compared to 6% DX-60. In both groups, elevated pO2 values on the surface of liver and skeletal muscle (p < 0.01) as well as the shift in the pO2 histograms toward higher pO2 values indicated a more homogeneous tissue perfusion upon HD, independent of the diluent applied. CONCLUSION: In comparison to 6% DX-60, the solution of 3% DX-60 is of equivalent efficacy as volume substitute and in the induction of normovolemic HD. The main advantage of 3% DX-60 solution, however, is the fact that twice as much volume can be administered before the recommended maximal daily dose of 1.5 g/kg DX is reached. Of the rheological factors influencing oxygen delivery, hematocrit thus plays the predominant role, while plasma viscosity is of minor importance.

[Modified hemoglobin as a blood substitute in a rat model]. / Modifiziertes Hämoglobin als Blutersatzmittel im Rattenmodell.

The use of modified haemoglobin solutions as blood substitutes has been investigated extensively during the past decades. Ultrapurified, polymerised bovine haemoglobin (upbHb) is a promising new substance in this respect. It was the aim of the present investigation to study the cardiovascular and respiratory effects of massive blood replacement with upbHb in a new model of conscious rats with continuous haemodynamic monitoring. METHODS. The right femoral artery and vein of 13 male Sprague-Dawley rats were catheterised during halothane-N2O-O2 anaesthesia. A thermistor catheter was placed in the descending aorta via the left femoral artery for measuring cardiac output by the thermodilution method. After recovery from anaesthesia blood replacement was achieved by arterial blood withdrawal and simultaneous venous infusion of upbHb in equal amounts. The haematocrit was lowered to < 3% and the animals were then left undisturbed in a rat restrainer while breathing room air. RESULTS. The animals showed no signs of disturbed behaviour patterns, distress, or adverse reactions. There were no significant changes in cardiac index and oxygen delivery during the investigation period of 4 h. A marked increase in mean arterial pressure (MABP) and systemic vascular resistance (SVR) of 30% was observed while stroke volume remained unchanged. Blood gases, acid-base status, and plasma glucose showed no major changes. Plasma oncotic pressure increased during the investigation period. CONCLUSIONS. The results indicate that there is adequate oxygenation and sufficient systemic oxygen delivery in conscious and drug-free rats after isovolaemic haemodilution with upbHb to a final haematocrit of < 3%. In contrast to previous haemodilution studies, which have tested non-oxygen-carrying solutions, no changes in cardiac index were observed. The cause of the increase in MAP and SVR remains to be established.

Optimizing autologous blood donation by recombinant human erythropoietin (rhu-EPO) and interleukin 3 (IL-3).

The transfusion of autologous blood protects surgical patients from both the transfusion transmitted diseases (AIDS, posttransfusion hepatitis) and the immunosuppressive effects of homologous blood. Nevertheless, the use of autologous blood is still unsatisfactory, mainly because of the elaborated logistics, organization and technique required and the often insufficient amounts of autologous blood gained. Today, the major growth-factors of erythropoiesis are available as recombinant analogues. In the studies reviewed here, we investigated the effects of rhu-EPO and IL-3 on perioperative erythropoiesis in two canine models of acute isovolemic hemodilution. Different therapeutic concepts are compared with respect to preoperative changes in hematocrit, the volume of autologous blood gained and the duration of postdilutional anemia.

Erythropoietin accelerates the recovery from extreme hemodilution: a randomized, placebo-controlled study in dogs.

Six splenectomized beagles of either sex (13.8 +/- 2.2 kg) were randomly treated either with 500 U/kg recombinant human erythropoietin (rhu-EPO) (verum group, n = 3) or an equivalent volume of the vehicle (placebo group, n = 3). Both solutions were given intravenously for 3 days. At day 4 after onset of treatment, the dogs were anesthetized and subjected to isovolemic hemodilution using 6% Dextran 60 (MW 60,000) down to a hematocrit of 0.10. During the recovery period vehicle or rhu-EPO was given every other day until the hematocrit reached control values. Every day venous blood samples were withdrawn, and the hematocrit as well as the concentrations of hemoglobin and 2,3-diphosphoglycerate were determined. In addition, the platelets and reticulocytes were counted. Treatment with rhu-EPO shortened the time of hematocrit recovery from 20 (placebo) to 11 days (p less than 0.05). The reticulocyte count peaked at day 2 (verum) versus day 5 (placebo). These findings indicate a successful stimulation of red blood cell production after extreme hemodilution in animals treated with erythropoietin. Therefore, rhu-EPO may allow to optimize blood donation programs as well as preoperative hemodilution and yield both, higher amounts of autologous blood and an accelerated reversal of dilutional anemia.

Prevention of endogenous leukotriene production during anaphylaxis in the guinea pig by an inhibitor of leukotriene biosynthesis (MK-886) but not by dexamethasone.

Leukotriene C4 (LTC4) underwent rapid elimination from the circulating blood and was extensively converted to LTD4 within the vascular space of the guinea pig. To mimic the elimination and metabolism of endogenous LTC4 generated during anaphylaxis, 14,15-3H-labeled LTC4 was infused intravenously over a period of 15 min, leading to a recovery in bile of 85% of the infused LT radioactivity within 2 h. Corresponding to the tracer studies, LTD4 and, to a lesser extent, LTC4 were the predominant endogenous cysteinyl LTs in guinea pig bile. The biliary production rate of endogenous LTD4 increased from 0.3 +/- 0.1 to 6.2 +/- 1.8 pmol x min-1 x kg-1 (p less than 0.001) during anaphylactic shock induced by intravenous injection of OVA (0.2 mg/kg) into sensitized guinea pigs. A novel LT biosynthesis inhibitor (MK-886; 10 mg/kg, i.v., 15 min before antigen challenge) suppressed the antigen-induced cysteinyl LT production by greater than 92% (p less than 0.001). This inhibition of systemic LTC4 formation was associated with a complete protection against lethal anaphylactic shock in animals pretreated in addition with the H1 receptor antagonist pyrilamine. Pretreatment with either the inhibitor of LT synthesis or the histamine receptor antagonist reduced the lethality during anaphylactic shock from 100 to 60 and 78%, respectively. In artificially ventilated, pyrilamine-pretreated animals, the antigen-induced decrease in dynamic lung compliance and the rise in hematocrit were significantly reduced (p less than 0.05) by pretreatment with the inhibitor of LT synthesis. Dexamethasone at high doses (10 mg/kg, i.p., once daily for 7 d, or in a single dose of 10 mg/kg, i.v., 3.5 h before challenge) had no inhibitory effect on LT generation during anaphylaxis in vivo. However, in resident peritoneal macrophages, harvested from these dexamethasone-treated sensitized guinea pigs and stimulated with zymosan, both cysteinyl LT and 6-keto-PGF1 alpha formation were strongly suppressed. These studies indicate an important role of cysteinyl LTs in systemic anaphylaxis in vivo and demonstrate the blockade of anaphylactic LT generation by a novel inhibitor of LT biosynthesis (MK-886) but not by dexamethasone.