Biomedical subjects
Publications and source records attributed to R Fumagalli.
Fever is one of the most aspecific marker of disease, it is considered a protective host defense response and it is the result of a reset of the hypothalamic thermostat. Fever is a common problem in ICU patients and it is associated with infective and non infective causes. Fever presenting in ICU should always be a source of concern and the first and immediate priority is to determine its clinical significance.
ICU nurses hold an important role in the management of septic patients underlining with their ability to recognize SIRS that is the first step in the proinflammatory and procoagulant cascade following an infection. Early and timely approach to organ dysfunction can indeed modify the damages due to hypoperfusion. The ability to recognize organ dysfunction using different monitoring devices available should be part of the nursing attitudes.
Increased metabolic requirements by surgical trauma is responsible of the changes in cardiac index and oxygen delivery (DO2), represent compensatory adaptation in circulatory functions stimulated by increased metabolic needs. The amount of this compensation varies with age, gender, severity of illness, operation type, associated medical conditions, shock duration, complications, organ failure, and outcome. Hypotension, low cardiac index, arterial hemoglobin desaturation, low oxygen delivery, and low oxygen consumption served and sometimes are persistent over time; these abnormalities were more notorious in the nonsurvivors than in the survivors. Lethal circulatory dysfunctions may begin during the intraoperative period but become more apparent before and are responsible of organ failure during postoperative stages. An approach that measures adequacy of tissue perfusion is a fundamental objective in anesthesia and critical care medicine. Traditional measures of tissue perfusion have included arterial pressure monitoring, urine output, arterial pH and blood lactate. These measures have major limitations, and changes in these measures may significantly lag behind clinical interventions. After trauma and major surgery despite normalization of these variables, global tissue hypoxia may still persist. Unrecognized or untreated conditions may lead to organ failure and death. In critical or high risk patients, early invasive monitoring is necessary to precisely define the adequacy of the cardiac response and to individually tailor therapy. The care provided in the first hours significantly impacts the progression of organ failure and mortality. Although this period is brief compared with the total length of hospitalization, physiological determinants of outcome may be established before ICU admission. Early postoperative monitoring revealed differences in survivor and nonsurvivor patterns and provided goals for improving outcome.
BACKGROUND: Although placing patients with acute respiratory failure in a prone (face down) position improves their oxygenation 60 to 70 percent of the time, the effect on survival is not known. METHODS: In a multicenter, randomized trial, we compared conventional treatment (in the supine position) of patients with acute lung injury or the acute respiratory distress syndrome with a predefined strategy of placing patients in a prone position for six or more hours daily for 10 days. We enrolled 304 patients, 152 in each group. RESULTS: The mortality rate was 23.0 percent during the 10-day study period, 49.3 percent at the time of discharge from the intensive care unit, and 60.5 percent at 6 months. The relative risk of death in the prone group as compared with the supine group was 0.84 at the end of the study period (95 percent confidence interval, 0.56 to 1.27), 1.05 at the time of discharge from the intensive care unit (95 percent confidence interval, 0.84 to 1.32), and 1.06 at six months (95 percent confidence interval, 0.88 to 1.28). During the study period the mean (+/-SD) increase in the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, measured each morning while patients were supine, was greater in the prone than the supine group (63.0+/-66.8 vs. 44.6+/-68.2, P=0.02). The incidence of complications related to positioning (such as pressure sores and accidental extubation) was similar in the two groups. CONCLUSIONS: Although placing patients with acute respiratory failure in a prone position improves their oxygenation, it does not improve survival.
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Computerised tomography (CT) is being used with increasing frequency in acute respiratory distress syndrome (ARDS) patients. This brief review will discuss some of the clinical insights that a CT scan can offer. A large number of CT scan studies have provided new insights into the pathophysiology of ARDS and of mechanical ventilation, and are particularly focused on the recruitment-derecruitment phenomenon. To this end, newer fast CT scan technology promises a dynamic, rather than a static view of lung ventilation.
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Activated macrophages within the arterial wall secrete matrix-degrading metalloproteinases (MMPs) that weaken the atherosclerotic plaque and contribute to its fissuration. Preclinical studies have shown that calcium antagonists may reduce atherogenesis in the arterial wall. In the present study we evaluated the effect of lacidipine on 92-kDa gelatinase B (MMP-9) expression in human macrophages in cultures. Cells were treated for 24 h with lacidipine and the conditioned media were analyzed. Lacidipine (1-20 microM) significantly reduced, in a dose-dependent manner, MMP-9 potential gelatinolytic capacity up to 50%. When MMP-9 expression was stimulated by treatment with phorbol esters or tumor necrosis factor-alpha, lacidipine was able to inhibit this enhanced gelatinolytic capacity up to 50 and 60%, respectively. Western blot analysis and enzyme-linked immunosorbent assay showed a reduction of MMP-9 protein actually released by cells. The addition of lacidipine in the incubation media determined no significant variation in Ca(2+) concentration. The drug did not affect MMP-9 mRNA levels, but it effectively reduced the amount of both active and total free MMP-9 secreted by human macrophages. Lacidipine reduced also the secretion of the tissue inhibitor of metalloproteinase-1 (TIMP-1); however we observed an overall reduction of the gelatinolytic activity of the cells. Finally, peritoneal macrophages, obtained from mice treated with lacidipine, showed a reduced secretion of MMP-9. Together, our data indicate that lacidipine may potentially exert an antiatherosclerotic activity by modulating the secretion of MMP-9 by macrophages. This, in addition to the previously demonstrated inhibition of cholesterol esterification, may contribute to increase plaque stability.
OBJECTIVES: The aim of this study was to assess the efficacy and safety of low doses of diclofenac sodium (DCF) in attaining normothermia with minimal major side effects in patients with acute cerebral damage. The study was designed to verify the adequate, prolonged antipyretic action of DCF infusion, to quantify its haemodynamic and cerebral impact and to assess any negative effect on renal and liver function. DESIGN: Retrospective, cohort study on prospectively collected data. SETTING: Intensive care unit (ICU) of a university hospital. PATIENT POPULATION: Five patients with subarachnoid haemorrhage and seven severe head-trauma victims with febrile illness of various infectious origin. INTERVENTIONS: Continuous i.v. infusion of a low dose (0.04 mg/kg/h) of DCF for 48 h. MEASUREMENTS AND RESULTS: Systemic and cerebral haemodynamic data were collected at 4 h intervals for 8 h before diclofenac infusion and 48 h after. Renal and liver functions were monitored. Normothermia, defined as external temperature < 37.5 degrees Celsius (degrees C), was achieved in all cases. Intracranial pressure was significantly lowered and mean arterial pressure was unaffected, so cerebral perfusion pressure rose after DCF. Hepatic and renal function were not altered in the 48 h post DCF. Mean urinary output was preserved at high flow and was not influenced by DCF. CONCLUSIONS: Continuous infusion of low-dose DCF attained normothermia without any major cerebral or systemic side effects. Renal and liver functions were unaffected. Once normothermia was achieved, intracranial and cerebral perfusion pressure improved.
OBJECTIVE: To analyze the single effect and the interaction of prone position and inhaled nitric oxide (iNO) on lung function and hemodynamic variables. DESIGN: 2 x 2 factorial trial. SETTING: Department of intensive care medicine at a university hospital. PATIENTS: Fourteen patients on volume-controlled mechanical ventilation for acute respiratory distress syndrome (ARDS). INTERVENTION: Four experimental conditions, each one characterized by the patient's position (supine or prone) with iNO or without iNO. MEASUREMENTS AND RESULTS: Hemodynamic and gas exchange data were collected for each experimental condition. PaO2 was increased both by positioning (p < .01) and iNO (p < .01); iNO caused also a reduction in venous admixture (p < .01), pulmonary artery pressure (p < .01), and pulmonary vascular resistance index (p < .05). We could not demonstrate any significant interaction between the two treatments. The average effect of prone positioning was the same both with and without iNO, whereas the average effect of iNO was the same in both the prone and the supine position. CONCLUSION: In the studied acute respiratory distress syndrome patients the average effects of iNO and positioning on oxygenation were additive and no interaction could be shown. A strategy including both treatments could warrant the best improvement in oxygenation, and should take into account the individual response to each treatment and the possible combination of the two.
Techniques of tracheal gas insufflation (TGI) have been shown to enhance CO(2) clearance efficiency in mechanically ventilated patients with acute respiratory distress syndrome (ARDS). Clinical studies have explored the effects of such techniques only at moderate intratracheal gas flow rates, with TGI superimposed to mechanical ventilation in a continuous fashion, or synchronized to the expiratory phase of the duty cycle. We examined the effects of intratracheal pulmonary ventilation (ITPV), delivering the entire tidal volume (VT) in the proximity of the tracheal carina, with all the gas flow supplied continuously through a reverse-thrust catheter (RTC). A potential limitation in the application of TGI is dynamic hyperinflation. Therefore, in a subgroup of patients, we also evaluated the effects of ITPV on end-expiratory lung volume (EELV) by respiratory inductive plethysmography (RIP). Eleven patients with ARDS under volume-cycled mechanical ventilation were subsequently switched to ITPV at the same baseline respiratory rate, I:E ratio, and VT. At the same minute volume, Pa(CO(2)) decreased from 70 +/- 12.3 to 59 +/- 9.5 mm Hg, with a percent reduction of 15 +/- 4% (range from 10 to 20%). The CO(2) decrease was greater in patients with higher baseline Pa(CO(2)) levels (DeltaPa(CO(2)) = 0.29 x Pa(CO(2)) - 9.48, r = 0.95). During transition from mechanical ventilation to ITPV, tracheal positive end-expiratory pressure (PEEP(tr)) decreased with a correspondent decrease in EELV. Both were restored by increasing the PEEP at the ventilator by 3.6 +/- 2.0 cm H(2)O. These data suggest that in patients with ARDS ITPV effectively reduces dead space ventilation and the employment of the RTC may limit or avoid dynamic hyperinflation.
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The beneficial effects of statins are assumed to result from their ability to reduce cholesterol biosynthesis. However, because mevalonic acid is the precursor not only of cholesterol, but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase may result in pleiotropic effects. It has been shown that several statins decrease smooth muscle cell migration and proliferation and that sera from fluvastatin-treated patients interfere with its proliferation. Cholesterol accumulation in macrophages can be inhibited by different statins, while both fluvastatin and simvastatin inhibit secretion of metalloproteinases by human monocyte-derived macrophages. The antiatherosclerotic effects of statins may be achieved by modifying hypercholesterolemia and the arterial wall environment as well. Although statins rarely have severe adverse effects, interactions with other drugs deserve attention. Simvastatin, lovastatin, cerivastatin, and atorvastatin are biotransformed in the liver primarily by cytochrome P450-3A4, and are susceptible to drug interactions when co-administered with potential inhibitors of this enzyme. Indeed, pharmacokinetic interactions (e.g., increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of simvastatin or lovastatin and cyclosporine A, mibefradil, or nefazodone. In contrast, fluvastatin (mainly metabolized by cytochrome P450-2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, a 5- to 23-fold increase in pravastatin bioavailability has been reported in the presence of cyclosporine A. In summary, statins may have direct effects on the arterial wall, which may contribute to their antiatherosclerotic actions. Furthermore, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.
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PURPOSE: To assess the differences in CT appearance between adult respiratory distress syndrome due to pulmonary disease (ARDSP) and that due to extrapulmonary disease (ARDSEXP) and determine whether the variable appearances of ARDS are due, in part, to the initial pulmonary and systemic causes. MATERIALS AND METHODS: Thirty-three patients, 22 with ARDSP and 11 with ARDSEXP, underwent helical CT shortly after intubation. Two readers evaluated images for the type, extent, and distribution of pulmonary opacities; secondary findings; and correlation with survival and physiologic parameters. RESULTS: In both ARDSP and ARDSEXP, approximately 80% of the lung was abnormal. In ARDSP, ground-glass opacification and consolidation were equally prevalent, whereas in ARDSEXP ground-glass opacification was dominant. Ground-glass opacification was evenly distributed, whereas consolidation tended to be dorsal and caudal. ARDSP often caused asymmetric consolidation, whereas ARDSEXP caused symmetric ground-glass opacification. Air bronchograms were almost universal. Pleural effusions were present in one-half of the patients, and Kerley B lines and pneumatoceles were uncommon. Lung consolidation correlated with the ratio of mean partial pressure of arterial oxygen to fraction of inspired oxygen, shunt fraction, and pulmonary arterial pressure. The patients who died tended to have more consolidation and asymmetric disease. CONCLUSION: ARDSP tends to be asymmetric, with a mix of consolidation and ground-glass opacification, whereas ARDSEXP has predominantly symmetric ground-glass opacification. In both groups, pleural effusions and air bronchograms are common, and Kerley B lines and pneumatoceles are uncommon.
Picotamide is an antiplatelet drug with a peculiar dual mechanism of action: it inhibits thromboxane A2 synthase and antagonizes the pharmacological responses mediated by thromboxane A2 receptor. We investigated the in vitro effect of picotamide on smooth muscle cell migration and proliferation. Picotamide (1-500 microM) decreased human and rat smooth muscle cell proliferation, evaluated as cell number, in a concentration-dependent and reversible manner. Picotamide inhibited DNA synthesis induced by fetal calf serum (10%), platelet-derived growth factor (PDGF-BB (20 ng/ml)), epidermal growth factor (EGF (1 nM)) and (15S)-hydroxy-11,9-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619 (10 microM, thromboxane A2 receptor agonist)). Co-incubation of U46619 together with EGF or PDGF-BB resulted in a marked amplification of [3H]thymidine incorporation that was completely reversed by picotamide. The drug also inhibited smooth muscle cell migration induced by fibrinogen (600 microg/ml) or PDGF-BB (20 ng/ml) in a concentration-dependent manner. The ability of picotamide to interfere with myocyte migration and proliferation confers, at least in vitro, a pharmacological interest on the compound in atherogenesis.
Several studies have demonstrated that any beneficial effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events are linked to their hypocholesterolemic properties. However, since mevalonic acid (MVA), the product of the enzyme reaction, is the precursor of numerous metabolites, inhibition of HMG-CoA reductase has the potential to result in pleiotropic effects. MVA and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions, hence effects other than cholesterol reduction may help to explain the antiatherosclerotic properties of statins. Recently, we provided in vitro evidence that fluvastatin, simvastatin, lovastatin, cerivastatin, but not pravastatin, dose-dependently decrease smooth muscle cells (SMC) migration and proliferation, independently of their ability to reduce plasma cholesterol. Moreover, statins are able to reduce the in vitro cholesterol accumulation in macrophages, by blocking cholesterol esterification and endocytosis of modified lipoproteins. This in vitro inhibition was completely prevented by the addition of mevalonate and partially by all-trans farnesol and all-trans geranylgeraniol, confirming the specific role of isoprenoid metabolites--probably through a prenylated protein(s)--in regulating these cellular events. The inhibitory effect of lipophilic statins on SMC proliferation has been recently shown in different models of proliferating cells such as cultured arterial myocytes and rapidly proliferating carotid and femoral intimal lesions in rabbits. Finally, ex vivo studies recently showed that sera from fluvastatin-treated patients interfere with smooth muscle cell proliferation. These results suggest that HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect in the arterial wall, beyond their effects on plasma lipids, that could translate into a more significant prevention of cardiovascular disease.
The in vivo direct antiatherogenic activity of the antioxidant probucol (200 mg/kg per day) or the beta-blocker with antioxidant properties carvedilol (10 and 20 mg/kg per day) was tested in the same animal in two different types of atherosclerotic lesion (proliferative and fatty lesions) induced in cholesterol-fed rabbits (1%). Drugs were given daily mixed with standard diet for 8 weeks; body weight and plasma lipid profile were not different among groups throughout the study. Aortic fatty lesions were induced by cholesterol feeding (n = 25 in each group) and their extent expressed as % of aorta inner surface covered by plaques was significantly reduced by both drugs (28.2+/-9.6%, P <0.05, 19.9+/-6.2%, P <0.01 for low- and high-dose carvedilol, respectively; 22.3+/-7.6%, P <0.01 for probucol, versus 41.6+/-10.7% in control rabbits). Proliferative lesions were obtained by positioning a hollow silastic collar around one carotid artery 6 weeks after dietary and drug treatments started (n = 5 in each group). The neointimal formation, mostly composed by myocytes, was determined by measuring cross-sectional thickness ratio of intimal (I) and medial (M) tissue of fixed arteries. In untreated animals, collared arteries resulted in a significant neointimal cell accumulation compared to the sham (1.10+/-0.14 versus 0.02+/-0.01) without change in medial thickness. I/M ratio was reduced by about 50% in animals treated with probucol (0.51+/-0.1) and carvedilol (0.66+/-0.21 and 0.52+/-0.1 in the low- and high-dose group, respectively). Total plasma TBARS were more than 50% lower in both probucol- and high-dose carvedilol-treated rabbits. Results show that pharmacological pretreatment with antioxidants directly inhibits early atherogenic processes, representing a potentially useful approach in the prevention of atherosclerosis.