Adherence to Pediatric Sepsis Treatment Recommendations at Emergency Departments: A Multicenter Study in Latin America.

OBJECTIVE: Sepsis is one of the most urgent health care issues worldwide. Guidelines for early identification and treatment are essential to decrease sepsis-related mortality. Our aim was to collect data on the epidemiology of pediatric septic shock (PSS) from the emergency department (PED) and to assess adherence to recommendations for its management in the first hour. METHODS: A multicenter, prospective, cross-sectional study was conducted evaluating children with PSS seen at the PED of 10 tertiary-care centers in Latin America. Adherence to guidelines was evaluated. RESULTS: We included 219 patients (median age, 3.7 years); 43% had comorbidities, 31% risk factors for developing sepsis, 74% clinical signs of "cold shock," and 13% of "warm shock," 22% had hypotension on admission. Consciousness was impaired in 55%. A peripheral line was used as initial access in 78% (median placement time, 10 minutes). Fluid and antibiotics infusion was achieved within a median time of 30 minutes (interquartile range [IQR], 20-60 minutes) and 40 minutes (IQR, 20-60 minutes), respectively; 40% responded inadequately to fluids requiring vasoactive drugs (median time at initiation, 60 minutes; IQR, 30-135 minutes). Delay to vasoactive drug infusion was significantly longer when a central line was placed compared to a peripheral line (median time, 133 minutes [59-278 minutes] vs 42 minutes [30-70 minutes], respectively [ P < 0.001]). Adherence to all treatment goals was achieved in 13%. Mortality was 10%. An association between mortality and hypotension on admission was found (26.1% with hypotension vs 4.9% without; P < 0.001). CONCLUSIONS: We found poor adherence to the international recommendations for the treatment of PSS in the first hour at the PED in third-level hospitals in Latin America.

OBJECTIVE: Sepsis is one of the most urgent health care issues worldwide. Guidelines for early identification and treatment are essential to decrease sepsis-related mortality. Our aim was to collect data on the epidemiology of pediatric septic shock (PSS) from the emergency department (PED) and to assess adherence to recommendations for its management in the first hour. METHODS: A multicenter, prospective, cross-sectional study was conducted evaluating children with PSS seen at the PED of 10 tertiary-care centers in Latin America. Adherence to guidelines was evaluated. RESULTS: We included 219 patients (median age, 3.7 years); 43% had comorbidities, 31% risk factors for developing sepsis, 74% clinical signs of "cold shock," and 13% of "warm shock," 22% had hypotension on admission. Consciousness was impaired in 55%. A peripheral line was used as initial access in 78% (median placement time, 10 minutes). Fluid and antibiotics infusion was achieved within a median time of 30 minutes (interquartile range [IQR], 20­60 minutes) and 40 minutes (IQR, 20­60 minutes), respectively; 40% responded inadequately to fluids requiring vasoactive drugs (median time at initiation, 60 minutes; IQR, 30­135 minutes). Delay to vasoactive drug infusion was significantly longer when a central line was placed compared to a peripheral line (median time, 133 minutes [59­278 minutes] vs 42 minutes [30­70 minutes], respectively [ P < 0.001]). Adherence to all treatment goals was achieved in 13%. Mortality was 10%. An association between mortality and hypotension on admission was found (26.1% with hypotension vs 4.9% without; P < 0.001). CONCLUSIONS: We found poor adherence to the international recommendations for the treatment of PSS in the first hour at the PED in third-level hospitals in Latin America.

3-Bromopyruvate: A new strategy for inhibition of glycolytic enzymes in Leishmania amazonensis.

The compound 3-bromopyruvate (3-BrPA) is well-known and studies from several researchers have demonstrated its involvement in tumorigenesis. It is an analogue of pyruvic acid that inhibits ATP synthesis by inhibiting enzymes from the glycolytic pathway and oxidative phosphorylation. In this work, we investigated the effect of 3-BrPA on energy metabolism of L. amazonensis. In order to verify the effect of 3-BrPA on L. amazonensis glycolysis, we measured the activity level of three glycolytic enzymes located at different points of the pathway: (i) glucose kinases, step 1, (ii) glyceraldehyde 3-phosphate dehydrogenase (GAPDH), step 6, and (iii) enolase, step 9. 3-BrPA, in a dose-dependent manner, significantly reduced the activity levels of all the enzymes. In addition, 3-BrPA treatment led to a reduction in the levels of phosphofruto-1-kinase (PFK) protein, suggesting that the mode of action of 3-BrPA involves the downregulation of some glycolytic enzymes. Measurement of ATP levels in promastigotes of L. amazonensis showed a significant reduction in ATP generation. The O2 consumption was also significantly inhibited in promastigotes, confirming the energy depletion effect of 3-BrPA. When 3-BrPA was added to the cells at the beginning of growth cycle, it significantly inhibited L. amazonensis proliferation in a dose-dependent manner. Furthermore, the ability to infect macrophages was reduced by approximately 50% when promastigotes were treated with 3-BrPA. Taken together, these studies corroborate with previous reports which suggest 3-BrPA as a potential drug against pathogenic microorganisms that are reliant on glucose catabolism for ATP supply.

Effect of the antitumoral alkylating agent 3-bromopyruvate on mitochondrial respiration: role of mitochondrially bound hexokinase.

The alkylating agent 3-Bromopyruvate (3-BrPA) has been used as an anti-tumoral drug due to its anti-proliferative property in hepatomas cells. This propriety is believed to disturb glycolysis and respiration, which leads to a decreased rate of ATP synthesis. In this study, we evaluated the effects of the alkylating agent 3-BrPA on the respiratory states and the metabolic steps of the mitochondria of mice liver, brain and in human hepatocarcinoma cell line HepG2. The mitochondrial membrane potential (ΔΨ(m)), O(2) consumption and dehydrogenase activities were rapidly dissipated/or inhibited by 3-BrPA in respiration medium containing ADP and succinate as respiratory substrate. 3-BrPA inhibition was reverted by reduced glutathione (GSH). Respiration induced by yeast soluble hexokinase (HK) was rapidly inhibited by 3-BrPA. Similar results were observed using mice brain mitochondria that present HK naturally bound to the outer mitochondrial membrane. When the adenine nucleotide transporter (ANT) was blocked by the carboxyatractiloside, the 3-BrPA effect was significantly delayed. In permeabilized human hepatoma HepG2 cells that present HK type II bound to mitochondria (mt-HK II), the inhibiting effect occurred faster when the endogenous HK activity was activated by 2-deoxyglucose (2-DOG). Inhibition of mt-HK II by glucose-6-phosphate retards the mitochondria to react with 3-BrPA. The HK activities recovered in HepG2 cells treated or not with 3-BrPA were practically the same. These results suggest that mitochondrially bound HK supporting the ADP/ATP exchange activity levels facilitates the 3-BrPA inhibition reaction in tumors mitochondria by a proton motive force-dependent dynamic equilibrium between sensitive and less sensitive SDH in the electron transport system.