Involvement of nitric oxide in microcirculatory reactions after ischemia-reperfusion of the rat urinary bladder.

BACKGROUND: Nitric oxide (NO) plays a role in inflammation. Our aim was to investigate the role of NO in the microcirculatory changes after ischemia-reperfusion (I/R) of the bladder using intravital videomicroscopy (IVM). METHODS: In rats, 60 min of bladder ischemia followed by 30 min of reperfusion was performed in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME), the NO precursor L-arginine, or saline pre-treatments. Venular red blood cell velocity (RBCV), functional capillary density (FCD), vessel diameters, and leukocyte-endothelial cell interactions in postcapillary venules were determined. Concentrations of nitrite/nitrate in the plasma and myeloperoxidase (MPO) levels in the lungs and the bladder were measured. RESULTS: Elevations of the numbers of rolling and adherent leukocytes, and of plasma nitrite/nitrate levels were found, while FCD and RBCV decreased. L-NAME pretreatment ameliorated the enhanced leukocyte-endothelial cell interactions without influencing the microcirculatory perfusion. In contrast, the L-arginine pretreatment further increased plasma nitrite/nitrate levels and preserved the FCD and RBCV, but did not affect leukocyte-endothelial interactions. None of these treatments influenced MPO activities. CONCLUSION: Our results suggest that NO plays an enhancing role in the I/R-induced neutrophil-endothelial interactions of the bladder. Supplementation of NO ameliorates the microcirculatory perfusion deficit without influencing the postischemic microcirculatory inflammatory reactions.

Differential function of nitric oxide in murine antigen-induced arthritis.

BACKGROUND: The aim of our study was to investigate the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) production in different stages of murine antigen-induced arthritis (AiA). METHODS: Clinical, histological and microcirculatory parameters (measured by intravital fluorescence microscopy) were assessed in the knee joint during acute and chronic AiA after inhibition of iNOS with L-N(6)-(1-iminoethyl)lysine (L-NIL). Plasma concentrations of and were evaluated by the Griess reaction and the expression of iNOS, P- and E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) by immunohistochemistry. RESULTS: In both stages of the disease, plasma concentrations of and were increased and iNOS was expressed. In the acute phase, swelling, leucocyte adhesion, leucocyte infiltration and expression of adhesion molecules were increased in arthritic animals treated with L-NIL in comparison with untreated arthritic animals. In the chronic phase, no change in the disease parameters could be detected after L-NIL treatment. CONCLUSION: Increased NO production induced by iNOS during the acute phase of AiA can be regarded as a protective response in the prevention of further leucocytic infiltration and joint destruction, whereas it seems to play a subordinate role in chronic AiA.

Impact of hyperthermic preconditioning on postischemic hepatic microcirculatory disturbances in an isolated perfusion model of the rat liver.

Sublethal hyperthermia and the following recovery from this heat exposure, referred to as hyperthermic preconditioning, elicits a transient state of tolerance to oxidative insults through an intracellular protective response: stress response. The impact of hyperthermic preconditioning on hepatic microcirculatory disturbance, which is one of the determinants of ischemia/reperfusion-induced injury of the liver, was investigated by using intravital fluorescence microscopy. Thirty minutes of ischemia and a subsequent 120 minutes of reperfusion was induced in an in situ isolated perfusion model of Sprague-Dawley rats. Heat stress was given by whole-body hyperthermia, and a subsequent recovery was allowed for 18 or 48 hours, respectively. Postischemic decrease in sinusoidal perfusion rate and sinusoidal diameter, leukocyte stagnation in sinusoids, and leukocyte adhesion in postsinusoidal venules were significantly attenuated in both hyperthermia-pretreated groups. A recovery of bile production, a reduction of liver enzyme release, and an attenuation of tissue edema and histological damage were also observed. A marked expression of heat shock protein (HSP) 70 and heme oxygenase (HO-1)/HSP32 was correlatively observed in the liver tissue coincident with the induction of these protective effects. Hyperthermic preconditioning provides a continuous long-term and constant inhibitory effect (up to 48 hours after heat exposure) on postischemic injury of the liver through the attenuation of microcirculatory disturbances. These beneficial effects might be associated with a concomitant increase in HSP70 and HO-1/HSP32 expression.

Perflubron emulsion delays blood transfusions in orthopedic surgery. European Perflubron Emulsion Study Group.

BACKGROUND: Fluorocarbon emulsions have been proposed as temporary artificial oxygen carriers. The aim of the present study is to compare the effectiveness of perflubron emulsion with the effectiveness of autologous blood or colloid infusion for reversal of physiologic transfusion triggers. METHODS: A multinational, multicenter, randomized, controlled, single-blind, parallel group study was performed in 147 orthopedic patients. Patients underwent acute normovolemic hemodilution with colloid to a target hemoglobin of 9 g/dl with an inspiratory oxygen fraction (FIO2) of 0.40. Patients were then randomized into one of four treatment groups after having reached any of the protocol-defined transfusion triggers including tachycardia (heart rate > 125% of posthemodilution rate or > 110 bpm), hypotension (mean arterial pressure < 75% of posthemodilution level or < or = 60 mmHg), elevated cardiac output (> 150% of posthemodilution level) or decreased mixed venous oxygen partial pressure (PVO2; < 38 mmHg). Treatments in the four groups were 450 ml autologous blood harvested during acute normovolemic hemodilution given at FO2 = 0.40; 450 ml colloid at FIO2 = 1.0; 0.9 g/kg perflubron emulsion with colloid (total = 450 ml) at FIO2 = 1.0; and 1.8 g/kg perflubron emulsion with colloid (total = 450 ml) at FIO2 = 1.0. The primary endpoint was duration of transfusion-trigger reversal. A secondary end-point was percentage of transfusion-trigger reversal. RESULTS: Perflubron emulsion was well tolerated with no serious adverse event attributed to drug treatment. Duration of reversal was longest in the 1.8 g/kg perflubron group (median, 80 min; 95% confidence interval, 60-100 min; P = 0.014 vs. autologous blood, P < 0.001 vs. colloid) followed by the 0.9 g/kg perflubron group (median, 59 min; 95% confidence interval, 40-90 min), the autologous blood group (median, 55 min; 95% confidence interval, 30-70 min) and the colloid group (median, 30 min; 95% confidence interval, 27-60 min). Percentage of reversal was also highest in the 1.8 g/kg perflubron group (97%; P < 0.001 vs. autologous blood; P = 0.014 vs. colloid), followed by 0.9 g/kg perflubron (82%), colloid (76%), and autologous blood (60%). CONCLUSIONS: Perflubron emulsion (1.8 g/kg) combined with 100% oxygen ventilation is more effective than autologous blood or colloid infusion in reversing physiologic transfusion triggers.

Validation of MR thermometry technology: a small animal model for hyperthermic treatment of tumours.

BACKGROUND: Local hyperthermia has been shown to be an effective adjuvant therapy for cancer. However, progress in this treatment modality requires the non-invasive assessment of temperature distribution in the entire tumour to enable administration of an efficient thermal dose to all tumour areas. Magnetic resonance (MR) imaging offers a promising tool to quantify, non-invasively and three-dimensionally, temperature distribution within tumours. An animal model taking into account the complex interrelationship between pathophysiological changes within a tumour during hyperthermia and temperature-sensitive MR parameters is warranted for the development and validation of new MR thermometry technology. METHODS: An experimental set-up was implemented to allow simultaneous measurements of temperature, tumour blood flow and temperature-sensitive MR parameters under standardised conditions in vivo. Local hyperthermia was induced at 44 degrees C for 20 min under inhalation anaesthesia on seven Syrian Golden hamsters bearing an amelanotic melanoma. Fibreoptic probes were used for reference temperature measurements. Laser Doppler flowmetry served for on-line tumour blood flow determination, and MR thermometry was performed using longitudinal T1 relaxation time measurements. RESULTS: The experimental design enables multifunctional MR thermometry. T1 relaxation times of tumours were 1.44 s (1.36, 1.46) and 1.53 s (1. 48, 1.75) at 37 degrees C and during hyperthermia at 44 degrees C, respectively (median, 25% and 75% quartiles, respectively; P<0.05). At the end of 20 min of hyperthermic treatment at 44 degrees C, relative tumour blood flow was reduced to 40.5% (20.7, 43.3) compared to values before treatment (median, 25% and 75% quartiles, respectively; P<0.05). Imaging of T1 relaxation times revealed a heterogeneous distribution in temperature during hyperthermic treatment. CONCLUSION: This novel in vivo model allows standardised investigations for the development and validation of MR thermography methods.

Hypertonic saline dextran attenuates leukocyte accumulation in the liver after hemorrhagic shock and resuscitation.

BACKGROUND: Hemorrhagic shock and resuscitation triggers a global ischemia/reperfusion phenomenon, in which activated leukocytes are considered strong contributors to the ensuing tissue damage. METHODS: The aim of the study was to investigate the effects of hypertonic saline dextran (HSD) on the early leukocyte/endothelial interactions (intravital fluorescence microscopy) in a rat model of hemorrhagic shock (1 hour at mean arterial pressure of 40 mm Hg). The resuscitation was performed with lactated Ringer's solution (RL, four times shed blood/20 minutes, n = 6), 6% dextran 60 (DEX, 100% shed blood/5 minutes, n = 8), and 7.2% NaCl/10% dextran 60 (HSD, 10% shed blood/2 minutes, n = 8). RESULTS: After 1 hour of resuscitation, shock-induced stasis/adherence of leukocytes was further enhanced with RL (sinusoids 17.6+/-6.9%; venules 33.9+/-8.5%), whereas DEX and HSD attenuated leukocyte stagnation in sinusoids (DEX -7.4+/-6,1%; HSD -14.7+/-2.9%, p<0.01 vs. RL) and leukocyte adherence in postsinusoidal venules (DEX -12.2+/-8.6%, p<0.05 vs. RL; HSD -27+/-7.4%, p<0.01 vs. RL). CONCLUSION: HSD reduced significantly the number of leukocytes accumulated in the liver after resuscitation of hemorrhagic shock, probably due to a combination of mechanisms of both components.

IV perflubron emulsion versus autologous transfusion in severe normovolemic anemia: effects on left ventricular perfusion and function.

Intact cardiac compensatory mechanisms are necessary to maintain adequate tissue oxygenation during acute normovolemic hemodilution (ANH). Left ventricular (LV) perfusion, oxygenation and function were analyzed in an experimental whole-body model of profound ANH (Hct 9%) and effectiveness of a perfluorocarbon-based oxygen carrier in maintaining myocardial oxygenation and function was evaluated. A total of 22 anesthetized dogs were hemodiluted to Hct 20% followed by a simulated, controlled blood-loss phase in which dogs were randomized to either: (1) 1:1 exchange of lost blood with autologous red blood cells (RBC-group), (2) 1:1 exchange with a colloid (control-group) and (3) 1:1 exchange with a colloid after a single dose of 1.8 g/kg BW perflubron i.v. (PFC-group). Myocardial oxygen delivery and consumption as well as endocardial perfusion were determined using radioactive microspheres. LV myocardial contractility (LV MC) was assessed from: (1) the relationship between maximum rate of LV pressure increase (LVdp/dtmax) and LV enddiastolic volume (LVEDV) and (2) analysis of the LV endsystolic pressure volume relationship (ESPVR). LV diastolic properties were reflected by (1) minimum rate of LV pressure increase (LVdp/dtmin), (2) slope and intercept of the enddiastolic pressure-volume relationship (EDPVR) and (3) the time-constant of isovolumic LV pressure decline "tau 1/2". Full sets of LV MC data were obtained from 18 dogs (n = 6 per group). LV MC (LVdp/dtmax-LVEDV relation) increased after perflubron administration. At the lowest Hct level, all parameters reflecting LV MC as well as LVdp/dtmin were significantly higher in the PFC-group than in the control-group. After profound normovolemic hemodilution (Hct 9%) superiority of LV MC and LV diastolic properties was found, when myocardial oxygenation was supported by i.v. perflubron emulsion, a temporary O2 carrier.

Effects of adenosine on cardiopulmonary functions and oxygen-derived variables during endotoxemia.

OBJECTIVES: To determine the effects of a prophylactic intravenous infusion of adenosine on cardiopulmonary functions and oxygen-derived variables in a porcine model of endotoxemia. DESIGN: Prospective, randomized, placebo-controlled, unblinded study. SETTING: University research laboratory. SUBJECTS: Thirty country bred pigs, aged 6 to 7 wks, weighing 24.9 +/- 0.65 (SEM) kg body weight. INTERVENTIONS: Pigs were anesthetized by i.v. pentobarbital and fentanyl, intratracheally intubated, and mechanically normoventilated with a gas mixture of nitrous oxide/oxygen = 1:1. Intravascular catheters were inserted to allow for determination of arterial, central venous blood pressure, pulmonary artery occlusion pressure, cardiac output, and sampling of blood for gas analyses. Group 1 (n = 10) received a 330-min intravenous infusion of Salmonella abortus equi endotoxin (5 microg/kg body weight x hr). Group 2 (n = 10) received an additional intravenous infusion of adenosine (150 microg/kg body weight x min), started 30 mins before the infusion of endotoxin. Control groups 3 and 4 (n = 5 for both groups) received adenosine or physiologic saline, respectively. MEASUREMENTS AND MAIN RESULTS: Parameters of cardiopulmonary function and oxygen-derived variables were calculated from pulmonary artery catheter measurements and blood gas analyses using standard formula. Plasma concentrations of purine compounds (adenosine, inosine, hypoxanthine) were determined by high-performance liquid chromatography. Since tumor necrosis factor-alpha plays a central role in the development of endotoxic shock, concentrations of this cytokine were determined in serum by enzyme-linked immunosorbent assay. Infusion of adenosine before the beginning of the infusion of endotoxin increased plasma concentrations of the nucleoside from 193 +/- 72 to 553 +/- 65 nmol/L and decreased the systemic vascular resistance by 50%. Although acting as a potent vasodilator under control conditions, adenosine did not aggravate the arterial hypotension elicited by endotoxemia but significantly increased cardiac output by a comparably small decrease in systemic vascular resistance, prevention of pulmonary vasoconstriction, and improvement of left ventricular performance. Despite significant pulmonary vasodilation, gas exchange was not worsened but slightly improved by adenosine. With the increase in cardiac output and arterial oxygenation, systemic oxygen delivery almost doubled. This adenosine-induced oxygen flux was not a surplus but was most likely utilized by tissues, as suggested by the much earlier beginning of the increase in the systemic oxygen consumption and the attenuation of the decrease in the gastric mucosal pHi. No effects of adenosine were observed on the endotoxin-induced increase in serum concentrations of tumor necrosis factor-alpha. CONCLUSIONS: Infusion of adenosine might be useful to improve flow-dependent oxygen delivery and tissue oxygenation during endotoxic shock without the induction of adverse cardiopulmonary side effects. The beneficial hemodynamic effects of adenosine appear not to be mediated by the inhibition of the release of tumor necrosis factor-alpha.

Global tissue oxygenation during normovolaemic haemodilution in young children.

Sixteen patients (1-8 years) scheduled for major general surgery were chosen for the study. They were divided into two groups according to the replacement solution used for haemodilution (HD); whether 6% middle molecular weight hydroxyethyl starch (HES) or 6% dextran 60 (DEX). After induction of general anaesthesia and pulmonary artery catheterization, a precalculated amount of autologous blood was withdrawn while the patient's autologous blood was simultaneously replaced by either HES or DEX. Autologous blood was retransfused at a minimum haematocrit (Hct.) of 17% or at the end of surgery. The following parameters were measured and/or calculated before and after HD, every 20 min intraoperatively and hourly for 6 h postoperatively: heart rate (HR), mean arterial pressure (MAP), Cardiac index (CI), Hct., arterial and mixed venous oxygen content (CaO2, CvO2) and arterio-venous difference of oxygen content (avDO2), oxygen delivery index (DO2I), oxygen consumption index (VO2I). The cardiovascular system remained stable. There was no significant difference as regards SvO2, despite a significant decrease in CaO2 to 10.8 and 10.0 ml.dl-1 (median values) due to reduction of haemoglobin concentration in the HES and DEX groups respectively. In spite of the low hct. values during surgery DO2I remained in normal range (median value 602 and 710 ml.min-1.m-2) in HEX and DEX group respectively. There was no significant change in VO2I after haemodilution (median value 212 and 243 ml.min-1.m-2) in either group. No statistically significant difference was noticed between either groups regarding: CaO2, CvO2, DO2I, VO2I, and no side effects of the colloids were observed. Isovolaemic haemodilution (Hct. approximately 17%) is well tolerated by young children undergoing major elective surgery; global tissue oxygenation was preserved throughout the procedure and both solutions used for haemodilution were equally effective.

[Avoidance of homologous blood transfusion despite extreme blood loss]. / Vermeidbarkeit von Fremdblut trotz extremen Blutverlustes.

We report the case of a 22-year-old woman who underwent two-step scoliosis surgery without allogeneic transfusion, although the intraoperative blood loss (3500 ml) during the first procedure was higher than the calculated blood volume (3250 ml). Preoperatively the patient had donated four units of autologous blood. Intraoperatively blood-saving methods were combined. During the first operation acute normovolemic hemodilution (target hemoglobin 9.0 g/dl) was applied and during the second operation controlled hypotension (systolic blood pressure 80 mmHg). Intraoperative auto-transfusion was used in both procedures. During the first operation severe normovolemic anemia (minimal hemoglobin 3.5 g/dl) was accepted while the patient was ventilated with FiO2 1.0. The hemoglobin concentration was 8.6 g/dl after the first procedure and had increased to 11.6 g/dl 4 weeks after the second procedure. No severe complications occurred during the postoperative phase. This case report shows that also in surgical procedures with extreme blood loss any allogenic transfusion can be avoided by the combination of blood-saving methods, acceptance of low intraoperative transfusion trigger and ventilation with 100% oxygen.

Roundtable of Experts in Surgery Blood Management--consensus statement.

UNLABELLED: A Roundtable of Experts in Surgery Blood Management was held 7 to 9 April 1995, in Vienna, where all the available published and unpublished epoetin alfa clinical data was thoroughly discussed and where the following CONSENSUS STATEMENT was developed to give the clinician some practical guidelines for the administration of epoetin alfa in elective surgery patients. CONSENSUS STATEMENT: For elective surgery patients it is important to facilitate, via blood conservation methods, the elimination or reduction of exposure to allogeneic blood transfusion and its associated risks. Adjunctive use of epoetin alpha therapy in specific patients is one method to accomplish this goal. Patients with small body size, predicted low blood volume (< or = 51), and/or a hematocrit too low to be enrolled in or to complete their prescribed ABD (autologous blood donation) program especially benefit from epoetin alfa therapy. Generally, epoetin alfa therapy is well tolerated, with an acceptable risk-to-benefit ratio.

Inhalation of prostacyclin (PGI2) for 8 hours does not produce signs of acute pulmonary toxicity in healthy lambs.

OBJECTIVE: To study the potential side effects and toxicity of inhaling prostacyclin (PGI2) aerosol for 8 h. DESIGN: In a prospective, randomized study 14 healthy lambs received either PGI2 (n = 7) or 0.9% NaCl (n = 7) as an aerosol for 8 h. SETTING: Institute for Surgical Research of the Ludwig-Maximilians-University of Munich. INTERVENTIONS: All animals were studied under general anesthesia in a prone position. They were first intubated endotracheally and later tracheotomized. PGI2 solution (median dose 28 ng/kg per min) or 0.9% NaCl was administered with a jet nebulizer (delivery rate 4-10 ml/h; mass median diameter of aerosol particles 3.1 microns). Bronchoalveolar lavage was performed before and after the inhalation period to collect epithelial lining fluid of alveoli. MEASUREMENTS AND RESULTS: Hemodynamic and respiratory parameters, systemic resorption (plasma levels of 6-keto-prostaglandin-F 1 alpha), in vitro bleeding time, collagen-induced platelet aggregation and global biochemical and cellular composition of the epithelial lining fluid were examined in order to assess the side effects and signs of acute pulmonary toxicity induced by inhaled PGI2. No statistically significant differences were found between the PGI2 and the control groups for any of the parameters examined. CONCLUSION: Inhalation of PGI2 (28 ng/kg per min) over a period of 8 h in healthy lambs does not produce major side effects or acute pulmonary toxicity.

Impact of vitamin E supplement in standard laboratory animal diet on microvascular manifestation of ischemia/reperfusion injury.

Aimed at improving animal fertility and health, diets for farm and laboratory animals have over the last few years been supplemented with increasing amounts of the antioxidant vitamin E. We now demonstrate by intravital microscopy that feeding hamsters with a vitamin E-supplemented "standard" rodent diet (60 ppm vitamin E) significantly reduces the microvascular manifestations of ischemia/reperfusion injury when compared to animals fed a nonsupplemented diet. Postischemic leukocyte adhesion to venular endothelium was reduced from 770 +/- 204 cells/mm2 at 24 h after reperfusion in control animals on the nonsupplemented diet to 403 +/- 105 cells/mm2 in animals on the "standard" rodent diet (means +/- SD, n = 7 animals per group, p < 0.01). Animals on the nonsupplemented diet showed a dramatic loss of capillary perfusion density until 7 days after reperfusion (to 21 +/- 13% of preischemic baseline values), whereas this loss was significantly attenuated (to 71 +/- 12% of preischemic values, p < 0.01) in animals on the "standard" rodent diet. No difference in the extent of reperfusion injury was seen between animals on the "standard" rodent diet and animals on diets with substantially higher vitamin E supplements (300 ppm-30,000 ppm). Besides underscoring the benefit of vitamin E in reducing the extent of ischemia/reperfusion injury, this study raises the concern that vitamin E supplements in "standard" laboratory animal diets may have a far-reaching impact on biomedical research by jeopardizing established animal models of disease.

Hyperbaric oxygen treatment enhances the recovery of blood flow and functional capillary density in postischemic striated muscle.

The effect of hyperbaric oxygen (HBO) at 2.5 atmospheres of absolute pressure (ATA) on postischemic reperfusion injury in striated muscle was studied using two different animal models. One used complete tourniquet ischemia (4 hr) in the rat hindlimb, measuring blood flow in the tibialis anterior muscle by the xenon washout method at 1-1.5 and 4.5-5 hr after the start of reperfusion. The other used 4 hr of pressure-induced ischemia in the fine striated skin muscle, contained within a dorsal skinfold chamber in hamsters. Vital fluorescence microscopy was employed to measure the functional capillary density using fluorescein isothiocyanate-dextran (mw 150,000) as a plasma marker. After 1-1.5 hr of reperfusion following 4 hr of total ischemia, postischemic blood flow was severely depressed, with no significant difference between the HBO-treated and the untreated rats. However, after 4.5-5 hr of reperfusion, blood flow rates in the postischemic muscle in the HBO-treated animals did not differ significantly from those in nonischemic muscle, compared to a persistent, significant depression in the untreated animals. No significant difference was seen in functional capillary density between HBO-treated and untreated hamsters following 1 hr of reperfusion. After 5 hr of reperfusion, capillary density was significantly improved in HBO-treated animals compared to untreated animals. These results suggest that HBO treatment enhances the recovery of blood flow and functional capillary density in postischemic muscle tissue, indicating attenuation of the microvascular dysfunction or damage in the postischemic period.

Effect of intensive walking exercise on skeletal muscle blood flow in intermittent claudication.

Walking exercise is generally accepted as a valid therapeutic regimen in the treatment of peripheral arterial occlusive disease (PAOD) of Fontaine stage II. In order to quantify the effect of walking exercise and/or drug therapy on regional muscular blood flow, PAOD Fontaine stage II was induced by multiple ligations of the femoral artery and of all side branches in one hindlimb of mongrel dogs; the contralateral extremity served as control. The animals underwent walking exercise with increasing intensities on a treadmill five days per week over one year; one group received 600 mg buflomedil (BF) per day orally in addition. At the end of the training period, the regional blood flow in all skeletal muscles of both hindlimbs was quantified by means of 15 microns radioactively labeled microspheres at resting conditions, after treadmill exercise (ten minutes) with or without preinjection of BF (3 mg/kg body weight) into the abdominal aorta. At resting condition and at the end of treadmill exercise the regional muscular blood flow did not differ significantly between the diseased and control extremity. Supplementary oral treatment with BF over one year had no significant effect; the increase in muscular blood flow during treadmill exercise was not enhanced after intra-aortic injection of BF. Consequently walking exercise has the potential to increase the functional capacity of collaterals in intermittent claudication and to restore blood supply to skeletal muscle.

Interstitial fluid pressure in solid tumors following hyperthermia: possible correlation with therapeutic response.

Elevated interstitial fluid pressure (IFP) of tumors may be a physiological barrier to the delivery of certain therapeutic agents. The objective of this study was to find out if IFP could be lowered using localized hyperthermia and if the reduction in IFP could predict the tumor response to treatment. Amelanotic melanoma (A-Mel-3) implanted into the dorsal skin of Syrian golden hamsters was exposed to hyperthermic treatment after 7 days of tumor growth at tumor volumes of about 100-150 mm3. Hyperthermia was induced by immersing the tumor in a water bath at 43 degrees C for 30 or 60 min. Forty-eight h later the IFP of control and treated tumors was determined by using the wick-in-needle technique. The mean IFP in control tumors was 12.6 mmHg. Hyperthermic treatment for 30 min induced a significant decrease to 2.8 mmHg (P less than 0.001 versus controls), whereas a 60-min immersion of the tumors induced a further decrease to 0.8 mmHg (P less than 0.05 versus 43 degrees C for 30 min). Separate experiments on tumor growth in corresponding groups of animals revealed a significant growth delay of 2.7 days after hyperthermia for 30 min. Enhanced growth delay and partial tumor response in 66% of the tumors were found following 60 min of hyperthermia at 43 degrees C. The thermal dose-dependent decrease in IFP presumably results from the dose-dependent damage to the tumor vasculature. In addition, the association of an enhanced biological effect with a more pronounced reduction of interstitial fluid pressure suggests that the IFP might serve as a quantitative parameter to predict the response of tumors to hyperthermic therapy.

Impact of ischemia on tissue oxygenation and wound healing: improvement by vasoactive medication.

The influence of vasoactive medication on tissue oxygenation and wound healing was investigated in the ear model of the hairless mouse. Ischemia was induced to the ears by ligating 2 of the 3 main vessel bundels and verified by measurements of tcpO2. Reduced tissue oxygenation was followed by a prolongation of the time required for complete healing of standardized wounds. Treatment with the vasoactive drug Buflomedil (3 mg/kg/day iv.) resulted in enhanced recovery of the tissue from reduced oxygenation and likewise reversed the adverse effects of ischemia on wound healing. These results warrant the use of the drug in patients suffering from delayed wound healing due to peripheral arterial disease.

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.