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Intravenous fluid therapy is the most frequent therapeutic intervention in acutely hospitalized patients. They are administered in order to resuscitate the circulation in hypovolemia-associated shock states, to compensate for an impending or existing fluid extracellular deficit, or as a maintenance infusion if the patient is incapable of taking fluid by other means. Any fluid should be prescribed with the same caution as with any other drug. Errors in fluid therapy adversely affect patient - centered outcome. This may be the result of an incorrectly selected amount or inappropriate fluid composition for a given clinical situation. Prescribing intravenous fluids is a complex process involving a decision on the type, composition, dose, rate and possible toxicity of the particular solution. Balanced crystalloid solutions are the first choice for most acute conditions. The need for fluids dynamically changes over time in acutely ill patients. Uncontrolled cumulative positive balance is associated with substantial morbidity and mortality.
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Soluciones Cristaloides , Fluidoterapia , Enfermedad Aguda , Administración Intravenosa , Humanos , Soluciones Isotónicas , ResucitaciónRESUMEN
UNLABELLED: Sepsis is the primary cause of death from infection. However, its early recognition remains a fundamental challenge in clinical practice. In February 2016, a newly revised sepsis definition has been published (SEPSIS-3). Sepsis has been redefined as life-threatening organ dysfunction caused by a dysregulated host response to infection. In this article, we introduce the updated definition of sepsis, discuss its pros and cons and suggest practical implications. The emphasis is put on basic and comprehensive clinical assessment. KEY WORDS: definition - early recognition of sepsis - infection - sepsis - septic shock.
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Sepsis/diagnóstico , Sepsis/etiología , Humanos , Sepsis/terapiaRESUMEN
Spontaneous regression of testicular germ cell tumors is a well-known phenomenon; however, the precise mechanisms of spontaneous regression are still unknown. Our study aimed to investigate programmed death-ligand 1 (PD-L1) expression in spontaneously regressed testicular germ cell tumors, exploring the link between the immune response and spontaneous regression. From a sample of 356 testicular germ cell tumors, we singled out 5 completely regressed and 6 partially regressed tumors. In four out of six cases with partial regression, a residual seminoma component was found, while in the remaining two cases, an embryonal carcinoma component was found. Comparisons were made with 20 pure seminomas and 20 mixed germ cell tumors (MGCTs). A semiquantitative immunohistochemical analysis of PD-L1 expression in tumor cells and intra/peritumoral lymphocytes was performed. There was no PD-L1 expression in tumors with complete regression. All partially regressed tumors showed expression in intra/peritumoral lymphocytes within the tumor remnants. Expression was significantly more frequent in pure seminomas compared to MGCTs (P = 0.004). A positive correlation was demonstrated between the seminoma component and the proportion of PD-L1 positive lymphocytes, with a Kendall's Tau-b coefficient of 0.626 (P < 0.001). Tumor cells showed PD-L1 expression in three MGCTs within the embryonal carcinoma component. Our results support an immunological mechanism of spontaneous tumor regression, with the strongest potential in testicular tumors containing seminoma components. However, further research is necessary to determine the role of PD-L1 ligand more precisely in the microenvironment of spontaneously regressed tumors.
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Precision analysis of the key biological metabolites such as L-lactate has great practical importance for many technological processes in food technology, including beverage production. Here we describe a new, highly selective, and sensitive biosensor for accurate L-lactate assay based on a combination of peroxidase-mimetic nanozymes with microbial lactate oxidase (LOx) immobilized onto the surface of a graphite-rod electrode (GE). The peroxidase-like nanozymes were synthesized using the debris of carbon microfibers (CFs) functionalized with hemin (H) and modified with gold nanoparticles (AuNPs) or platinum microparticles (PtMPs). The nanozyme formed with PtMPs as well as corresponding bioelectrodes based on it (LOx-CF-H-PtMPs/GE) is characterized by preferable catalytic and operational characteristics, so it was selected for the analysis of L-lactate content in real samples of grape must and red wine. The results of the L-lactate analysis obtained by the developed biosensors are highly correlated with a very selective spectrophotometric approach used as a reference. The developed biosensor, due to its high selectivity and sensitivity, is very prospective not only for the beverage industry and food technology, but also for clinical diagnostics and medicine, as well as in other applications where the accurate analysis of L-lactate is highly important.
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Técnicas Biosensibles , Grafito , Nanopartículas del Metal , Ácido Láctico/análisis , Peroxidasa , Oro/análisis , Estudios Prospectivos , Enzimas Inmovilizadas/metabolismo , Técnicas Biosensibles/métodos , Platino (Metal) , Bebidas/análisisRESUMEN
BACKGROUND: Selective in-circuit blood cooling was recently shown to be an effective anticoagulation strategy during short-term haemofiltration. The aim of this study was to examine the safety of this novel method and circuit life. METHODS: Fourteen pigs were randomly assigned to receive continuous haemofiltration with anticoagulation achieved either by selective cooling of an extracorporeal circuit (ECC) (COOL; n = 8) or through systemic heparinization (HEPARIN; n = 6). Before (T0) as well as 1 (TP1) and 6 h (TP6) after starting the procedure the following parameters were assessed: animal status, variables reflecting haemostasis, oxidative stress, inflammation and function of blood elements. RESULTS: All animals remained haemodynamically stable with unchanged body core temperature and routine biochemistry. Regional ECC blood cooling did not alter clinically relevant markers of haemostasis, namely activated partial thromboplastin and prothrombin times, thrombin-antithrombin complexes, von Willebrand factor and plasminogen activator inhibitor-1. Platelet aggregability, serum levels of free haemoglobin, leukocyte count, oxidative burst and blastic transformation of T-lymphocytes were all found to be stable over the treatment period in both groups. ECC blood cooling affected neither plasma malondialdehyde concentrations (a surrogate marker of oxidative stress) nor plasma levels of cytokines (tumour necrosis factor-α, interleukin-6 and -10). While the patency of all circuits treated with systemic heparin was well maintained within the pre-selected period of 24 h, the median filter lifespan in the COOL group was 17 h. CONCLUSION: Utilizing clinically relevant markers, selective in-circuit blood cooling was demonstrated to be a safe and feasible means of achieving regional anticoagulation in healthy pigs. The long-term safety issues warrant further evaluation.
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Anticoagulantes/uso terapéutico , Modelos Animales de Enfermedad , Circulación Extracorporea , Hemofiltración , Heparina/uso terapéutico , Insuficiencia Renal/terapia , Animales , Coagulación Sanguínea , Inflamación , Interleucina-6 , Estrés Oxidativo , PorcinosRESUMEN
INTRODUCTION: Voriconazole represents an essential part of antimicrobial therapy in critically ill patients. The aim of this study was to exclude a significant alteration in voriconazole pharmacokinetics in critically ill patients undergoing continuous venovenous hemofiltration (CVVH). METHODS: Six patients dependent on CVVH with evidence of an invasive mycotic infection treated with intravenous voriconazole at the standard dosing regimen were investigated. The total serum concentration of voriconazole in arterial blood and the concentration in ultrafiltrate were measured by reverse-phase high-performance liquid chromatography with ultraviolet detection. The authors profiled a 5-point pharmacokinetic concentration-time curve during the 12-hour standard maintenance dosing interval and derived the basic pharmacokinetic parameters. RESULTS: The serum voriconazole concentration did not decrease <1.0 mg/L at any time point, and the mean was 4.3 ± 2.6 mg/L and the median (range) 3.6 (9.0) mg/L. The sieving coefficient of the drug did not exceed 0.30 in any patient (0.22 ± 0.08). The mean serum AUC0-12, the mean total clearance, and the mean clearance via CVVH were 53.52 ± 29.97 mg·h/L [the median (range) of 57.74 (62.34) mg·h/L], 0.11 ± 0.07 L·h-1·kg-1, and 0.007 ± 0.003 L·h-1·kg-1, respectively. The clearance by the CVVH method ranged from 4% to 20% of the total drug clearance. The disposition of voriconazole was not compromised. The mean elimination half-life was 27.58 ± 35.82 hours [the median of 13.10 (92.21) hours], and the mean distribution volume value was 3.28 ± 3.10 L/kg [the median of 2.01 (8.10) L/kg]. Marked variability in serum concentrations, elimination half-life, distribution volume, and total clearance was seen. Half of the patients showed some drug accumulation. CONCLUSIONS: The clearance of voriconazole by CVVH is not clinically significant. In view of this finding, voriconazole dose adjustment in patients undergoing the standard method of CVVH is not required. However, the observed potential for an unpredictable voriconazole accumulation suggests the usefulness for monitoring its levels in critically ill patients.
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Antiinfecciosos/farmacocinética , Hemofiltración , Micosis/metabolismo , Pirimidinas/farmacocinética , Triazoles/farmacocinética , Antiinfecciosos/administración & dosificación , Antiinfecciosos/sangre , Área Bajo la Curva , Enfermedad Crítica , Monitoreo de Drogas/métodos , Semivida , Humanos , Micosis/sangre , Micosis/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/sangre , Triazoles/administración & dosificación , Triazoles/sangre , VoriconazolRESUMEN
INTRODUCTION: In almost half of all sepsis patients, acute kidney injury (AKI) develops. However, the pathobiologic differences between sepsis patients with and without AKI are only poorly understood. We used a unique opportunity to examine dynamic inflammatory, renal hemodynamic, and microvascular changes in two clinically relevant large-animal models of sepsis. Our aim was to assess variability in renal responses to sepsis and to identify both hemodynamic and nonhemodynamic mechanisms discriminating individuals with AKI from those in whom AKI did not develop. METHODS: Thirty-six pigs were anesthetized, mechanically ventilated, and instrumented. After a recovery period, progressive sepsis was induced either by peritonitis (n = 13) or by continuous intravenous infusion of live Pseudomonas aeruginosa (n = 15). Eight sham operated-on animals served as time-matched controls. All animals received standard intensive care unit (ICU) care, including goal-directed hemodynamic management. Before, and at 12, 18, and 22 hours of sepsis, systemic and renal (ultrasound flow probe) hemodynamics, renal cortex microcirculation (laser Doppler), inflammation (interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), oxidative stress (thiobarbituric acid reactive species (TBARS), nitrite/nitrate concentrations (NOx), and renal oxygen kinetics and energy metabolism were measured. RESULTS: In 14 (50%) pigs, AKI developed (62% in peritonitis, 40% in bacteria infusion model). Fecal peritonitis resulted in hyperdynamic circulation, whereas continuous bacteria infusion was associated with normodynamic hemodynamics. Despite insults of equal magnitude, comparable systemic hemodynamic response, and uniform supportive treatment, only those pigs with AKI exhibited a progressive increase in renal vascular resistance. This intrarenal vasoconstriction occurred predominantly in the live-bacteria infusion model. In contrast to AKI-free animals, the development of septic AKI was preceded by early and remarkable inflammatory response (TNF-α, IL-6) and oxidative stress (TBARS). CONCLUSIONS: The observed variability in susceptibility to septic AKI in our models replicates that of human disease. Early abnormal host response accompanied by subsequent uncoupling between systemic and renal vascular resistance appear to be major determinants in the early phase of porcine septic AKI. Nonuniform and model-related renal hemodynamic responses that are unpredictable from systemic changes should be taken into consideration when evaluating hemodynamic therapeutic interventions in septic AKI.
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Lesión Renal Aguda/etiología , Sepsis/complicaciones , Lesión Renal Aguda/sangre , Lesión Renal Aguda/fisiopatología , Animales , Biomarcadores/sangre , Modelos Animales de Enfermedad , Hemodinámica/fisiología , Interleucina-6/sangre , Estrés Oxidativo/fisiología , Porcinos , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Development of artificial enzymes, including nanozymes as an alternative for non-stable and expensive natural enzymes, is a booming field of modern Biosensorics and Biofuel Technology. In this study, we describe fabrication and characterization of sensitive biosensors for the detection of ethanol and glucose based on new micro/nanocomposite electrodes with peroxidase-like activity (nanozyme) coupled with microbial oxidases: alcohol oxidase (AOX) and glucose oxidase (GOX). The nanozyme was synthesized by modification of carbon microfibers (CF) by hemin (H) and gold (Au) nanoparticles. The formation of gold nanoparticles on the surface of hemin-modified carbon microfibers has been confirmed by the UV-Vis and X-ray spectroscopy as well by the SEM analysis. Compared to hemin-only modified electrodes, the resulting micro/nanocomposite CF-H-Au electrodes exhibit a higher specific catalytic activity and a better affinity for H2O2 in solution. The H2O2-sensitive CF-H-Au-modified electrodes showed a higher sensitivity (1.3-2.6-fold) compared with the nearest carbon-derived analogs and were used for the construction of highly sensitive ethanol and glucose biosensors. To eliminate diffusion limitation for substrates, AOX or GOX were fixed on the CF-H-Au-modified electrodes using a highly porous Nafion membrane. The main biosensors' characteristics have been investigated. The developed biosensors were tested for ethanol and glucose analysis in the real samples of both grape must and wine. The results are in good agreement with the results obtained using enzymatic kits as reference approaches.
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Técnicas Biosensibles , Nanopartículas del Metal , Nanocompuestos , Electrodos , Enzimas Inmovilizadas , Etanol , Glucosa , Glucosa Oxidasa , Oro , Peróxido de Hidrógeno , Oxidorreductasas , PeroxidasasRESUMEN
OBJECTIVE: To hypothesize that reduced L-type calcium current with consequent shortening of cardiac repolarization is present in a clinically relevant porcine model of hyperdynamic septic shock. Myocardial depression is a well-recognized manifestation of sepsis and septic shock. Reduction of L-type calcium current was demonstrated to contribute to the myocardial depression in endotoxemic rodents. DESIGN: Laboratory animal experiments. SETTING: Animal research laboratory at a university. SUBJECTS: Twenty-two domestic pigs of either gender. INTERVENTIONS: In anesthetized, mechanically ventilated, and instrumented pigs, sepsis was induced by bacteremia (central venous infusion of live Pseudomonas aeruginosa) and continued for 22 hrs. MEASUREMENTS AND MAIN RESULTS: Electrocardiogram was recorded before and 22 hrs after induction of bacteremia. RR, QT, and QTc intervals were significantly shortened by sepsis. In vitro, action potentials were recorded in right ventricular trabeculae. Action potential durations were shortened in septic preparations. Tumor necrosis factor-alpha did not influence action potential durations. L-type calcium current was measured in isolated ventricular myocytes. Peak L-type calcium current density was reduced in myocytes from septic animals (8.3 +/- 0.4 pA/pF vs. 11.2 +/- 0.6 pA/pF in control). The voltage dependence of both L-type calcium current activation and inactivation was shifted to more negative potentials in myocytes from septic animals. Action potential-clamp experiments revealed that the contribution of L-type calcium current to the septic action potential was significantly diminished. In cardiac myocytes incubated with tumor necrosis factor-alpha, L-type calcium current was not further affected. CONCLUSIONS: In a clinically relevant porcine model, hyperdynamic septic shock induced shortening of ventricular repolarization and reduction of L-type calcium current. The contribution of L-type calcium current to the action potential in septic ventricular myocytes was significantly diminished. Tumor necrosis factor-alpha probably did not contribute to this effect.
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Potenciales de Acción/fisiología , Canales de Calcio Tipo L/fisiología , Miocitos Cardíacos/fisiología , Choque Séptico/fisiopatología , Animales , Calcio/fisiología , Modelos Animales de Enfermedad , Electrocardiografía , Femenino , Ventrículos Cardíacos/fisiopatología , Masculino , Sus scrofa/fisiología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
In this study, we describe the fabrication of sensitive biosensor for the detection of phenolic substrates using laccase immobilized onto two types of microporous carbon fibers (CFs). The main characteristics of microporous CFs used for preparation of biosensors are given. Two CFs were characterized by different specific surface area, CFA (<1 m2·g-1) and CFB (1448 m2·g-1), but with comparable size of the micropores estimated by positron annihilation lifetime spectroscopy. The structural analysis was shown that CFA is formed by thin interwoven fibers forming a highly porous structure, as well as CFB - by granular formations with uneven edges that shape a cellulose membrane of lower porosity. The results of amperometric analysis revealed that the laccase-bound CFs possesses better electrochemical behavior for laccase than non-modified rod carbon electrodes (control). Using chronoamperometric analysis, the operational parameters of the CFs-modified bioelectrodes were compared to control bioelectrodes. The bioelectrodes based on CFs have demonstrated 2.4-2.7 folds enhanced maximal current at substrate saturation (Imax) values, 1.2-1.4 folds increased sensitivity and twice wide linearity compared with control bioelectrodes. The sensitivity of the developed CFs-based bioelectrodes was improved compared with the laccase-bound electrodes, described in literature. The developed biosensor was tested for catechol analysis in the real communal wastewater sample.
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Técnicas Biosensibles , Carbono/química , Catecoles/análisis , Técnicas Electroquímicas , Proteínas Fúngicas/química , Lacasa/química , Polyporaceae/enzimología , Aguas Residuales/análisisRESUMEN
OBJECTIVE: Sepsis has been defined as the systemic host response to infection with an overwhelming systemic production of both proinflammatory and anti-inflammatory mediators. Continuous hemofiltration has been suggested as possible therapeutic option that may remove the inflammatory mediators. However, hemodialysis and hemofiltration were reported to influence cardiac electrophysiologic parameters and to increase the arrhythmogenic risk. We hypothesize that sepsis affects electrophysiologic properties of the pig heart and that the effects of sepsis are modified by hemofiltration. DESIGN: Laboratory animal experiments. SETTING: Animal research laboratory at university medical school. SUBJECTS: Forty domestic pigs of either gender. INTERVENTIONS: In anesthetized, mechanically ventilated, and instrumented pigs sepsis was induced by fecal peritonitis and continued for 22 hours. Conventional or high-volume hemofiltration was applied for the last 10 hours of this period. MEASUREMENTS AND MAIN RESULTS: Electrocardiogram was recorded before and 22 hours after induction of peritonitis. RR, QT, and QTc intervals were significantly shortened by sepsis. The plasma levels of interleukin-6 and tumor necrosis factor-alpha were increased in sepsis. High-volume hemofiltration blunted the sepsis-induced increase in tumor necrosis factor-alpha. Action potentials were recorded in isolated ventricular tissues obtained at the end of in vivo experiments. Action potential durations were significantly shortened in septic preparations at all stimulation cycle lengths tested. Both conventional and high-volume hemofiltrations lead to further shortening of action potential durations measured afterward in vitro. This action potential duration shortening was reversed by septic hemofiltrates obtained previously by conventional or high-volume hemofiltration. Tumor necrosis factor-alpha (500 ng/L) had no effect on action potential durations in vitro. CONCLUSIONS: In a clinically relevant porcine model of hyperdynamic septic shock, both sepsis and continuous hemofiltration shortened duration of cardiac repolarization. The continuous hemofiltration was not associated with an increased prevalence of ventricular arrhythmias. Tumor necrosis factor-alpha or interleukin-6 did not contribute to the observed changes in action potential durations.
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Corazón/fisiopatología , Hemofiltración , Choque Séptico/fisiopatología , Choque Séptico/terapia , Potenciales de Acción , Animales , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/prevención & control , Modelos Animales de Enfermedad , Electrocardiografía , Femenino , Hemodinámica , Interleucina-6/biosíntesis , Masculino , Respiración Artificial , Choque Séptico/metabolismo , Sus scrofa , Factor de Necrosis Tumoral alfa/biosíntesis , Función VentricularRESUMEN
INTRODUCTION: Our understanding of septic acute kidney injury (AKI) remains incomplete. A fundamental step is the use of animal models designed to meet the criteria of human sepsis. Therefore, we dynamically assessed renal haemodynamic, microvascular and metabolic responses to, and ultrastructural sequelae of, sepsis in a porcine model of faecal peritonitis-induced progressive hyperdynamic sepsis. METHODS: In eight anaesthetised and mechanically ventilated pigs, faecal peritonitis was induced by inoculating autologous faeces. Six sham-operated animals served as time-matched controls. Noradrenaline was administered to maintain mean arterial pressure (MAP) greater than or equal to 65 mmHg. Before and at 12, 18 and 22 hours of peritonitis systemic haemodynamics, total renal (ultrasound Doppler) and cortex microvascular (laser Doppler) blood flow, oxygen transport and renal venous pressure, acid base balance and lactate/pyruvate ratios were measured. Postmortem histological analysis of kidney tissue was performed. RESULTS: All septic pigs developed hyperdynamic shock with AKI as evidenced by a 30% increase in plasma creatinine levels. Kidney blood flow remained well-preserved and renal vascular resistance did not change either. Renal perfusion pressure significantly decreased in the AKI group as a result of gradually increased renal venous pressure. In parallel with a significant decrease in renal cortex microvascular perfusion, progressive renal venous acidosis and an increase in lactate/pyruvate ratio developed, while renal oxygen consumption remained unchanged. Renal histology revealed only subtle changes without signs of acute tubular necrosis. CONCLUSION: The results of this experimental study argue against the concept of renal vasoconstriction and tubular necrosis as physiological and morphological substrates of early septic AKI. Renal venous congestion might be a hidden and clinically unrecognised contributor to the development of kidney dysfunction.
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Hemodinámica/fisiología , Riñón/metabolismo , Riñón/patología , Microcirculación/fisiología , Peritonitis/complicaciones , Choque Séptico/fisiopatología , Animales , República Checa , Riñón/diagnóstico por imagen , Flujometría por Láser-Doppler , Proyectos de Investigación , Porcinos , UltrasonografíaRESUMEN
The presented work describes an effective method for 226Ra determination using laboratory- prepared MnO2-SiO2 composite resin. Samples were traced with 133Ba for radium radiochemical recoveries monitoring which were in the range of (77 - 100%). MnO2- SiO2 composite resin was used to collect for 226Ra from water samples (pH = 6.5-7.0). Radium was eluted from the column with 50â¯mL of 4â¯molâ¯L-1 HNO3 at a flow rate of 1.5â¯mLâ¯min-1. Alpha-spectrometric counting of Ba(Ra)SO4 microprecipitate was used for 226Ra determination. The new developed method was used to the 226Ra determination in samples of natural mineral, mountain spring, drinking and natural healing waters from Slovakia and Czech Republic.
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Coagulation abnormalities have been implicated in the pathogenesis of sepsis and organ dysfunction. Nitric oxide (NO) is regarded as a critical mediator of many vascular pathologies, including sepsis. However, limited evidence is available to document a relationship between NO generated by inducible NO synthase (iNOS) and hemostatic abnormalities in sepsis. Therefore, we evaluated the effects of selective iNOS inhibition on markers of endothelial and coagulation homeostasis in a clinically relevant model of porcine bacteremia induced and maintained for 24 hours (h) with a continuous infusion of live P. aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n=7) or continuous infusion of selective iNOS inhibitor L-NIL (n=7). Before as well as 12, 18 and 24 h after starting P. aeruginosa following variables related to i) endothelial dysfunction (von Willebrand factor [vWf]; tissue plasminogen activator activity [t-PA]; ii) coagulation (thrombin-antithrombin complexes [TAT]; platelet count); iii) fibrinolysis (t-PA activity, activity of plasminogen activator inhibitor type 1 (PAI-1 act); and iv) oxidative/nitrosative stress (isoprostanes, nitrate/nitrite levels) were measured. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite and isoprostanes concentrations, prevented hypotension and acidosis. L-NIL significantly attenuated sepsis-induced rise in plasma vWF and TAT. P. aeruginosa-induced drop in t-PA activity was blunted by iNOS inhibition, while increased PAI-1 and reduced platelet count were not reversed by the treatment. In conclusion, selective iNOS inhibition was associated with attenuation of sepsis-induced coagulation and endothelial dysfunction suggesting the interplay between mediators of vascular system and hemostatic balance. Reduction of oxidative stress probably contributes to the beneficial effects afforded by iNOS blockade.
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Bacteriemia/sangre , Coagulación Sanguínea/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Lisina/análogos & derivados , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Infecciones por Pseudomonas/sangre , Equilibrio Ácido-Base/efectos de los fármacos , Animales , Bacteriemia/metabolismo , Bacteriemia/microbiología , Bacteriemia/fisiopatología , Sistema Cardiovascular/efectos de los fármacos , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Fibrinógeno/efectos de los fármacos , Lisina/farmacología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/fisiopatología , Pseudomonas aeruginosa , Porcinos , Factores de TiempoRESUMEN
Complex interactions of nitric oxide and other free radicals have been implicated in the pathogenesis of sepsis and organ dysfunction. We hypothesized that simultaneous inducible nitric oxide synthase inhibition (L-N6-[1-iminoethyl]-lysine [L-NIL]) and neutralization of superoxide (O2-) (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl [Tempol]) would protect from detrimental consequences of long-term, volume-resuscitated, hyperdynamic porcine bacteremia. In this prospective, randomized, controlled experimental study, 16 anesthetized, mechanically ventilated and instrumented pigs were exposed to 24 h of continuous infusion of live Pseudomonas aeruginosa. After 12 h of hyperdynamic sepsis, animals were randomized to receive either vehicle (control, n = 8) or combination of L-NIL and Tempol (n = 8). Systemic and hepatosplanchnic hemodynamics, oxygen exchange, metabolism, ileal mucosal microcirculation and tonometry, oxidative stress and coagulation parameters were assessed before, 12, 18, and 24 h of P. aeruginosa infusion. Combined treatment inhibited sepsis-induced increase in plasma nitrate/nitrite, 8-isoprostane, and thiobarbituric acid reactive species concentrations, prevented hypotension, and reversed hyperdynamic circulation. Despite lower intestinal macrocirculation, combined regimen attenuated the otherwise progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. Treatment substantially attenuated mesenteric and hepatic venous acidosis, preserved sepsis-induced impairment of hepatosplanchnic redox state, and prevented the development of renal dysfunction. Finally, coinfusion of L-NIL and Tempol largely attenuated the sepsis-induced rise in plasma von Willebrand factor and thrombin-antithrombin complexes. Thus, hemodynamic, microcirculatory, metabolic, renal, and coagulation data indicate that combining inducible inhibition with cell permeable O2(-) radical scavenger afforded significant protection in porcine sepsis, thus suggesting an important interactive role of O2(-) and nitric oxide in mediating organ dysfunction.
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Bacteriemia/tratamiento farmacológico , Óxidos N-Cíclicos/farmacología , Depuradores de Radicales Libres/farmacología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Infecciones por Pseudomonas/tratamiento farmacológico , Porcinos/microbiología , Animales , Bacteriemia/fisiopatología , Infecciones por Pseudomonas/fisiopatología , Pseudomonas aeruginosa/fisiología , Marcadores de Spin , Porcinos/fisiologíaRESUMEN
OBJECTIVE: To evaluate attitudes of Europeans regarding end-of-life decisions. DESIGN AND SETTING: Responses to a questionnaire by physicians and nurses working in ICUs, patients who survived ICU, and families of ICU patients in six European countries were compared for attitudes regarding quality and value of life, ICU treatments, active euthanasia, and place of treatment. MEASUREMENTS AND RESULTS: Questionnaires were distributed to 4,389 individuals and completed by 1,899 (43%). Physicians (88%) and nurses (87%) found quality of life more important and value of life less important in their decisions for themselves than patients (51%) and families (63%). If diagnosed with a terminal illness, health professionals wanted fewer ICU admissions, uses of CPR, and ventilators (21%, 8%, 10%, respectively) than patients and families (58%, 49%, 44%, respectively). More physicians (79%) and nurses (61%) than patients (58%) and families (48%) preferred being home or in a hospice if they had a terminal illness with only a short time to live. CONCLUSIONS: Quality of life was more important for physicians and nurses than patients and families. More medical professionals want fewer ICU treatments and prefer being home or in a hospice for a terminal illness than patients and families.
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Actitud , Familia , Cuidados para Prolongación de la Vida , Enfermeras y Enfermeros , Pacientes , Médicos , Cuidado Terminal , Enfermo Terminal , Adulto , Actitud del Personal de Salud , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Incidence of Gram-positive infections caused by bacteria resistant to commonly used antibiotics has increased in the last decades. Resistant strains appeared later in the Czech Republic, however their number has been increasing and new antibiotics have to be used. The greatest increase of frequency can be seen in infections caused by methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci. Vancomycin-resistant enterococci are usually found in hematooncology patients. Curative use of vancomycin is limited due to a narrow spectrum of activity, nephrotoxicity, and limited penetration into tissues (lung) and cerebrospinal fluid. Linezolid is a good option mainly in infections of skin and soft tissues, and it has an evincible advantage over vancomycin in the treatment of nosocomial pneumonia and surgical-site infections. Oral formulations are favourable allowing switch therapy and earlier discharge from hospital.
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Infección Hospitalaria , Linezolid , Antibacterianos/uso terapéutico , Infección Hospitalaria/microbiología , República Checa , Humanos , Resistencia a la Meticilina , Staphylococcus aureus Resistente a Meticilina , Staphylococcus aureus/efectos de los fármacosRESUMEN
BACKGROUND: We investigated glucose metabolism in septic patients during hyperglycemic clamps and compared the different levels of insulinemia and glycemia. METHODS: In 10 non-diabetic stable septic patients on mechanical ventilation with baseline glycemia >6 mmol/L and continuous insulin infusion, 3 steps of hyperinsulinemic clamp were performed after 8 hours without caloric intake. In step 1, the targets were insulinemia of 250 mIU/L and glycemia of 5 mmol/L; in step 2, insulinemia of 250 mIU/L and glycemia of 10 mmol/L; in step 3, insulinemia of 1250 mIU/L and glycemia of 5 mmol/L. Glucose uptake was calculated as the amount of glucose per time needed to maintain the target level of glycemia. Glucose oxidation was calculated from indirect calorimetry and urinary nitrogen losses. Values are provided as means +/- SD. A two-way analysis of variance and Scheffe's method were used for statistical analysis and p < .05 was considered significant. RESULTS: At step 1, glucose uptake was lower than at step 2 (3.8 +/- 2.48 mg/kg/min and 7.9 +/- 3.45 mg/kg/min, respectively; p < .001). Glucose oxidation was also lower at step 1 (2.6 +/- 0.98 and 4.2 +/- 1.85 mg/kg/min, respectively; p < .01). Glucose storage was low at step 1 (0.7 +/- 1.39) and increased at step 2 (3.5 +/- 2.18; p < .05). In step 3, glucose uptake was 7.0 +/- 2.1, oxidation was 3.6 +/- 1.37, and storage was 2.9 +/- 2.79. There was no significant difference in all these parameters between steps 2 and 3. Energy expenditure between steps 1, 2 and 3 did not change (2294 + 307.42, 2334 + 341.53, and 2342 + 426.67 kcal/day, respectively). Alanine in plasma dropped significantly (p < .05): 10 mmol/L (311 +/- 55.88 mmol/L) at glycemia compared with 5 mmol/L (390 +/- 76 micromol/L) at insulinemia 250 mIU/L. It did not differ significantly from the values obtained at glycemia 5 mmol/L and insulinemia 1250 mIU/L (348 +/- 70.68 mmol/L). Even if the level of cytokines in sepsis was higher, there was no correlation between the insulin level in plasma (250 and 1250 mIU/L), glycemia (5 and 10 mmol/L) and cytokine level (IL-1beta, IL-2, IL-6, IL-8 and TNFalpha). CONCLUSION: At insulinemia 250 mIU/L, a glucose level of 10 mmol/L seems to increase glucose uptake, oxidation, and storage compared with glycemia 5 mmol/L. This glucose uptake and oxidation at glycemia 10 mmol/L is comparable with the effect of extremely high insulinemia (1250 mIU/L) clamped at glycemia 5 mmol/L. A higher level of blood glucose or a high level of insulinemia significantly increases glucose uptake but not energy expenditure.
Asunto(s)
Glucemia/metabolismo , Metabolismo Energético/fisiología , Insulina/sangre , Sepsis/metabolismo , Análisis de Varianza , Calorimetría Indirecta , Citocinas/biosíntesis , Técnica de Clampeo de la Glucosa , Humanos , Infusiones Parenterales , Insulina/administración & dosificación , Insulina/uso terapéutico , Nitrógeno/orina , Sepsis/sangre , Índice de Severidad de la EnfermedadRESUMEN
Lactate is a key metabolite that is produced by every cell and oxidized by most of them, provided that they do contain mitochondria. Its metabolism is connected to energetic homeostasis and the cellular redox state. It is well recognized as an indicator of severe outcome in severely ill patients, however, it is not a detrimental factor per se. Conversely, some recent data tend even to indicate a beneficial effect in several metabolic disorders. Although the liver has long been recognized as a key organ in lactate homeostasis, the kidney also plays a major role as a gluconeogenic organ significantly involved in the glucose-lactate cycle. In acute renal failure, sodium lactate is widely used as a buffer in replacement fluids because the anion (lactate - ) is metabolized and the cation (Na + ) remains, leading to decreased water dissociation and proton concentration. The metabolic disorders related to acute renal failure or associated with it, such as liver failure, may affect lactate metabolism, and therefore they are often regarded as limiting factors for the use of lactate-containing fluids in such patients. By investigating endogenous lactate production in severe septic patients with acute renal failure, we found that an acute exogenous load of lactate did not affect the basal endogenous lactate production and metabolism. This indicates that exogenous lactate is well metabolized even in patients suffering from acute renal failure and severe sepsis with a compromised hemodynamic status.
Asunto(s)
Lesión Renal Aguda/metabolismo , Homeostasis , Ácido Láctico/metabolismo , Uremia/metabolismo , Adenosina Trifosfato/metabolismo , Metabolismo Energético , Glucosa/metabolismo , Hemodinámica , Humanos , Riñón/metabolismo , Ácido Láctico/administración & dosificación , Ácido Láctico/sangre , Hígado/metabolismoRESUMEN
We have recently demonstrated that selective inducible nitric oxide (NO) synthase (iNOS) inhibition with 1400W attenuated the hemodynamic and metabolic alterations affiliated with hyperdynamic porcine endotoxemia. In contrast to endotoxemia, limited evidence is available to document a relationship between NO and organ dysfunction in large animal bacteremic models. Therefore, using the same experimental setup, we investigated the role of selective iNOS blockade in porcine bacteremia induced and maintained for 24 h with a continuous infusion of live Pseudomonas aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n = 8) or continuous infusion of selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysine (L-NIL; n = 8). Measurements were performed before, and 12, 18, and 24 h after P. aeruginosa infusion. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite concentrations and prevented hypotension without affecting cardiac output. Despite comparable hepatosplanchnic macrocirculation, L-NIL blunted the progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. L-NIL largely attenuated mesenteric and hepatic venous acidosis, significantly improved P. aeruginosa-induced impairment of hepatosplanchnic redox state, and mitigated the decline in liver lactate clearance. Furthermore, the administration of L-NIL reduced the hepatocellular injury and prevented the development of renal dysfunction. Finally, treatment with L-NIL significantly attenuated the formation of 8-isoprostane concentrations, a direct marker of lipid peroxidation. Thus, selective iNOS inhibition with L-NIL prevented live bacteria from causing key features of metabolic derangements in porcine hyperdynamic sepsis. Underlying mechanisms probably include reduced oxidative stress with improved microcirculatory perfusion and restoration of cellular respiration.