Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding.

Sepsis represents the host's systemic inflammatory response to a severe infection. It causes substantial human morbidity resulting in hundreds of thousands of deaths each year. Despite decades of intense research, the basic mechanisms still remain elusive. In either experimental animal models of sepsis or human patients, there are substantial physiological changes, many of which may result in subsequent organ injury. Variations in age, gender, and medical comorbidities including diabetes and renal failure create additional complexity that influence the outcomes in septic patients. Specific system-based alterations, such as the coagulopathy observed in sepsis, offer both potential insight and possible therapeutic targets. Intracellular stress induces changes in the endoplasmic reticulum yielding misfolded proteins that contribute to the underlying pathophysiological changes. With these multiple changes it is difficult to precisely classify an individual's response in sepsis as proinflammatory or immunosuppressed. This heterogeneity also may explain why most therapeutic interventions have not improved survival. Given the complexity of sepsis, biomarkers and mathematical models offer potential guidance once they have been carefully validated. This review discusses each of these important factors to provide a framework for understanding the complex and current challenges of managing the septic patient. Clinical trial failures and the therapeutic interventions that have proven successful are also discussed.

Cecal ligation and puncture-induced murine sepsis does not cause lung injury.

OBJECTIVE: The cause of death in murine models of sepsis remains unclear. The primary purpose of this study was to determine if significant lung injury develops in mice predicted to die after cecal ligation and puncture-induced sepsis compared with those predicted to live. DESIGN: Prospective, laboratory controlled experiments. SETTING: University research laboratory. SUBJECTS: Adult, female, outbred Institute of Cancer Research mice. INTERVENTIONS: Mice underwent cecal ligation and puncture to induce sepsis. Two groups of mice were euthanized at 24 and 48 hrs postcecal ligation and puncture and samples were collected. These mice were further stratified into groups predicted to die (Die-P) and predicted to live (Live-P) based on plasma interleukin-6 levels obtained 24 hrs postcecal ligation and puncture. Multiple measures of lung inflammation and lung injury were quantified in these two groups. Results from a group of mice receiving intratracheal normal saline without surgical intervention were also included as a negative control. As a positive control, bacterial pneumonia was induced with Pseudomonas aeruginosa to cause definitive lung injury. Separate mice were followed for survival until Day 28 postcecal ligation and puncture. These mice were used to verify the interleukin-6 cutoffs for survival prediction. MEASUREMENTS AND MAIN RESULTS: After sepsis, both the Die-P and Live-P mice had significantly suppressed measures of respiratory physiology but maintained normal levels of arterial oxygen saturation. Bronchoalveolar lavage levels of pro- and anti-inflammatory cytokines were not elevated in the Die-P mice compared with the Live-P. In addition, there was no increase in the recruitment of neutrophils to the lung, pulmonary vascular permeability, or histological evidence of damage. In contrast, all of these pulmonary injury and inflammatory parameters were increased in mice with Pseudomonas pneumonia. CONCLUSIONS: These data demonstrate that mice predicted to die during sepsis have no significant lung injury. In murine intra-abdominal sepsis, pulmonary injury cannot be considered the etiology of death in the acute phase.

Shorter Duration of Post-Operative Antibiotics for Cecal Ligation and Puncture Does Not Increase Inflammation or Mortality.

Antimicrobial therapy for sepsis has beneficial effects, but prolonged use fosters emergence of resistant microorganisms, increases cost, and secondary infections. We tested whether 3 days versus 5 days of antibiotics in the murine model of cecal ligation and puncture (CLP) negatively influences outcomes. Following CLP mice were randomized to receive the antibiotic imipenem-cilastatin (25mg/kg) in dextrose 5% in Lactated Ringer's solution every 12 hours for either three or five days. Serial monitoring over 28 days included body weight, temperature, pulse oximetry, and facial vein sampling for hematological analysis and glucose. A separate group of mice were euthanized on post-CLP day 5 to measure cytokines and peritoneal bacterial counts. The first study examined no antimicrobial therapy and demonstrated that antibiotics significantly improved survival compared to fluids only (p = 0.004). We next tested imipenem-cilastatin therapy for 3 days versus 5 days. Body weight, temperature, glucose, and pulse oximetry measurements remained generally consistent between both groups as did the hematological profile. Pro-inflammatory plasma cytokines were comparable between both groups for IL-6, IL-1ß, MIP-2 and anti-inflammatory cytokines IL-10, and TNF SRI. At 5 days post-CLP, i.e. 2 days after the termination of antibiotics in the 3 day group, there were no differences in the number of peritoneal bacteria. Importantly, shortening the course of antibiotics by 40% (from 5 days to 3 days) did not decrease survival. Our results indicate that reducing the duration of broad-spectrum antibiotics in murine sepsis did not increase inflammation or mortality.

Does the Fibula Need to be Fixed in Complex Pilon Fractures?

OBJECTIVES: To review a series of patients with complex plafond injuries with a metadiaphyseal dissociation who did not have the fibula fixed and compare with patients who had their fibula fixed using patients without a fibula fracture as a control group. DESIGN: Retrospective case-control study. SETTING: Level 1 Trauma center at a university hospital. PATIENTS/PARTICIPANTS: Skeletally mature patients with a complete metadiaphyseal plafond fracture, and adequate presentation, postreduction, and healed radiographs to measure varus and valgus alignment. INTERVENTION: Surgical treatment [external fixator or open reduction internal fixation (ORIF)] of high energy pilon fractures. MAIN OUTCOME MEASUREMENTS: Metaphyseal alignment at the time of presentation, after fixation, and at union, surgical procedures performed, and complications. METHODS: From 364 patients with plafond fractures, 111 had high energy injuries with metadiaphyseal dissociation and form the basis of the study. Radiographs and charts were reviewed for fracture characteristics, metaphyseal alignment at the time of presentation, after fixation, and at union, surgical procedures performed, and complications. RESULTS: Of the 111 study patients, 93 patients were treated definitively with ORIF of the tibia and 18 patients were treated definitively in an external fixator. Within the 93 patients treated definitively with ORIF of the tibia, we identified 3 groups of patients those with a fibula fracture that was fixed (26 patients), those with a fibula fracture that was not fixed (37 patients), and those without a fibula fracture acting as the control group (30 patients). Between the 2 groups having a fibula fracture treated with ORIF of the tibia, there was no difference in fibula fracture pattern or location. For the 26 patients who had fibular fixation, it was performed in 11 patients at an average of 17 days for inability to hold length and alignment and in 15 patients to augment fixation in poor bone stock or to aid in the reduction. Patients with initial valgus deformity were more likely to have their fibula fixed. There was no difference in the postoperative or final alignment between the patients with fibula fractures (with or without fixation) and those without fibula fractures (P = 0.92). When comparing the 3 groups, the only statistical finding between the 2 groups was that those with fibula fixation required plate removal (P < 0.0001). CONCLUSIONS: Fibular fixation is not a necessary step in the reconstruction of pilon fractures, although it may be helpful in specific cases to aid in tibial plafond reduction or augment external fixation. We found a higher rate of plate removal if the fibula was fixed. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Early murine polymicrobial sepsis predominantly causes renal injury.

Multiple organ failure in sepsis substantially increases mortality. This study examined if there was greater hepatic, pancreatic, splenic, or renal injury in mice that would die during sepsis induced by cecal ligation and puncture (CLP) compared with that of those that would survive. Mice were stratified into groups predicted to die (Die-P) or predicted to live (Live-P) in the first 5 days after CLP based on plasma interleukin 6 levels. Groups were sacrificed to harvest organs for histology. Separate animals were followed for survival with daily blood sampling to examine renal function. No significant histological evidence of organ injury was observed in either the Live-P or Die-P mice. Minimal hepatic injury occurred as plasma aspartate transaminase demonstrated less than a 2-fold increase over normal in both groups. In addition, pancreatic injury was minimal as there was also less than a 2-fold increase in plasma amylase levels. In contrast, blood urea nitrogen levels were nearly five times higher within 24 h in Die-P mice compared with those of mice predicted to live. Mice with blood urea nitrogen levels higher than 44 mg/dL had a 17.6 higher relative risk of dying (95% confidence interval, 4.5-69.4). Cystatin C, a more specific kidney function biomarker, was also elevated at 24 h after CLP. When the cystatin C levels were analyzed relative to the hours before death, rather than hours after CLP, they were also significantly increased in mice Dead by day 5 compared with those Alive after day 5. We conclude that limited liver, pancreas, and spleen injury develops during murine CLP-induced sepsis while significant kidney injury is present. The renal injury becomes worse closer to death.