Introdução: É provável que o tratamento precoce da sepse grave e do choque séptico possa melhorar o desfecho dos pacientes. Objetivo: O objetivo deste estudo foi avaliar como o atraso no início da ressuscitação da sepse influencia a gravidade da doença, a intensidade das medidas de ressuscitação necessárias para atingir estabilidade hemodinâmica, o desenvolvimento da disfunção orgânica e a função mitocondrial. Métodos: Estudo experimental, prospectivo, randomizado e controlado, realizado em um laboratório experimental de um hospital universitário. Trinta e dois porcos submetidos à anestesia geral e ventilados mecanicamente foram randomizados (8 animais por grupo) em um grupo controle sadio ou para um de três grupos em que induziu-se peritonite fecal (instilação peritoneal de 2,0 g/kg de fezes autólogas) e, após 6 (deltaT-6h), 12 (deltaT-12h) ou 24 (deltaT-24h) horas, iniciou-se um período de 48 horas de ressuscitação protocolada. Resultados: O retardo no início da ressuscitação da sepse foi associada a sinais progressivos de hipovolemia e ao aumento dos níveis plasmáticos de interleucina-6 e do fator de necrose tumoral alfa. O atraso no início do tratamento da sepse resultou em balanço hídrico progressivamente positivo (2,1 ± 0,5 mL/kg/h, 2,8 ± 0,7 mL/kg/h e 3,2 ± 1,5 mL/kg/h, respectivamente, para os grupos deltaT-6h, deltaT-12h, e deltaT-24h, p < 0,01), maior necessidade de administração de noradrenalina durante as 48 horas de ressuscitação (0,02 ± 0,04 mcg/kg/min, 0,06 ± 0,09 mcg/kg/min e 0,13 ± 0,15 mcg/kg/min, p=0,059), redução da capacidade máxima de respiração mitocondrial cerebral dependente do Complexo II (p=0,048) e tendência a aumento da mortalidade (p=0,08). Houve redução do trifosfato de adenosina (ATP) na musculatura esquelética em todos os grupos estudados (p < 0,01), com os valores mais baixos nos grupos deltaT-12h e deltaT-24h. Conclusões: O aumento do tempo entre o início da sepse e o início das manobras de ressuscitação resultou no aumento da gravidade da doença, na maior intensidade das manobras de ressuscitação e na disfunção mitocondrial cerebral associada à sepse. Nossos resultados suportam o conceito da existência de uma janela crítica de oportunidade para ressuscitação da sepse / Introduction: Early treatment in sepsis may improve outcome. Objective: The aim of this study was to evaluate the impact of delays in resuscitation on disease severity, need for resuscitation, and the development of sepsis-associated organ and mitochondrial dysfunction. Methods: Prospective, randomized, controlled experimental study performed at an experimental laboratory in a university hospital. Thirty-two anesthetized and mechanically ventilated pig were randomly assigned (n = 8 per group) to a nonseptic control group or one of three groups in which fecal peritonitis (peritoneal instillation of 2 g/kg autologous feces) was induced, and a 48 hour period of protocolized resuscitation started 6 (deltaT-6 hrs), 12 (deltaT-12 hrs), or 24 (deltaT-24 hrs) hours later. Results: Any delay in starting resuscitation was associated with progressive signs of hypovolemia and increased plasma levels of interleukin-6 and tumor necrosis factor-alfa prior to resuscitation. Delaying resuscitation increased cumulative net fluid balances (2.1 ± 0.5 mL/kg/hr, 2.8 ± 0.7 mL/kg/ hr, and 3.2 ± 1.5 mL/kg/hr, respectively, for groups deltaT-6 h rs, delta T-12 hrs, and ?T-24 hrs; p < 0.01) and norepinephrine requirements during the 48-hr resuscitation protocol (0.02 ± 0.04 mcg/kg/min, 0.06 ± 0.09 mcg /kg/min, and 0.13 ± 0.15 mcg/kg/min; p=0.059), decreased maximal brain mitochondrial Complex II respiration (p=0.048), and tended to increase mortality (p=0.08). Muscle tissue adenosine triphosphate decreased in all groups (p < 0.01), with lowest values at the end in groups deltaT-12 hrs and deltaT-24 hrs. Conclusions: Increasing the delay between sepsis initiation and resuscitation increases disease severity, need for resuscitation, and sepsis-associated brain mitochondrial dysfunction. Our results support the concept of a critical window of opportunity in sepsis resuscitation

Early administration of broad-spectrum antibiotics is the first goal in sepsis treatment. Besides from bacteriostatic/bactericidal effects, some antibiotics may also modify the host´s response to infection. The novel antibiotic tigecycline may exert such properties; however, this property has not been evaluated in large-animal trials. We compared tigecycline with doxycycline and placebo in relation to anti-inflammatory, circulatory and organ dysfunction effects in a sterile pig model of sepsis. Doxycycline, but not tigecycline, reduced the inflammatory response as manifested by tumor necrosis factor alpha levels in plasma. Tigecycline, however, had a stabilizing effect on the circulation not exerted by doxycycline or placebo. To achieve rapid restoration of the circulating blood volume - another major goal in sepsis treatment - fluid bolus administration of is some-times practiced. In addition to crystalloids, albumin-containing solutions are suggested. Yet, some animal-experimental data suggests that rapid bolus administration of albumin reduces albumin’s plasma-expanding effect. We compared a rapid intravenous bolus of radiolabeled albumin with a slow infusion in a sterile pig model of sepsis. Rapid bolus of administration did not reduce plasma levels of albumin following administration and did not increase the amount of albumin that left the circulation. Inadequate oxygen delivery (DO2) by the circulation to the tissues may cause increased plasma lactate, which is the most striking effect of sepsis on the metabolism. However, experimental data and clinical trials refute this link, instead, suggesting other mechanisms, including impaired oxygen extraction, mitochondrial dysfunction and accelerated aerobic glycolysis. We investigated the impact of DO2, oxygen consumption (VO2), hemodynamic parameters and inflammatory response on plasma lactate and organ dysfunction in two experimental sepsis models. In the most severe cases of shock, with DO2, there was an increase in plasma lactate, but without a decrease in VO2, invalidating the assumption that the increase in lactate is due to anaerobic metabolism. To identify critical steps in the sepsis-induced increase in lactate, we inhibited the major energy-producing step in the electron transport chain (ETC). The combination of sepsis and ETC inhibition led to a cellular energy crisis. This finding suggests that early sepsis induces a partial mitochondrial dysfunction.

<p>Veno-arterijski gradijent ugljen-dioksida (Pv-aCO2) se smatra pokazateljem adekvatnosti microcirculatornog venskog protoka. U stanjima usporenog protoka dolazi do povećavanja Pv-aCO2 zbog fenomena zadržavanja CO2. Vrednost Pv-aCO2 predložena je kao dodatni cilj rane usmerene terapije kod pacijenata sa septičnim &scaron;okom. Cilj rada bilo je utvrditi postojanje korelacije promene Pv-aCO2 s promenom SOFA (&ldquo;Sequential Organ Failure Assessment&rdquo;) skora (delta SOFA) nakon primene rane ciljane terapije, kao i korelacije vrednosti različitih pokazatelja krvnog protoka unutar prvih 12 sati od početka lečenja pacijenata sa sepsom. Sekundarni cilj bilo je utvrditi postojanje korelacije Pv-aCO2 6 sati nakon početka rane ciljane terapije (T6) s dužinom boravka u intenzivnoj jedinici i ishodom lečenja. Prospektivnim, neintervencijskim ispitivanjem obuhvaćeno je 150 pacijenata sa sepsom ili septičnim &scaron;okom. Merenja serumskog laktata, saturacije kiseonikom me&scaron;ane venske krvi (ScvO2) i Pv-aCO2 vr&scaron;ena su na početku rane ciljane terapije (T0), posle 6 i 12 sati (T6, T12). Pv-aCO2 se računao kao razlika između parcijalnog pritiska ugljen dioksida arterijske i me&scaron;ane venske krvi. Vrednost SOFA skora određivana je u vremenu T0 i nakon 48 časova (T48). Pacijenti su za potrebe analize podeljeni u dve grupe na osnovu promene SOFA skora [(1) pacijenti kod kojih je do&scaron;lo do smanjenja SOFA skora (delta SOFA &lt; 0); (2) pacijenti kod kojih je smanjenje SOFA skora izostalo (delta SOFA &ge; 0)] i na osnovu vrednosti Pv-aCO2 u vremenu T6 [(1) pacijenti sa visokim Pv-aCO2 (&ge; 0.8 kPa); (2) pacijenti sa normalnim Pv-aCO2 (&lt; 0.8 kPa)]. Između dve grupe pacijenata, sa normalnim i visokim Pv-aCO2, statistički značajne razlike uočene su samo u odnosu na najvi&scaron;u vrednost respiratorne komponente SOFA skora (p=0.01). Uočena je statistički značajna korelacija između vrednosti Pv-aCO2 i laktata u vremenu T6 (r=0.2), Pv-aCO2 i ScvO2 u vremenu T0 (r=-0.4) i T12 (r=-0.24) kao i laktata i ScvO2 u vremenu T0 (r=-0.26) i T12 (r=-0.18). Analizom ponavljanih merenja nije utvrđena statistički značajna korelacija između promene vrednosti Pv-aCO2 unutar prvih 6 sati s promenom SOFA skora unutar prvih 48 sati nakon početka rane ciljane terapije (p=0.12). Utvrđeno je da su vrednosti Pv-aCO2 u vremenu T6 bile lo&scaron; prediktor smrtnog ishoda. Nisu utvrđene statistički značajne razlike u dužini boravka u intenzivnoj jedinici i ishodu lečenja u zavisnosti od vrednosti Pv-aCO2.</p> / <p>Central venous-arterial CO2 difference (Pv-aCO2) reflects adequacy of microcirculatory venous flow. Widening of Pv-aCO2 due to CO2-stagnant phenomenon is described in the low flow states. Pv-aCO2 was proposed as an additional resuscitation target for patients with septic shock.The aim of this study was to examine correlation between changes in Pv-aCO2 and SOFA score as well as different blood flow indices (lactate, mixed venous oxygen saturation) 12 hours after onset of resuscitation in patients with sepsis or septic shock. Secondary aim was to evaluate association of delta CO2 6 hours after onset of resuscitation and patient outcomes (length of stay in the ICU, mortality). Prospective observational study included 150 patients with sepsis. Simultaneous measurements of lactate, mixed venous oxygen saturation (ScvO2) and delta PCO2 were performed at onset of resuscitation (T0) and after 6 hours (T6). Delta PCO2 was calculated as a difference between arterial PCO2 and PCO2 from mixed venous blood. Organ dysfunction was evaluated with the Sequential Organ Failure Assessment (SOFA) score at T0 and after 48 hours (T48). Mortality was assessed after 28 days. For data analysis purposes two groups were created based on delta SOFA [(1) patients with SOFA score decrease (delta SOFA &lt;0); (2) patients without SOFA score decrease (delta SOFA &ge; 0)] and based on Pv-aCO2 [(1) patients with high Pv-aCO2 (&ge;0.8 kPa); (2) patients with normal Pv-aCO2 (&lt;0.8 kPa). Patients with high and normal Pv-aCO2 differed only with respect to highest respiratory SOFA score (p=0.01) Change in Pv-aCO2 between T0 and T6 was not in correlation with change in SOFA score between T0 and T48 (p=0.12). Moderate statistically significant correlation was found between Pv-aCO2 and lactate at T6 (r=0.2), and moderate inverse correlation between Pv-aCO2 and ScvO2 at T0 (r=-0.4) and T12 (r=-0.25) and ScvO2 and lactate at T0 (r=-0.27) and T12 (r=-0.18). Pv-aCO2 at T6 was not associated with 28-day mortality and length of stay in the ICU.</p>