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The influence of iloprost on blood rheology and tissue perfusion in patients with intermittent claudication.

BACKGROUND: In peripheral vascular disease (PVD), impaired blood viscosity (BV) plays a major role in residual microvascular perfusion. Indeed, during acute leg ischaemia factors influencing microvascular BV include the plasma fibrinogen concentration, red and white blood cell rheology, as well as platelet aggregation and activation. AIM: To assess the effects of Iloprost in patients with PVD. METHODS: The effects of an infusion of a single dose of Iloprost (from 0.5 up to a maximum of 2 ng/kg/min. over 6 hours) in 16 patients with stage II peripheral vascular disease on blood rheology and tissue perfusion were determined in a double-blind placebo-controlled study, using repeated treadmill exercise test to stress leg circulation. Blood viscosity at low shear, soluble P-selectin levels (expression of platelet activation), unfractionated leukocyte and erythrocyte filterability rates, plasma fibrinogen concentration, haematocrit, leukocyte and platelet counts and transcutaneous oxygen pressure (TcPO(2)) were measured in two matched groups of 8 PVD patients before and after Iloprost infusion. RESULTS: Controlled peripheral ischaemia generated an impaired haemorheological profile; Iloprost reduced the impairments in BV and the filterability rates of unfractionated leukocytes and erythrocytes, inhibited platelet activation, and improved erythrocyte deformability. These changes were associated with significant shortening of the TcPO(2) half recovery time (the drop of TcPO(2) occurs because the ischaemic skeletal muscle steals oxygen from the skin), indicating that ischaemic damage had been contained. CONCLUSIONS: Our results show that the infusion of a single dose of Iloprost in patients with PVD is associated with a significant improvement in microvascular functioning

Blood Viscosity↗

A compartment model for fluorometric indication of tissue perfusion.

Sodium fluorescein is an in vivo blood perfusion indicator for soft tissue. When fluorescein dye is introduced into the blood, it distributes throughout the vasculature and the extravascular space. Incident light from an external source causes the dye to fluoresce, the level of which is monitored by a photodetector placed over the tissue. In this study, theoretical analysis incorporating a multicompartmental model for dye distribution is applied to describe the relationship among perfusion, dye kinetics, and fluorescence readings. Errors in calculating perfusion from fluorescence are related to dye concentrations and to measurement errors. These error sources are minimized by selecting the measurement time. The alternatives of measurement during wash-in or during wash-out of dye are compared, as well as the alternatives of introducing dye by bolus injection or by constant infusion. Compensation of wash-in measurements for differences in skin pigmentation is accomplished by the matching of skin optical properties between incident and fluorescing wavelengths. A laboratory study at 80 measurement sites (from ten graded perfusion canine flaps) demonstrated a correlation of wash-in and wash-out perfusion data ranging from 0.88 to 0.96 at typical levels of fluorescein in blood. Since wash-in can be completed in a matter of a few minutes, this is likely to be preferable in the clinical setting to wash-out which can take much longer to complete.

Animals↗

Measurement of tissue perfusion by oxygen transport patterns in experimental shock and in high-risk surgical patients.

Survivors of high-risk general (noncardiac) surgery were observed to have cardiac index (CI) values averaging 4.5 l/min.m2, oxygen delivery (DO2) of greater than 600 ml/min.m2, and oxygen consumption (VO2) of 170 ml/min.m2. In contrast, these values were relatively normal in patients who subsequently died. A very early predictive index based on these observations was found to predict outcome in 94% of high-risk patients. The hypotheses that increased DO2 and VO2 in the survivors represent compensatory physiologic responses and that these values were appropriate therapeutic goals were tested in prospective randomized clinical trials and found to reduce mortality and morbidity significantly. The optimal goals were more easily attained with colloids, red cells, dobutamine, and vasodilators, according to their capacity to improve tissue perfusion, as reflected by increased flow and oxygen transport. The extremely complex interactions between DO2 and VO2 are reviewed.

Animals↗

Adenoviral-mediated delivery of early growth response factor-1 gene increases tissue perfusion in a murine model of hindlimb ischemia.

To test the hypothesis that overexpression of early growth response factor-1 (Egr-1) contributes to the revascularization of ischemic limbs, a constitutively active form of Egr-1 (Egr-1*) was made and evaluated in vitro and in vivo. Analyses of the transduced myocytes revealed significant upregulation of bFGF, PDGF-A, PDGF-B, IGF-II, and TGF-beta1. A coculture assay of the paracrine effects indicated that Ad-Egr-1* promoted proliferation and migration of endothelial cells. When Ad-Egr-1* was injected into the tibialis anterior muscle of mice, followed by explant culture in growth factor-reduced Matrigel, many capillary-like structures were observed in the Egr-1* group compared with minimal sprouting from the LacZ group, suggesting an angiogenic potential of Egr-1*. Next we evaluated Ad-Egr-1* in a murine model of hindlimb ischemia. Compared with slow revascularization in the control PBS or LacZ group, a rapid increase in tissue perfusion was observed in the Egr-1* group and the difference in flux ratio was statistically significant at day 7. In the injected muscle, expression of Egr-1*, upregulation of its target genes, and increased number of vessels staining positive for smooth muscle alpha-actin were observed. These results suggest that Egr-1 plays an important role in vascular recovery after occlusion and could be a potential target for therapeutic angiogenesis.

Adenoviridae↗

[Evaluation of tissue perfusion by simultaneous monitoring of aortic flow rate and capnography].

Ten patients under general anaesthesia were subjected to non-invasive haemodynamic monitoring, together with arterial gasometry and capnography. When enflurane was administered for maintenance anaesthesia, a 33 percent fall in aortic flow rate was observed (P less than 0.01), together with prolongation of the pre-ejection period and left ventricular pre-ejection/ejection ratio, an increase of central venous pressure and total vascular systemic resistances. The end-expiratory CO2 (Pet CO2) was reduced by 13 percent (P less than 0.05). There was no significant variation in arteriolo-alveolar CO2 difference (P(a-A)CO2). Under dobutamine (mean dose: 3.4 +/- 0.5 micrograms/kg/min), the haemodynamic parameters returned to their initial values. Pet CO2 rose above its initial level (+ 12 percent; P less than 0.05), but P(a-A)CO2 was not significantly modified. The variations of Pet CO2 were parallel with those of aortic flow rate. It is concluded that the changes in Pet CO2 observed during haemodynamic modifications could be used as markers for qualitative evaluation of tissue perfusion.

Aged↗

Application of the medical anti-shock trouser (MAST) increases cardiac output and tissue perfusion in simulated, mild hypovolaemia.

We have studied the haemodynamic effects of the application of the medical anti-shock trouser (MAST) in 10 healthy subjects in the semi-upright position in order to simulate mild hypovolaemia. Left ventricular end diastolic dimension (EDD) was measured by M-mode echocardiography and cardiac output (CO) by the Doppler ultrasound technique. Forearm blood flow (FBF) was measured by plethysmography and blood pressure (BP) by the standard cuff technique. Systematic increases in MAST pressure of up to 80 mm Hg were applied. EDD increased to a maximum of 9.3% (p less than or equal to 0.01) which was associated with a maximum increase in CO of 31.7% (p less than or equal to 0.05). FBF increased by a maximum of 54.2% (p less than or equal to 0.001) whilst BP increased by a maximum of 12% (p less than or equal to 0.001). These results demonstrate that the application of the MAST is an effective means of transferring blood to the central circulation by compression of the capacitance vessels resulting in significant increases in cardiac output and tissue perfusion. At high pressures there was evidence of compression of resistance vessels, which may be useful in reducing blood loss. The ease and rapidity with which his suit can be applied suggests that it may be useful in the short term treatment of hypovolaemia.

Adult↗

Tissue perfusion after intramedullary nailing of tibial shaft fracture.

BACKGROUNDS AND AIMS: To measure noninvasively the effect of circulative changes caused by fracture and intramedullary nailing on tibialis posterior (TPA), dorsalis pedis (DPA) and sum (TPA + DPA) arterial peak signals, transcutaneous oxygen tension (PtcO2) as well as local skin temperature (T) in patients with tibial shaft fractures. PATIENTS, MATERIAL AND METHODS: A total of thirty tibias consisting of ten closed, reamed, intramedullary nailed simple tibial shaft fractures (Type AO A), ten contralateral tibias and as controls, ten intact tibias of healthy volunteers. The measurements took place one day before and immediately after nailing, six hours later and during five days postoperatively. The values were compared to those of contralateral legs and to control legs. RESULTS: In the nailed legs the mean TPA and PtcO2 remained at a significantly lower level compared to the contralateral legs throughout the study (p < 0.003 in both cases). However, the alterations in DPA and TPA + DPA were not statistically significant. Additionally, skin temperature on the fracture site was averagely 3 degrees C warmer than that of the contralaterals (p < 0.001). All the measured parameters were statistically significantly higher in control legs compared to contralateral legs. There were no statistically significant differences between pre- and postoperative values in any measured parameters. CONCLUSION: The changes in the local tissue perfusion variables measured in the present study reflect rather the injury mechanism itself than the effect of reaming and intramedullary nailing in simple tibial fractures. Additionally, arterial circulation was reduced in the contralateral legs.

Adult↗

Leg tissue perfusion in simple tibial shaft fractures treated with unreamed and reamed nailing.

BACKGROUND: To compare the effects of unreamed and reamed intramedullary nailing on tibialis posterior, dorsalis pedis, and sum (tibialis posterior plus dorsalis pedis) distal arterial peak pulses. Additionally, leg skin temperature and transcutaneous oxygen tension were measured in patients with low energy, closed tibial shaft fractures. METHODS: The patients were randomized to unreamed and reamed groups, and intramedullary nailing without or with reaming was performed under spinal anesthesia. The measurements were carried out before the operation and on 5 postoperative days. RESULTS: In the unreamed group, the only significant difference between contralateral and nailed legs was in raised leg skin temperature (p = 0.0001). In the reamed group, tibialis posterior distal arterial peak pulses and transcutaneous oxygen tension remained at a significantly lower level and leg skin temperature at a significantly higher level, respectively, in the nailed legs after the operation when compared with contralateral legs (p = 0.0026, p = 0.0001, and p = 0.0001, respectively). There were no statistical differences between preoperative and postoperative values in the measured parameters in both groups. Additionally, there were no intergroup changes in the measured parameters in the injured legs. CONCLUSION: The present study suggests that altered distal arterial pulsations, decreased transcutaneous oxymetry values, and thermal reaction are not due to differences in nailing method but caused by a manifestation of the trauma mechanism of the tibial shaft fracture. The potentially negative effects of reaming to soft tissue perfusion parameters could not be established.

Adult↗

Ghrelin improves tissue perfusion in severe sepsis via downregulation of endothelin-1.

OBJECTIVES: Severe sepsis is associated with increased total peripheral resistance (TPR) and decreased organ blood flow, in which endothelin-1 (ET-1) plays an important role. Plasma levels of ghrelin, a newly-identified endogenous ligand for growth hormone secretagogue receptor and a potent vasodilatory peptide, are significantly reduced in sepsis. Ghrelin downregulation heralds the hypodynamic response in severe sepsis. Therefore, we hypothesized that the administration of exogenous ghrelin improves organ blood flow by downregulation of ET-1 under such conditions. METHODS: Male adult Sprague-Dawley rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 h post-CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed mini-pump over 15 h. At 20 h post-CLP (i.e., severe sepsis), cardiac output (CO), stroke volume (SV), TPR, and organ blood flow were measured using (141)Ce-microspheres. Plasma ET-1 levels and preproET-1 gene expression in the liver, small intestine, and kidneys were measured by ELISA and RT-PCR, respectively. The direct effect of ghrelin on ET-1 production was studied using cultured human umbilical vein endothelial cells (HUVECs) treated with tumor necrosis factor-alpha (TNF-alpha). RESULTS: Ghrelin administration reduced TPR, increased CO, SV, and organ blood flow, downregulated preproET-1 gene expression, and decreased plasma levels of ET-1 in sepsis. Ghrelin inhibited TNF-alpha-induced ET-1 release from HUVECs in a dose-dependent manner. Moreover, ghrelin inhibited TNF-alpha-induced activation of nuclear factor-kappaB (NF-kappaB) in HUVECs. CONCLUSIONS: The improvement of tissue perfusion by ghrelin in severe sepsis appears to be mediated by downregulation of ET-1 involving a NF-kappaB-dependent pathway.

Acute Disease↗

Splanchnic oxygen transport after cardiac surgery: evidence for inadequate tissue perfusion after stabilization of hemodynamics.

OBJECTIVE: To evaluate the adequacy of visceral oxygen transport and gastric pHi after open heart surgery in patients with stable hemodynamics. DESIGN: Nonrandomized control trial. SETTING: A general intensive care unit in a tertiary care center. PATIENTS: Sixteen postoperative cardiac surgery patients were studied after stabilization of systemic hemodynamics. INTERVENTIONS: The effect of dobutamine infusion (6 mu g kg-1 min-1) on systemic and regional oxygen transport was studied in ten patients, with six patients serving as controls. Systemic oxygen consumption was measured by indirect calorimetry and splanchnic and femoral blood flow, by continuous infusion of indocyanine green using regional catheters and gastric mucosal pHi by gastric tonometer. MEASUREMENTS AND RESULTS: Gastric mucosal acidosis was observed in half of the patients. Dobutamine increased cardiac output (3.2 +/- 0.6 vs 4.4 +/- 0.7 l x min-1 x min-2; P <0.05), splanchnic blood flow (0.68 +/- 0.28 vs 0.91 +/- 0.28 l x min-1 x m-2; p <0.05) and femoral blood flow (0.25 +/- 0.08 vs 0.32 +/- 0.11 l x min-1 x m-2; p <0.05). Changes in splanchnic oxygen delivery and consumption were parallel in the two study groups. In response to dobutamine, gastric pHi did not change (7.30 +/- 0.08 vs 7.31 +/- 0.06; NS), while in the control group, gastric pHi tended to decrease (7.32 +/- 0.04 vs 7.28 +/- 0.06; NS). Systemic oxygen consumption increased in response to dobutamine (141 +/- 11 vs 149 +/- 11 ml x min-1 x m-2; P <0.05) but did not change in the control group. CONCLUSIONS: We conclude that a mismatch between splanchnic oxygen delivery and demand may be present despite stabilization of systemic hemodynamics after cardiac surgery. This is suggested by the parallel changes in splanchnic oxygen delivery and consumption. Dobutamine is likely to improve splanchnic tissue perfusion at this phase.

Acidosis↗

[Microcirculation of striated muscle in closed soft tissue injury: effect on tissue perfusion, inflammatory cellular response and mechanisms of cryotherapy. A study in rat by means of laser Doppler flow-measurements and intravital microscopy].

The authors investigated the effects of closed soft tissue injury (CSTI) and cryotherapy on microvascular perfusion by means of laser Doppler flowmetry. In a different protocol interactions between leukocytes and the microvascular endothelium of skeletal muscle, which are first steps in local inflammatory response were documented in an intravital microscopy model. Rats were chronically instrumented with dorsal skinfold chambers. Leukocyte rolling and adherence in postcapillary venules of striated muscle before and after standardized muscle contusion (group T: n = 6), cryotherapy following muscle contusion (TK: n = 6) or sham contusion (group N: n = 6) were quantitated prospectively and in random order using intravital microscopy. Tissue perfusion was assessed by laser Doppler flowmetry in the microvasculature of the flap over a period of 96 hours following CSTI (group T: n = 8), cryotherapy following CSTI (group TK: n = 8), sham trauma (group N: n = 8, control 1), or cryotherapy following sham trauma (group K: n = 8, control 2). 300 minutes after trauma the number of rolling and adherent leukocytes in striated muscle microvasculature was significantly reduced by cryotherapy. We found an acute effect of cryotherapy on perfusion of traumatized tissue (reduction of perfusion around 25 %). However, there was no long-term effect (96 hours evaluation) on microvascular perfusion of cryotherapy either in the presence or absence of CSTI. The effectiveness of ice application in reducing edema in striated muscle following contusion may be due in part to a reduction of the leukocyte/endothelial interactions accompanying CSTI.

Animals↗

3D numerical reconstruction of the hyperthermia induced temperature distribution in human sarcomas using DE-MRI measured tissue perfusion: validation against non-invasive MR temperature measurements.

Essential to the success of optimized thermal treatment during hyperthermia is accurate modelling. Advection of energy due to blood perfusion significantly affects the temperature. Without accurate estimates of the magnitude of the local tissue blood perfusion, accurate estimates of the temperature distribution can not be made. It is shown here that the blood mass flow rate per unit volume of tissue in the Pennes' bio-heat equation can be modelled using a relative perfusion index (RPI) determined with dynamic-enhanced magnetic resonance imaging (DE-MRI). Temperature distributions in two patients treated with hyperthermia at Duke University Medical Center for high-grade leg tissue sarcomas are modelled, and the resultant temperatures are compared to measured temperatures using a non-invasive MR thermometry technique. Significant correlations are found between the DE-MRI perfusion images, the MR temperature images, and the numerical simulation of the temperature field. The correlation between DE-MRI measured values and advective heat loss in tissue is used to scale the perfusion distribution, thereby allowing the continuum model to account for the local thermal impact of vasculature in the tumour. Large vessels in tumour and neighbouring healthy tissue need to be taken into account in order to accurately describe the complete temperature distribution.

Chemotherapy, Cancer, Regional Perfusion↗

Functional capillary density: an indicator of tissue perfusion?

Functional capillary density (FCD) is one of the parameters obtained by intravital microscopy using epi-illumination of the tissue surface or trans-illumination of thin tissue layers. FCD, defined as the length of red cell-perfused capillaries per observation area (cm-1), has been used as an indicator of the quality of tissue perfusion in various animal models. Quantitative analysis of FCD in randomly selected regions of the tissue is performed by means of a computer-assisted video analysis system which allows calculation of the length of RBC-perfused capillaries. Basically, two different mathematical approaches can be employed: the first approach is based on the addition of the distances between two neighboring points (pixels) on the video screen (Pythagorean principle). The second approach uses the superimposition of a grid system that allows estimation of the capillary length by counting the number of intersections between the capillaries and the grid lines (stereological approach). The immanent error has been calculated in our laboratory to be +/- 1% with the Pythagorean and +/- 5% with the stereological method. Beside these systematic errors of computerized measurement, the individual (user-dependent) errors occurring during recognition and redrawing of the capillaries on the video image with use of a digitizing tablet are in the range of +/- 10% (intraindividual) and +/- 70% (interindividual) for the recognition and +/- 3% (interindividual) for the redrawing procedure. Our studies indicate that the errors resulting from the use of a computer-assisted calculation (Pythagorean or stereological approach) or the user-assisted redrawing of the capillaries are negligible when compared to the errors made during recognition of the capillaries on the video screen. The methods are applied for assessment of FCD in two different microcirculation models of skin muscle and pancreas yielding highly reproducible, user-independent results under physiologic conditions and the pathophysiologic conditions of ischemia-reperfusion.

Animals↗

Effect of defocused CO2 laser on equine tissue perfusion.

Treatment with defocused CO2 laser can have a therapeutic effect on equine injuries, but the mechanisms involved are unclear. A recent study has shown that laser causes an increase in equine superficial tissue temperature, which may result in an increase in blood perfusion and a stimulating effect on tissue regeneration. However, no studies have described the effects on equine tissue perfusion. The aim of the present study was to investigate the effect of defocused CO2 laser on blood perfusion and to correlate it with temperature in skin and underlying muscle in anaesthetized horses. Differences between clipped and unclipped haircoat were also assessed. Eight horses and two controls received CO2 laser treatment (91 J/cm2) in a randomised order, on a clipped and unclipped area of the hamstring muscles, respectively. The significant increase in clipped skin perfusion and temperature was on average 146.3 +/- 33.4 perfusion units (334%) and 5.5 +/- 1.5 degrees C, respectively. The significant increase in perfusion and temperature in unclipped skin were 80.6 +/- 20.4 perfusion units (264%) and 4.8 +/- 1.4 degrees C. No significant changes were seen in muscle perfusion or temperature. In conclusion, treatment with defocused CO2 laser causes a significant increase in skin perfusion, which is correlated to an increase in skin temperature.

Animals↗

Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue.

The imaging of phosphorescence provides a method for monitoring oxygen distribution within the vascular system of intact tissues. Isolated rat lives were perfused through the portal vein with media containing palladium coproporphyrin, which phosphoresced and was used to image the liver at various perfusion rates. Because oxygen is a powerful quenching agent for phosphors, the transition from well-perfused liver to anoxia (no flow of oxygen) resulted in large increases of phosphorescence. During stepwise restoration of oxygen flow, the phosphorescence images showed marked heterogeneous patterns of tissue reoxygenation, which indicated that there were regional inequalities in oxygen delivery.

Animals↗

Protein synthesis in lactating guinea-pig mammary tissue perfused in vitro. II. Biogenesis of milk-fat-globule membrane proteins.

Guinea-pig mammary tissue was perfused in vitro, radiolabelled with [35S]methionine and intracellular protein precursors of the milk-fat-globule membrane (FGM) recovered by immunoabsorption techniques. Labelled xanthine oxidase was solely detected in post-microsomal supernatants and butyrophilin in carbonate-washed membranes. A major glycoprotein (Gp 55), was initially present in a membrane-bound form, but after longer perfusion times a fraction of this protein was recovered in the post-microsomal supernatant. These results are discussed with reference to formation of the apically-derived FGM.

Animals↗

Impaired myocardial tissue perfusion early after successful thrombolysis. Impact on myocardial flow, metabolism, and function at late follow-up.

BACKGROUND: Impaired tissue reperfusion after successful recanalization of an epicardial coronary artery has been documented both in animals and in patients with acute myocardial infarction. Whether this phenomenon can be demonstrated with positron emission tomography (PET) and whether it has an effect on late recovery of flow, metabolism, and function are unknown. METHODS AND RESULTS: Thirty patients with an acute myocardial infarction and TIMI flow grade 3 of the infarcted vessel at 90 minutes after thrombolytic therapy were studied. Within 24 hours after thrombolysis, at 5 days and at 3 months, myocardial blood flow was measured with 13NH3. 18FDG uptake was measured at 5 days. Radionuclide left ventricular angiograms were acquired at 5 days and at 3 months. In 11 patients (37%), regional myocardial flow was severely impaired (< 50% of normally perfused myocardium) despite successful thrombolysis. No recovery of left ventricular function occurred in any of these patients at 3 months. In 12 patients (40%), intermediate flows (50% to 75% of normal) were found, with functional improvement after angioplasty only in regions with a PET mismatch. Seven patients (23%) had high flow values early after successful thrombolysis (> 75% of normal) and showed preserved regional contractile function at 3 months. CONCLUSIONS: This study is the first demonstration with PET of impaired myocardial tissue perfusion in patients with an acute myocardial infarction after successful thrombolysis. Functional recovery of the reperfused myocardium is observed only when adequate tissue flow is restored. PET may be helpful in selecting patients in whom additional revascularization can improve recovery of left ventricular function.

Aged↗