Almost a quarter of a millennium after the discovery of an acidic substance in sour milk by Swedish chemist Carl Wilhelm Scheele and more than 100 years after the demonstration of a tight connection between this lactic acid and tissue hypoxia in shock, we are still surrounded by false beliefs and misunderstandings regarding this fascinating molecule. Common perceptions of lactate, the conjugate base of lactic acid, as a plain waste product of anaerobic metabolism and a marker of cellular distress could not be further from the truth. Lactate is formed and utilized continuously by our cells, even under fully aerobic conditions, in large quantities, and although marked hyperlactatemia is always a red flag in our patients, not all these conditions are life-threatening and vice versa-not all critically ill patients have hyperlactatemia. Lactate also does not promote acidosis by itself; it is not toxic, nor is it a metabolic renegade. On the contrary, it has many beneficial properties, and an interpretation of hyperlactatemia might be trickier than we tend to think. The aim of this article is to debunk some of the deeply rooted myths regarding this fascinating molecule.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Komunitní pneumonie je akutní zánětlivé onemocnění plicního parenchymu vzniklé mimo zdravotnické zařízení nebo do 48 hodin od přijetí do nemocnice. I přes dostupnost kauzální antibiotické léčby se dle dat Světové zdravotnické organizace jedná o celosvětově nejčastější příčinu úmrtí z infekčních příčin. Přestože by se mohlo zdát, že léčba infekčních onemocnění dolních cest dýchacích je uzavřenou kapitolou, opak je pravdou. Diagnostický rámec pneumonie zahrnuje heterogenní skupinu pacientů, kteří svým individuálním fenotypem onemocnění vyžadují specifický terapeutický přístup. Kontroverzní otázkou posledních dvaceti let je především adjuvantní použití kortikosteroidů s cílem modulace imunitně ‐inflamatorního poškození plicního parenchymu u těžké komunitní pneumonie. Výsledky klinických studií a jejich metaanalýz jsou bohužel protichůdné. Poslední konsensus čtyř významných evropských odborných společností doporučuje podání kortikoidů pouze u pacientů se současně přítomným septickým šokem. Stanovisko však bylo vydáno před uveřejněním dosud největší studie (CAPE COD), která svými závěry kontrastuje s uvedeným doporučením a velmi pravděpodobně v dohledné době změní přísné vymezení kortikoidů u pacientů se závažnou komunitní pneumonií. Cílem tohoto sdělení je poskytnout krátký klinicky orientovaný přehled ve stále kontroverzním problému a nabídnout k další odborné diskuzi pohled našeho pracoviště do doby, než budou k dispozici nová data a doporučení relevantních odborných grémií.
Community-acquired pneumonia (CAP) is an acute inflammatory disease of the lung parenchyma acquired outside the healthcare facilities or within 48 hours after admission to the hospital. Despite the availability of antibiotics, pneumonia remains the leading cause of death from infectious causes, according to World Health Organization data. Although it might seem that the treatment of lower respiratory tract infections is a closed chapter in a medical textbooks, it is quite the opposite. Our perception of pneumonia as a unifying diagnosis comes with a burden of heterogeneity and we need to approach each patient individually, based on their disease-specific phenotype. The adjuvant use of corticosteroids to modulate and dampen inflammation-induced lung injury in severe community-acquired pneumonia has been a matter of debate for the last twenty years. Up until recently, clinical trials and meta-analyses yielded conflicting results. Therefore, the last consensus of four respected European societies, recommends using corticosteroids in patients with severe community-acquired pneumonia only if septic shock is present. Unfortunately, those guidelines had been released shortly before the largest trial ever conducted on this group of patients (CAPE COD), which indicated different conclusions. This will probably lead to a reevaluation of the current strict recommendations for the use of corticosteroids. The following text aims to provide a brief clinically-oriented review of this controversial topic and present a perspective of our intensive care unit for further discussion until we have new relevant data and subsequent guidelines.
- MeSH
- hormony kůry nadledvin * terapeutické užití MeSH
- infekce získané v komunitě farmakoterapie prevence a kontrola MeSH
- klinická studie jako téma MeSH
- klinické rozhodování MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- pneumonie * farmakoterapie prevence a kontrola MeSH
- riziko MeSH
- zánět farmakoterapie prevence a kontrola MeSH
- Check Tag
- lidé MeSH
Infectious diseases, which often result in deadly sepsis or septic shock, represent a major global health problem. For understanding the pathophysiology of sepsis and developing new treatment strategies, reliable and clinically relevant animal models of the disease are necessary. In this review, two large animal (porcine) models of sepsis induced by either peritonitis or bacteremia are introduced and their strong and weak points are discussed in the context of clinical relevance and other animal models of sepsis, with a special focus on cardiovascular and immune systems, experimental design, and monitoring. Especially for testing new therapeutic strategies, the large animal (porcine) models represent a more clinically relevant alternative to small animal models, and the findings obtained in small animal (transgenic) models should be verified in these clinically relevant large animal models before translation to the clinical level.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Porcine model of peritonitis-induced sepsis is a well-established clinically relevant model of human disease. Interindividual variability of the response often complicates the interpretation of findings. To better understand the biological basis of the disease variability, the progression of the disease was compared between animals with sepsis and septic shock. Peritonitis was induced by inoculation of autologous feces in fifteen anesthetized, mechanically ventilated and surgically instrumented pigs and continued for 24 h. Cardiovascular and biochemical parameters were collected at baseline (just before peritonitis induction), 12 h, 18 h and 24 h (end of the experiment) after induction of peritonitis. Analysis of multiple parameters revealed the earliest significant differences between sepsis and septic shock groups in the sequential organ failure assessment (SOFA) score, systemic vascular resistance, partial pressure of oxygen in mixed venous blood and body temperature. Other significant functional differences developed later in the course of the disease. The data indicate that SOFA score, hemodynamical parameters and body temperature discriminate early between sepsis and septic shock in a clinically relevant porcine model. Early pronounced alterations of these parameters may herald a progression of the disease toward irreversible septic shock.
- Publikační typ
- časopisecké články MeSH
As controversy persists regarding the benefits of mechanical circulatory support in septic shock with a predominantly vasoplegic phenotype, preclinical studies may provide a useful alternative to fill the actual knowledge gap. Here, we investigated the physiologic responses to venoarterial extracorporeal membrane oxygenation therapy (VA-ECMO) in a clinically relevant porcine peritonitis-induced model of refractory vasodilatory septic shock. In 12 anesthetized, mechanically ventilated, and instrumented domestic pigs, septic shock was induced by intraperitoneally inoculating autologous feces. After reaching the threshold for refractory vasodilatory shock (norepinephrine dose ≥1 μg/kg/min), the pigs were randomized into the conservative treatment group (control) or the VA-ECMO group (target flow 100 mL/kg/min). The time to develop refractory vasodilatory shock was similar in both groups (18.8 h in the ECMO group, 18.1 h in the control group). There was no difference between the groups in terms of time to death measured from the point of reaching the predefined vasopressor threshold (7.1 h for the ECMO group, 7.9 h for the control group). The initiation of ECMO resulted in a markedly increased fluid and vasopressor support. Although treatment with ECMO compromised neither renal nor carotid blood flow initially, both progressively decreased later during the experiment. The pattern of sepsis-induced multiorgan injury, alterations in energy metabolism, and the systemic inflammatory response were remarkably similar between both groups. In conclusion, the application of VA-ECMO in this model of peritonitis-induced refractory vasodilatory septic shock aggravated hemodynamic deterioration. Our findings contribute to increasing equipoise with respect to the clinical utility of VA-ECMO in refractory vasodilatory shock.
BACKGROUND: Septic acute kidney injury affects 40-50% of all septic patients. Molecular differences between septic patients with and without acute kidney injury (AKI) are only poorly understood. Here, we investigated gene expression changes that differentiated the subjects who developed septic AKI from those who did not and coupled this approach with traditional parameters of renal physiology. METHODS: In 15 anesthetized, mechanically ventilated and instrumented pigs, progressive sepsis was induced either by peritonitis or by continuous intravenous infusion of Pseudomonas aeruginosa. Animals received standard intensive care including goal-directed hemodynamic management. Analyses were performed on kidneys from sham operated animals, septic pigs without AKI, and pigs with septic AKI. Before, and at 12, 18 and 22 h of progressive sepsis, systemic and renal hemodynamics, cortex microcirculation and plasma IL-6 and TNF-α were measured. At 22 h whole kidney expression of pre-selected genes was analyzed by quantitative Real Time PCR. RESULTS: Animals with septic AKI had systemic hemodynamic phenotype (normo- or hyperdynamic) comparable with non-AKI subjects, but demonstrated higher plasma levels of cytokines, an increase in renal vascular resistance and early fall in cortical microcirculatory blood flow. The genes whose expression discriminated septic AKI from non-AKI included Toll like receptor 4 (up-regulated 2.7-fold, P = 0.04); Cyclooxygenase-2 (up-regulated 14.6-fold, P = 0.01), Angiotensin II Receptor (up-regulated 8.1-fold, P = 0.01), Caspase 3 (up-regulated 5.1-fold, P = 0.02), Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Alpha (down-regulated 2-fold, P = 0.02). CONCLUSIONS: In this preliminary experimental study, kidney gene expression was profoundly different in animals that developed septic AKI as opposed to septic animals that did not. The biological functions of the genes differentially expressed support a role of inflammatory overstimulation coupled with metabolic and apoptotic molecular responses in early septic AKI. Cyclooxygenase-2 and angiotensin type 2 receptor-dependent downstream mechanisms appear fruitful targets for future mechanistic research.
- MeSH
- akutní poškození ledvin genetika mikrobiologie patofyziologie MeSH
- cyklooxygenasa 2 genetika MeSH
- exprese genu * MeSH
- genetická predispozice k nemoci MeSH
- hemodynamika MeSH
- interleukin-6 krev MeSH
- kaspasa 3 genetika MeSH
- modely nemocí na zvířatech MeSH
- PPARGC1A genetika MeSH
- prasata MeSH
- receptory angiotensinu genetika MeSH
- sepse komplikace patofyziologie MeSH
- TNF-alfa krev MeSH
- toll-like receptor 4 genetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Depression of heart-rate variability (HRV) in conditions of systemic inflammation has been shown in both patients and experimental animal models and HRV has been suggested as an early indicator of sepsis. The sensitivity of HRV-derived parameters to the severity of sepsis, however, remains unclear. In this study we modified the clinically relevant porcine model of peritonitis-induced sepsis in order to avoid the development of organ failure and to test the sensitivity of HRV to such non-severe conditions. In 11 anesthetized, mechanically ventilated and instrumented domestic pigs of both sexes, sepsis was induced by fecal peritonitis. The dose of feces was adjusted and antibiotic therapy was administered to avoid multiorgan failure. Experimental subjects were screened for 40 h from the induction of sepsis. In all septic animals, sepsis with hyperdynamic circulation and increased plasma levels of inflammatory mediators developed within 12 h from the induction of peritonitis. The sepsis did not progress to multiorgan failure and there was no spontaneous death during the experiment despite a modest requirement for vasopressor therapy in most animals (9/11). A pronounced reduction of HRV and elevation of heart rate developed quickly (within 5 h, time constant of 1.97 ± 0.80 h for HRV parameter TINN) upon the induction of sepsis and were maintained throughout the experiment. The frequency domain analysis revealed a decrease in the high-frequency component. The reduction of HRV parameters and elevation of heart rate preceded sepsis-associated hemodynamic changes by several hours (time constant of 11.28 ± 2.07 h for systemic vascular resistance decline). A pronounced and fast reduction of HRV occurred in the setting of a moderate experimental porcine sepsis without organ failure. Inhibition of parasympathetic cardiac signaling probably represents the main mechanism of HRV reduction in sepsis. The sensitivity of HRV to systemic inflammation may allow early detection of a moderate sepsis without organ failure. Impact statement A pronounced and fast reduction of heart-rate variability occurred in the setting of a moderate experimental porcine sepsis without organ failure. Dominant reduction of heart-rate variability was found in the high-frequency band indicating inhibition of parasympathetic cardiac signaling as the main mechanism of heart-rate variability reduction. The sensitivity of heart-rate variability to systemic inflammation may contribute to an early detection of moderate sepsis without organ failure.
- MeSH
- modely nemocí na zvířatech MeSH
- peritonitida komplikace MeSH
- sepse patologie MeSH
- srdeční frekvence * MeSH
- Sus scrofa MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Accumulating evidence suggests that heart rate variability (HRV) alterations could serve as an indicator of sepsis progression and outcome, however, the relationships of HRV and major pathophysiological processes of sepsis remain unclear. Therefore, in this experimental study HRV was investigated in a clinically relevant long-term porcine model of severe sepsis/septic shock. HRV was analyzed by several methods and the parameters were correlated with pathophysiological processes of sepsis. In 16 anesthetized, mechanically ventilated, and instrumented domestic pigs of either gender, sepsis was induced by fecal peritonitis. Experimental subjects were screened up to the refractory shock development or death. ECG was continuously recorded throughout the experiment, afterwards RR intervals were detected and HRV parameters computed automatically using custom made measurement and analysis MATLAB routines. In all septic animals, progressive hyperdynamic septic shock developed. The statistical measures of HRV, geometrical measures of HRV and Poincaré plot analysis revealed a pronounced reduction of HRV that developed quickly upon the onset of sepsis and was maintained throughout the experiment. The frequency domain analysis demonstrated a decrease in the high frequency component and increase in the low frequency component together with an increase of the low/high frequency component ratio. The reduction of HRV parameters preceded sepsis-associated hemodynamic changes including heart rate increase or shock progression. In a clinically relevant porcine model of peritonitis-induced progressive septic shock, reduction of HRV parameters heralded sepsis development. HRV reduction was associated with a pronounced parasympathetic inhibition and a shift of sympathovagal balance. Early reduction of HRV may serve as a non-invasive and sensitive marker of systemic inflammatory syndrome, thereby widening the therapeutic window for early interventions.
- Publikační typ
- časopisecké články MeSH
Although the burden of septic acute kidney injury continues to increase, the molecular pathogenesis remains largely obscure. The aim of this exploratory study was a discovery-driven analysis of dynamic kidney tissue protein expression changes applied for the first time in a classic large mammal model of sepsis. To achieve this goal, analyses of protein expression alterations were performed in serial samples of kidney cortical biopsies (before, 12 and 22 h of sepsis) in mechanically ventilated pigs challenged with continuous infusion of pseudomonas aeruginosa and compared with sham-operated control data. Global protein expression was analyzed using two-dimensional gel electrophoresis and mass spectrometry-based proteomics. Normodynamic sepsis was associated with 43% reduction in glomerular filtration. The exposure to surgical stress per se altered the renal protein expression profile, while sepsis induced distinct and highly dynamic proteome evolution shifting the balance toward cellular distress phenotype. We identified 20 proteins whose expression changes discriminated effects of sepsis from those induced by surgery. The data implicate endoplasmic reticulum stress, oxidative stress, mitochondrial energy metabolism, immune/inflammatory signaling, and tubular transport as major activated pathways. Thus, by coupling the power of sequential tissue proteomics with whole-animal physiological studies, our study helped to establish a first global overview of critical renal proteomic events occurring during surgical trauma and early sepsis in a porcine model. The study supports the notion that multiple potentially subtle and even transient changes in several proteins which are members of key functional interrelated systems appear to play a role in septic acute kidney injury.
- MeSH
- 2D gelová elektroforéza MeSH
- akutní poškození ledvin metabolismus MeSH
- biopsie metody MeSH
- hmotnostní spektrometrie MeSH
- ledviny zranění metabolismus MeSH
- modely nemocí na zvířatech MeSH
- prasata MeSH
- proteom metabolismus MeSH
- proteomika metody MeSH
- rány a poranění metabolismus MeSH
- sepse metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
