Reprogramação metabólica mitocondrial em linfócitos como um biomarcador de desfechos clínicos em pacientes com choque séptico

A sepse é definida como uma disfunção orgânica causada por uma resposta desregulada do hospedeiro a uma infecção. A sua forma mais grave, o choque séptico, é caracterizado como sendo o subgrupo da sepse no qual as anormalidades circulatórias e metabólicas associadas a infecção são profundas o suficiente para aumentar substancialmente a mortalidade destes pacientes. Isso acontece devido ao desenvolvimento de falências multiorgânicas, as quais, atualmente, são reconhecidas como sendo em decorrência, principalmente, de uma disfunção metabólica; cenário no qual se destaca a ineficiência na produção de ATP via fosforilação oxidativa. Este estudo, realizado com pacientes com choque séptico, propõe mudanças no metabolismo mitocondrial de linfócitos como biomarcador clínico. Considerando este contexto, investigamos: i. uma coorte prospectiva avaliando o papel da disfunção mitocondrial em linfócitos isolados de pacientes com choque séptico, sua evolução temporal e a sua associação com o prognóstico destes pacientes; ii. um estudo avaliando a associação entre a bioenergética mitocondrial, as variáveis perfusionais e os níveis de lactato numa população de choque séptico, na fase pós-ressuscitação volêmica; iii. um estudo analisando as diferentes assinaturas metabólicas da mitocôndria e sua possível modulação por antimicrobianos usados na rotina da UTI; iv. a associação entre o metabolismo mitocondrial dos linfócitos e a atividade de interleucinas pró- e anti-inflamatórias no choque séptico; e finalmente, v. realizamos uma revisão sobre o estado da arte da disfunção mitocondrial na sepse e sua importância na fisiopatologia, as possíveis técnicas para avaliação do metabolismo mitocondrial no ambiente clinico, e o seu valor prognóstico.Sepsis is defined as an organ dysfunction caused by a dysregulated host response to an infection. Its most severe form, septic shock, is characterized as the sepsis subgroup in which the circulatory and metabolic abnormalities associated with infection are profound enough to substantially increase the mortality of these patients. This evolves through the development of multiorgan failures, which are currently recognized as being mainly due to metabolic dysfunction; scenario in which the inefficiency in the production of ATP via oxidative phosphorylation stands out. This work carried out with patients with septic shock proposes that changes in the mitochondrial metabolism of lymphocytes may serve as a clinical biomarker. Taking into account this context, we performed: i. a prospective cohort evaluating the role of mitochondrial dysfunction in lymphocytes isolated from patients with septic shock, its temporal evolution, and its association with the prognosis of these patients; ii. a study evaluating the association between mitochondrial activity, perfusion variables, and lactate levels in a population with septic shock, in the post-volemic resuscitation phase; iii. a study analyzing the different metabolic signatures of mitochondria and their possible modulation by antimicrobials routinely used in the ICU; iv. a study on the association between the mitochondrial metabolism of lymphocytes and the activity of pro and anti-inflammatory interleukins in septic shock; and finally, v. we performed a review of the state of the art of mitochondrial dysfunction in sepsis and its importance in pathophysiology, possible methods to assess mitochondrial metabolism in the clinical settings, and its prognostic value

Sepsis-induced mitochondrial dysfunction : a narrative review

Sepsis represents a deranged and exaggerated systemic inflammatory response to infection and is associated with vascular and metabolic abnormalities that trigger systemic organic dysfunction. Mitochondrial function has been shown to be severely impaired during the early phase of critical illness, with a reduction in biogenesis, increased generation of reactive oxygen species and a decrease in adenosine triphosphate synthesis of up to 50%. Mitochondrial dysfunction can be assessed using mitochondrial DNA concentration and respirometry assays, particularly in peripheral mononuclear cells. Isolation of monocytes and lymphocytes seems to be the most promising strategy for measuring mitochondrial activity in clinical settings because of the ease of collection, sample processing, and clinical relevance of the association between metabolic alterations and deficient immune responses in mononuclear cells. Studies have reported alterations in these variables in patients with sepsis compared with healthy controls and non-septic patients. However, few studies have explored the association between mitochondrial dysfunction in immune mononuclear cells and unfavorable clinical outcomes. An improvement in mitochondrial parameters in sepsis could theoretically serve as a biomarker of clinical recovery and response to oxygen and vasopressor therapies as well as reveal unexplored pathophysiological mechanistic targets. These features highlight the need for further studies on mitochondrial metabolism in immune cells as a feasible tool to evaluate patients in intensive care settings. The evaluation of mitochondrial metabolism is a promising tool for the evaluation and management of critically ill patients, especially those with sepsis. In this article, we explore the pathophysiological aspects, main methods of measurement, and the main studies in this field

Corticosteroids for severe influenza pneumonia : a critical appraisal

Influenza pneumonia is associated with high number of severe cases requiring hospital and intensive care unit (ICU) admissions with high mortality. Systemic steroids are proposed as a valid therapeutic option even though its effects are still controversial. Heterogeneity of published data regarding study design, population demographics, severity of illness, dosing, type and timing of corticosteroids administered constitute an important limitation for drawing robust conclusions. However, it is reasonable to admit that, as it was not found any advantage of corticosteroid therapy in so diverse conditions, such beneficial effects do not exist at all. Its administration is likely to increase overall mortality and such trend is consistent regardless of the quality as well as the sample size of studies. Moreover it was shown that corticosteroids might be associated with higher incidence of hospital-acquired pneumonia and longer duration of mechanical ventilation and ICU stay. Finally, it is reasonable to conclude that corticosteroids failed to demonstrate any beneficial effects in the treatment of patients with severe influenza infection. Thus its current use in severe influenza pneumonia should be restricted to very selected cases and in the setting of clinical trials

Mortality of septic shock patients is associated with impaired mitochondrial oxidative coupling efficiency in lymphocytes : a prospective cohort study

Background: Septic shock is a life-threatening condition that challenges immune cells to reprogram their mitochondrial metabolism towards to increase ATP synthesis for building an appropriate immunity. This could print metabolic signatures in mitochondria whose association with disease progression and clinical outcomes remain elusive. Method: This is a single-center prospective cohort study performed in the ICU of one tertiary referral hospital in Brazil. Between November 2017 and July 2018, 90 consecutive patients, aged 18 years or older, admitted to the ICU with septic shock were enrolled. Seventy-five patients had Simplified Acute Physiology Score (SAPS 3) assessed at admission, and Sequential Organ Failure Assessment (SOFA) assessed on the first (D1) and third (D3) days after admission. Mitochondrial respiration linked to complexes I, II, V, and biochemical coupling efficiency (BCE) were assessed at D1 and D3 and Δ (D3–D1) in isolated lymphocytes. Clinical and mitochondrial endpoints were used to dichotomize the survival and death outcomes. Our primary outcome was 6-month mortality, and secondary outcomes were ICU and hospital ward mortality. Results: The mean SAPS 3 and SOFA scores at septic shock diagnosis were 75.8 (± 12.9) and 8 (± 3) points, respectively. The cumulative ICU, hospital ward, and 6-month mortality were 32 (45%), 43 (57%), and 50 (66%), respectively. At the ICU, non-surviving patients presented elevated arterial lactate (2.8 mmol/L, IQR, 2–4), C-reactive protein (220 mg/L, IQR, 119–284), and capillary refill time (5.5 s, IQR, 3–8). Respiratory rates linked to CII at D1 and D3, and ΔCII were decreased in non-surviving patients. Also, the BCE at D1 and D3 and the ΔBCE discriminated patients who would evolve to death in the ICU, hospital ward, and 6 months after admission. After adjusting for possible confounders, the ΔBCE value but not SOFA scores was independently associated with 6-month mortality (RR 0.38, CI 95% 0.18–0.78; P = 0.009). At a cut-off of − 0.002, ΔBCE displayed 100% sensitivity and 73% specificity for predicting 6-month mortality. Conclusions: The ΔBCE signature in lymphocytes provided an earlier recognition of septic shock patients in the ICU at risk of long-term deterioration of health status

Pressure-support ventilation or T-piece spontaneous breathing trials for patients with chronic obstructive pulmonary disease : a randomized controlled trial

Background Little is known about the best strategy for weaning patients with chronic obstructive pulmonary disease (COPD) from mechanical ventilation. Spontaneous breathing trials (SBT) using a T-piece or pressure-support ventilation (PSV) have a central role in this process. Our aim was to compare T-piece and PSV SBTs according to the duration of mechanical ventilation (MV) in patients with COPD. Methods Patients with COPD who had at least 48 hours of invasive MV support were randomized to 30 minutes of T-piece or PSV at 10 cm H2O after being considered able to undergo a SBT. All patients were preemptively connected to non-invasive ventilation after extubation. Tracheostomized patients were excluded. The primary outcome was total invasive MV duration. Time to liberation from MV was assessed as secondary outcome. Results Between 2012 and 2016, 190 patients were randomized to T-piece (99) or PSV (91) groups. Extubation at first SBT was achieved in 78% of patients. The mean total MV duration was 10.82 ± 9.1 days for the T-piece group and 7.31 ± 4.9 days for the PSV group (p < 0.001); however, the pre-SBT duration also differed (7.35 ± 3.9 and 5.84 ± 3.3, respectively; p = 0.002). The time to liberation was 8.36 ± 11.04 days for the T-piece group and 4.06 ± 4.94 for the PSV group (univariate mean ratio = 2.06 [1.29±3.27], p = 0.003) for the subgroup of patients with difficult or prolonged weaning. The study group was independently associated with the time to liberation in this subgroup.Conclusions The SBT technique did not influence MV duration for patients with COPD. For the difficult/ prolonged weaning subgroup, the T-piece may be associated with a longer time to liberation, although this should be clarified by further studies

Relato de 21 casos de candidemia em pacientes não-internados : candidemia adquirida na comunidade?

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Candidemia nosocomial numa população pediátrica : estudo comparando fatores de risco e desfechos entre população pediátrica e adulta

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Candidemia em pacientes usando antifúngicos (Breakthrough) : comparação com casos não-Breakthrough

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Relato de 21 casos de candidemia em pacientes não-internados : candidemia adquirida na comunidade?

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