RESUMO
BACKGROUND: Recent studies identify large quantities of inflammatory cellular debris within Fresh Frozen Plasma (FFP). As FFP is a mainstay of hemorrhagic shock resuscitation, we used a porcine model of hemorrhagic shock and ischemia/reperfusion to investigate the inflammatory potential of plasma-derived cellular debris administered during resuscitation. METHODS: The porcine model of hemorrhagic shock included laparotomy with 35 % hemorrhage (Hem), 45 min of ischemia from supraceliac aortic occlusion with subsequent clamp release (IR), followed by protocolized resuscitation for 6 h. Cellular debris (Debris) was added to the resuscitation phase in three groups. The four groups consisted of Hem + IR (n = 4), Hem + IR + Debris (n = 3), Hem + Debris (n = 3), and IR + Debris (n = 3). A battery of laboratory, physiologic, cytokine, and outcome data were compared between groups. RESULTS: As expected, the Hem + IR group showed severe time dependent decrements in organ function and physiologic parameters. All animals that included both IR and Debris (Hem + IR + Debris or IR + Debris) died prior to the six-hour end point, while all animals in the Hem + IR and Hem + Debris survived. Cytokines measured at 30-60 min after initiation of resuscitation revealed significant differences in IL-18 and IL-1ß between all groups. CONCLUSIONS: Ischemia and reperfusion appear to prime the immune system to the deleterious effects of plasma-derived cellular debris. In the presence of ischemia and reperfusion, this model showed the equivalency of 100 % lethality when resuscitation included quantities of cellular debris at levels routinely administered to trauma patients during transfusion of FFP. A deeper understanding of the immunobiology of FFP-derived cellular debris is critical to optimize resuscitation for hemorrhagic shock.
Assuntos
Choque Hemorrágico , Humanos , Suínos , Animais , Transfusão de Sangue , Citocinas , Ressuscitação , IsquemiaRESUMO
Background: Sepsis is a life-threatening condition that results from a dysregulated host response to infection, leading to organ dysfunction. Despite the prevalence and associated socioeconomic costs, treatment of sepsis remains limited to antibiotics and supportive care, and a majority of intensive care unit (ICU) survivors develop long-term cognitive complications post-discharge. The present study identifies a novel regulatory relationship between amyloid-ß (Aß) and the inflammasome-caspase-1 axis as key innate immune mediators that define sepsis outcomes. Methods: Medical ICU patients and healthy individuals were consented for blood and clinical data collection. Plasma cytokine, caspase-1 and Aß levels were measured. Data were compared against indices of multiorgan injury and other clinical parameters. Additionally, recombinant proteins were tested in vitro to examine the effect of caspase-1 on a functional hallmark of Aß, namely aggregation. Results: Plasma caspase-1 levels displayed the best predictive value in discriminating ICU patients with sepsis from non-infected ICU patients (area under the receiver operating characteristic curve=0.7080). Plasma caspase-1 and the Aß isoform Aßx-40 showed a significant positive correlation and Aßx-40 associated with organ injury. Additionally, Aß plasma levels continued to rise from time of ICU admission to 7â days post-admission. In silico, Aß harbours a predicted caspase-1 cleavage site, and in vitro studies demonstrated that caspase-1 cleaved Aß to inhibit its auto-aggregation, suggesting a novel regulatory relationship. Conclusions: Aßx-40 and caspase-1 are potentially useful early indicators of sepsis and its attendant organ injury. Additionally, Aßx-40 has emerged as a potential culprit in the ensuing development of post-ICU syndrome.
RESUMO
BACKGROUND: Bacterial pneumonia and sepsis are both common causes of end-organ dysfunction, especially in immunocompromised and critically ill patients. Pre-clinical data demonstrate that bacterial pneumonia and sepsis elicit the production of cytotoxic tau and amyloids from pulmonary endothelial cells, which cause lung and brain injury in naïve animal subjects, independent of the primary infection. The contribution of infection-elicited cytotoxic tau and amyloids to end-organ dysfunction has not been examined in the clinical setting. We hypothesized that cytotoxic tau and amyloids are present in the bronchoalveolar lavage fluid of critically ill patients with bacterial pneumonia and that these tau/amyloids are associated with end-organ dysfunction. METHODS: Bacterial culture-positive and culture-negative mechanically ventilated patients were recruited into a prospective, exploratory observational study. Levels of tau and Aß42 in, and cytotoxicity of, the bronchoalveolar lavage fluid were measured. Cytotoxic tau and amyloid concentrations were examined in comparison with patient clinical characteristics, including measures of end-organ dysfunction. RESULTS: Tau and Aß42 were increased in culture-positive patients (n = 49) compared to culture-negative patients (n = 50), independent of the causative bacterial organism. The mean age of patients was 52.1 ± 16.72 years old in the culture-positive group and 52.78 ± 18.18 years old in the culture-negative group. Males comprised 65.3% of the culture-positive group and 56% of the culture-negative group. Caucasian culture-positive patients had increased tau, boiled tau, and Aß42 compared to both Caucasian and minority culture-negative patients. The increase in cytotoxins was most evident in males of all ages, and their presence was associated with end-organ dysfunction. CONCLUSIONS: Bacterial infection promotes the generation of cytotoxic tau and Aß42 within the lung, and these cytotoxins contribute to end-organ dysfunction among critically ill patients. This work illuminates an unappreciated mechanism of injury in critical illness.
Assuntos
Pneumonia Bacteriana , Sepse , Masculino , Animais , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Feminino , Estudos Prospectivos , Estado Terminal , Células Endoteliais , Insuficiência de Múltiplos Órgãos , Irrigação Terapêutica , Líquido da Lavagem Broncoalveolar/microbiologia , Pneumonia Bacteriana/microbiologia , Amiloide , Citotoxinas , Peptídeos beta-Amiloides , Proteínas tauRESUMO
BACKGROUND: Infection is a common cause of mortality within intensive care units (ICUs). Antibiotic resistance patterns and culture data are used to create antibiograms. Knowledge of antibiograms facilitates guiding empiric therapies and reduces mortality. Most major hospitals utilize data collection to create hospital-wide antibiograms. Previous studies have shown significant differences in susceptibility patterns between hospital wards and ICUs. We hypothesize that institutional or combined ICU antibiograms are inadequate to account for differences in susceptibility for patients in individual ICUs. METHODS: Culture and susceptibility data were reviewed over a 1-year period for 13 bacteria in the following ICUs: Surgical/Trauma, Medical, Neuroscience, Burn, and Emergency department. Antibiotic management decisions are made by individual teams. RESULTS: Nine species had sufficient data for inclusion into an All-ICU antibiogram. E coli and S aureus were the most common isolates. Seven species had significant differences in susceptibility patterns between ICUs. E cloacae showed higher rates of resistance to multiple antibiotics in the STICU than other ICUs. P aeruginosa susceptibility rates in the NSICU and BICU were 88% and 92%, respectively, compared to 60% and 55% in the STICU and MICU. Cephalosporins and Aztreonam had reduced efficacy against E coli in the NSICU, however remain effective in other ICUs. CONCLUSIONS: The results of this study show that different ICUs do have variability in antibiotic susceptibility patterns within a single hospital. While this only represents a single institution, it shows that the use of hospital-wide antibiograms is inadequate for creating empiric antibiotic protocols within individual ICUs.