Laser Doppler flux measurement for the assessment of cutaneous microcirculatio--critical remarks.

Back scattered Laser Doppler (LD) signals are composed of two different individual signals. The number of the moving particles and the speed of the particles in the measured tissue volume determine the frequency shift and the band width of the Doppler signal. The dependence of the Laser Doppler flux on the number of scattering particles is highly nonlinear: at very low hematocrit and high speed the axial migration of the cells to the centre of the blood vessels is very strong, so that in these cases - because of the parabolic flow profile - the Doppler flux measurement overestimates the mean real blood flow (up to two- or three-fold). The opposite is the case when the hematocrit is very high, then the blood flow might be underestimated (due to the increased amounts of blood cells near the vessel wall). In addition, a very change in number of moving particles - as can occur during the postprandial phase or during therapy - can change the signal also at a constant cell number. Also, it must be mentioned that the LD signal possibly is not only reflected by moving blood cells in the different skin layers but also by blood cells flowing in tissues below the skin (particularly below atrophied skin areas of older patients) so that in such cases the LD Flux signal reflects not exclusively the skin blood flow. Therefore, LD flux at rest may still be within the normal range even in advanced states of disease, since the scattered light is sampled from a tissue volume which may contain also non-nutritive shunt vessels. This critical analysis of the LD signals of course shall not lead to an overall rejection of the application of laser Doppler systems. Actual progress only can, however, be obtained under the exact consideration of anatomical conditions, technical restrictions and when generalizations are avoided.

Cardiovascular benefits in moderate increases of blood and plasma viscosity surpass those associated with lowering viscosity: Experimental and clinical evidence.

Decreasing blood viscosity has been proposed since the advent of hemodilution as a means for increasing perfusion in many pathological conditions, and increased plasma viscosity is associated with the presence of pathological conditions. However, experimental studies show that microvascular functions as represented by functional capillary density in conditions of significantly decreased viscosity is impaired, a problem corrected by increasing plasma and blood viscosity. Blood viscosity, primarily dependent on hematocrit (Hct) is a determinant of peripheral vascular resistance, and therefore blood pressure. In the healthy population Hct presents a variability, which is not reflected by the variability of blood pressure. This is due to a regulatory process at the level of the endothelium, whereby the increase of Hct (and therefore blood viscosity) leads to increased shear stress and the production of the vasodilator nitric oxide (NO), a finding supported by experimental studies showing that the acute increase of Hct lowers blood pressure. Studies that in the healthy population show that blood pressure and Hct have a weak positive correlation. However, when the effect of blood viscosity is factored out, blood pressure and Hct are negatively and significantly correlated, indicating that as blood viscosity increases, the circulation dilates. Conversely, lower Hct and blood viscosity conditions lead to a constricted circulation, associated with a condition of decreased NO bioavailability, and therefore a pro-inflammatory condition.

Veno-active drugs in the management of chronic venous disease. An international consensus statement: current medical position, prospective views and final resolution.

BACKGROUND: Veno-active drugs (VAD) have effects on edema and symptoms related to chronic venous disease (CVD), especially so-called venous pain. VAD's effectiveness, although well established, is regularly debated. OBJECTIVE: Our purpose was to select all randomized controlled trials (RCTs) and meta-analyses devoted to VAD and symptoms in CVD, to submit them to a group of international experts in CVD and to vote with secrete ballot to determine the level of efficacy of each drug, according to EBM (Evidence-Based Medicine) rules and critical analysis. METHODS: Publications in any language devoted to VAD and venous symptoms were searched for in different databanks and submitted to the experts prior to the meeting. RESULTS: 83 papers were analyzed, including 72 RCTs or meta-analyses. Experts determined the level of EBM of each drug, according to the literature and personal experience, using 3 levels of recommendation, A, B and C (from large RCTs to non-randomized trials). CONCLUSIONS: VAD are effective and may be applied in CVD when symptomatic, from C0s to C6s. However, etiological treatment of venous reflux and venous hypertension has always priority. In some cases VAD may replace compression and/or complement its effects. If respecting these prerequisites, VAD are safe and effective.

Prognostic role of C-reactive protein in very old patients with acute ischaemic stroke.

BACKGROUND AND SCOPE: Recent literature has demonstrated that inflammation contributes to all phases of atherosclerosis and brain damage caused by stroke. In acute phase of cerebrovascular diseases biochemical markers of inflammation, such as C-reactive protein (CRP), could represent an indicator of severity of stroke, but few studies have verified this hypothesis, especially in very old patients. The aim of this study was to evaluate the role of CRP on short- and long-term prognosis in 75-year old and over elderly patients with acute ischaemic stroke. MATERIALS AND METHODS: We retrospectively evaluated CRP values (nephelometric method), performed within 12 h from hospital admission, in 196 elderly patients (124 females and 72 males with mean age+/-SD 83.32+/-10.46 years), discharged with diagnosis of acute ischaemic stroke, 68 of them with atherothrombotic large vessel stroke, 38 with lacunar stroke and 90 with cardioembolic stroke. We studied the relationship between CRP values and short-term prognosis [30-day mortality, length of hospitalization (LOS) and physical disability measured by modified Rankin scale and long-term prognosis (12-month mortality and re-hospitalization)]. RESULTS: Mean values of CRP were significantly higher in patients with cardioembolic stroke compared with atherothrombotic large vessel and lacunar stroke, in patients who died in the first 30 days from the acute event compared with survivors. LOS and physical disability score rose with increasing values of CRP for all subtypes of stroke. Higher CRP values were associated with the 12-month re-hospitalization for cerebrovascular events, whereas it did not influence the 12-month cumulative re-hospitalization and 12-month mortality. CONCLUSIONS: Elevation of CRP values at hospital admission could represent a negative prognostic index in elderly patients with ischaemic stroke, in particular, for short-term prognosis.

Endothelium and hemorheology.

Hemorheological alterations which can be found in ischaemic vascular diseases are well known and widely studied; less clear is the relationship between these alterations and endothelial function. Our studies showed that modifications in endothelial function caused by physical stress are associated with a worsening in hemorheological parameters mainly in patients affected by ischaemic vascular diseases: major vascular alterations have been found in patients with very high levels of plasma markers endothelial dysfunction. The control of the basal tone of the vessels is given by the complex interaction between vasoconstrictor and vasodilator endothelial factors and when this equilibrium is broken we have the endothelial dysfunction. From a methodological point of view we can find an endothelial dysfunction index determining the various substances produced by the endothelium, but it is very difficult to have a value which clearly identifies the real state of the endothelial alteration. The function of the NO, which is one of the more powerful endogenous vasodilators and whose synthesis is catalysed by nitric oxide synthase (NOS), can be determined by the ratio between blood concentrations of citrulline and arginine (the co-product and the precursor of the way of NO synthesis), which represents the level of activity of the enzyme. A very affordable index of the endothelial dysfunction is the asymmetric dimethylarginine (ADMA), a powerful endogenous inhibitor of NOS; in fact several studies demonstrated a strong relationship between ischaemic vascular diseases and high levels of plasma ADMA. Evaluation of these parameters is measured by means of high performance liquid chromatography (HPLC): this technique provides very affordable results and allows to obtain evaluations of substances in very small concentrations, like ADMA.

Haemorheological and endothelial-dependent alterations in heart failure after ACE inhibitor, calcium antagonist and beta blocker.

The aim of our study was to evaluate endothelium-dependent dilatation induced by an ACE-inhibitor, calcium antagonist and beta blocker in patients suffering from heart failure (NYHA class II and III). We studied 34 patients (19M, 15F, mean age 76.96+/-8.82) in pharmacological wash-out for at least one week, divided into 3 groups: Group A (15 patients, 9M and 6F) taking ramipril (5 mg/die); Group B (10 patients, 6M and 4F) taking amlodipine (10 mg/die), Group C: (9 patients, 4M and 5F) taking carvedilole (25 mg/die). The groups were homologous for NYHA class and instrumental echographic parameters (mean EF=22.5+/-6.7 and mean sAPP 38.4+/-8.7). At the beginning and after 3 weeks of therapy, we performed a clinical and instrumental assessment; we studied endothelial function by determination of L-arginine and L-citrulline (amino acids of the nitric oxide metabolic pathway), the L-citrulline/L-arginine ratio (an index of NOS activity) and VCAM-1 (endothelial dysfunction index); haemorheological parameters (blood viscosity, plasma fibrinogen and erythrocyte morphology); coagulative/fibrinolytic parameters (PT, aPTT, fibrinogen and PAI-1). The results show that L-citrulline and L-arginine increase, while VCAM-1 decreases. The L-citrulline/L-arginine ratio increases in a statistically significant way. This trend is maintained in each group. These results demonstrate that the drugs used induce an improvement of endothelium-dependent dilatation. In addition, there is progressive haemorheological and fibrinolytic improvement, with a reduction of PAI-1 and blood viscosity.

Spontaneous echo-contrast as an in vivo indicator of rheological imbalance in dilatative cardiomyopathy.

The aim of this study was to evaluate coagulative and hemorheologic assessment in patients with dilatative cardiomyopathy with or without spontaneous echo contrast (SEC). We studied 45 patients, 35 males and 10 females (mean age 72.1 +/- 9.2). We measured whole blood viscosity, plasmatic fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer and red cell morphology with Zipursky-Forconi method. Transthoracic and transesophageal echocardiography was performed in all patients to evaluate the presence of SEC in left atrium. We divided all the patients into two groups: the 1st group of 20 patients with SEC and Atrial Fibrillation (AF) in 80% of cases, and the 2nd group of 25 patients without SEC and AF in 31%. Our results show that in patients with SEC there is a statistically significant increase of whole blood viscosity and plasma fibrinogen in comparison with patients without SEC. Red cell morphology in all patients demonstrates a reversed EMI. D-Dimer, was out of the normal range in about 1/3 of the patients in both groups. An analysis of our results points out that in patients with SEC and AF, with a major risk factor for cardioembolic stroke, we have alterations of hemorheologic assessment with an increase of whole blood viscosity and fibrinogen that seems to be caused by an increase of red cells aggregability favoured by fibrinogen. Our conclusions are that SEC in patients with dilatative cardiomyopathy and AF is an important in vivo indicator of hemorheologic imbalance and an important marker for cardioembolic risk stroke evaluation.

Arterial blood gas analysis and alveolar-arterial oxygen gradient in diagnosis and prognosis of elderly patients with suspected pulmonary embolism.

BACKGROUND: Arterial blood gas analysis (BGA) remains a first-step diagnostic approach in patients with suspected pulmonary embolism (PE). The aim of this study was to evaluate BGA parameters in elderly patients with suspected pulmonary embolism for diagnosis and 14-day prognosis. METHODS: We performed a retrospective cohort observational study of 6 years (1994-1999) in a 60-bed acute geriatric ward of University Hospital in Siena, Italy. Room air arterial oxygen partial pressure (pO2), arterial carbon dioxide partial pressure (pCO2), pH, arterial oxyhemoglobin saturation (SO2), and alveolar-arterial oxygen gradient [D(A-a)O2] were performed on hospital admission of 75 patients with confirmed PE (CPE) and were compared with data from 43 patients with unconfirmed PE (UCPE). The same parameters of 54 CPE surviving patients were compared with 21 CPE nonsurviving patients. RESULTS: Significantly lower PO2 and SO2, and higher DA-aO2 were found in CPE patients. Respiratory alkalosis was found in one third of the patients in both groups (no significant difference). In the CPE group, there was a significantly lower SO2 in nonsurviving patients, without significant differences for the other parameters. Metabolic acidosis was significantly more frequent in nonsurviving patients. CONCLUSION: More severe hypoxemia, oxyhemoglobin hyposaturation, and higher D(A-a)O2 are associated with the diagnosis of PE in elderly patients. Respiratory alkalosis is less frequent than in younger patients, and metabolic disorders are negative prognostic indicators.

Blood viscosity and red cell morphology in subjects suffering from cirrhosis before and after treatment with S-adenosyl-L-methionine (SAM).

Alterations of fluidity of the hepatocytic membrane and of the transport related systems are the basis of the cholesteatic syndrome and favour the tissue accumulation of cytotoxic metabolites. S-Adenosyl-L-Methionine (SAM) is a natural molecule which acts as a giver of methylic groups and as an enzymatic activator in several enzymatic actions of transmethylase and of transulphuration and plays a key role in biochemical processes of hepatic cell. The aim of our study was to evaluate the effects of SAM on the restoration of the membrane fluidity and on the hepatic function in general. In studying the fluidity of the cell membrane we evaluated some hemorheological parameters (total blood viscosity and red cell morphology). Fluidity of the red cell membrane is one of the most important elements of red cell rheology. We studied 15 patients (Group A) suffering from micro- and macro-nodular cirrhosis verified through hepatic biopsy, with alcoholic or post-viral causes. We evaluated the values of: blood viscosity (with a cone-plate rheometer by Carri-med), haematocrit, plasma fibrinogen and the erythrocytic morphology at the optical microscope with the Zipursky-Forconi method before and after 7 days of therapy with SAM i.v.. Data were compared with those of a similar group (Group B) treated with traditional therapy only (hyposodic and hypoprotein diet supplemented with multivitamin preparations, vitamin K in particular, if necessary, and potassium sparing diuretics). We also measured biliary salts, alkaline phosphatase, transaminase and gamma-GT. In the first group we observed a statistically significant reduction of blood viscosity, haematocrit didn't change significantly; biliary salts reduced in a statistically significant way. Evaluation of red cell morphology showed in all cases a pathological percentage (>15%) of echinocytes and knizocytes which reduced to a mean of 5% after SAM therapy. We observed no further modifications of the other hemorheological parameters. Results demonstrate that SAM has a positive action on the fluidity of the membrane, as indicated by the improvement of haemorheological parameters and by the significant decrease of biliary salts, indicating the presence of cholesteasis.

Pulmonary embolism in the elderly: clinical, instrumental and laboratory aspects.

OBJECTIVE: To focus on diagnostic and therapeutic problems of pulmonary embolism in the elderly. METHODS: Retrospective analysis of 5 years of clinical, instrumental, and laboratory data (collected at the time of hospital admission) for patients 65 years and older with pulmonary embolism proven by a high-probability scintigraphic lung scan or necropsy. Sixty-eight patients, 46 females and 22 males, 78.61 +/- (SD) 7.71 years old, were enrolled in the study. RESULTS: Dyspnea, chest pain, tachycardia, and tachypnea were the most common symptoms and signs; they were present alone or in combination in all patients. Bed rest over 4 days was found in 65% of the patients and deep vein thrombosis in the leg in 35%. Only 7 patients were on anticoagulant therapy which was likely to reduce the incidence of pulmonary embolism. The mortality was 29.5%. Major bleeding due to anticoagulant therapy was observed in 4.4% of the patients; 1 case was fatal. Sinus tachycardia, ST segment and T wave abnormalities in anterior leads, and incomplete bundle branch block were the most frequent electrocardiographic findings. Chest X-ray was normal in 19.5% of the patients and compatible with pulmonary embolism in 10%. A transthoracic two-dimensional echocardiogram was abnormal in 74% of the cases, with involvement of the right ventricle in the majority of them. Many patients had laboratory parameters within the normal range. The value of the latex agglutination D-dimer assay was less than the cutoff value of 500 microg/l in 16% of the patients. Hypoxemia and a high alveolar-arterial oxygen gradient were the most frequent aspects of the arterial blood gas analysis. Respiratory alkalosis was observed in only one third of the patients. CONCLUSIONS: Pulmonary embolism is often underdiagnosed in the elderly. Clinical, instrumental, and laboratory findings are nonspecific. Only acute suspicion can increase the number of diagnoses, reduce the time to diagnosis, and improve the prognosis.

Length of hospitalization in elderly patients with community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a serious social and medical problem in the elderly. Mortality, hospitalization and length of stay increase with age. The aim of this study was to determine the risk factors associated with prolonged hospital stay in elderly patients with CAP. Clinical and laboratory data were collected for 115 community-living patients, 65 years old and over, admitted to the geriatric ward of a University Hospital from 1995 to 1998 because of symptoms and signs of pneumonia confirmed by a pulmonary infiltrate on chest x-ray. We divided the patients into two groups, with length of stay more than 13 days (70 patients, cases), and length of stay less than 13 days (45 patients, controls) according to Diagnosis Related Groups criteria for complicated and uncomplicated pneumonia, respectively. A prolonged hospital stay was associated with a higher fever peak and a higher number of days with fever (p<0.005), greater comorbidity (p<0.001), urinary catheterization and secondary urinary infections (p<0.001), higher erythrocyte sedimentation rate (p<0.001), dehydration (p<0.005), and caloric-proteic malnutrition (p=0.01). In conclusion, knowledge of the risk factors for prolonged hospital stay in elderly patients with CAP may be used to identify high-risk patients, prevent the risks with prophylactic measures, and contain the costs of hospitalization.

Behavior of circulating endothelin-1 in a group of patients with acute myocardial infarction.

The aim of this study was to investigate the behavior of plasma endothelin-1 (ET-1) in 23 patients with acute myocardial infarction, complicated and uncomplicated by left ventricular failure, and treated with and without thrombolytic agents. ET-1 was measured on admission; on days 2, 3, and 5; and again on discharge. In addition, on discharge, ET-1 was correlated with left ventricular systolic function. Left ventricular failure was present, on admission, in 14 patients, whereas the other nine did not have any hemodynamic impairment. On discharge, no patients had left ventricular failure, but 11 had moderate to severe left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) < 40%. Fourteen subjects, matched for age and sex, served as a control group. Compared with the control range, ET-1 was highly elevated on the first day, in both uncomplicated (p < 0.01) and complicated patients (p < 0.001). Then it decreased rapidly in the uncomplicated group, reaching the control range within day 5, whereas in the complicated group it remained significantly elevated in comparison with both the control subjects and the uncomplicated patients, until discharge. ET-1 was not correlated with the peak of creatine-kinase MB isoenzyme in any group. In seven patients submitted to thrombolytic treatment ET-1 was always significantly lower than in the nonthrombolyzed patients (p < 0.05), but the pattern of variation across time was no different. On discharge, the difference in plasma ET-1 between patients with LVEF < 40% and the control group was significant (p < 0.001), as was the difference between patients with and without moderate to severe systolic dysfunction (p < 0.01). ET-1 was closely and inversely correlated with LVEF when patients were considered as a whole (p < 0.001). These results suggest that the ET-1 increase in the early phase of myocardial infarction could be due to an ischemic process, to stress reaction, and to cardiac hemodynamic impairment, and therefore, ET-1 may be a good marker of disease. In the following phase the ET-1, being correlated with LVEF, could be a reliable index of systolic function.