Objective To provide an appraisal of the evolving paradigms in the pathophysiology of sepsis, propose the evolution of a new phenotype of critically ill patients, its potential underlying mechanism, and its implications for the future of sepsis management and research. Design Literature search using PubMed, MEDLINE, EMBASE, and Google Scholar. Results Sepsis remains one of the most debilitating and expensive illnesses, and its incidence is not declining. What is changing is our definition(s), its clinical course, and how we manage the septic patient. Once thought to be predominantly a syndrome of over exuberant inflammation, sepsis is now recognized as a syndrome of aberrant host protective immunity. Earlier recognition and compliance with treatment bundles has fortunately led to a decline in multiple organ failure and in-hospital mortality. Unfortunately, more and more sepsis patients, especially the aged, are suffering chronic critical illness (CCI), rarely fully recover and often experience an indolent death. Patients with CCI often exhibit ‘a persistent inflammatory-immunosuppressive and catabolic syndrome’ or PICS, and it is proposed here that PICS contributes to many of these adverse clinical outcomes. The underlying cause of PICS is currently unknown, but there is increasing evidence that altered myelopoiesis, reduced effector T-cell function and expansion of immature myeloid-derived suppressor cells are all contributory. Conclusion Although newer therapeutic interventions are targeting the inflammatory, the immunosuppressive, and the protein catabolic responses individually, successful treatment of the septic patient with CCI and PICS may require a more complementary approach.

Prognostic, level II.

Over the past four decades the epidemiology of multiple organ failure (MOF) has evolved as a result of advances in care. A series of paradigms have been described to explain the pathophysiology of the new emerging predominant phenotypes. With the most recent improvements in the delivery of critical care, patients are less-frequently expiring early in their clinical course and in-hospital MOF-related mortality is on the decline. Unfortunately, this has resulted in a dramatic increase in the number of chronic critically ill patients (CCI) who linger in the intensive care unit (ICU), have high resource utilization, are discharged to non-home locations, experience sepsis recidivism requiring readmission, have persistent cognitive and functional impairments, and poor long-term survival. Within this population, we have proposed that a substantial subset of these patients suffer from a new phenotype termed Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) which underlies these poor outcomes. While the mechanism(s) of PICS are under investigation, there is evidence that myelodysplasia with expansion of myeloid derived suppressor cells, innate and adaptive immune suppression and protein catabolism with malnutrition are major contributors. Optimal care of these patients will require a novel multimodality intervention using pharmacotherapy, physiotherapy and nutritional support.

Septic patients demonstrate clinical and biological evidence to suggest they are immunosuppressed at the time of sepsis diagnosis. Those who develop CCI have a greater incidence of secondary infections and persistently aberrant markers of impaired host immunity, although measurements at the time of sepsis onset did not distinguish between subjects with RAP and CCI.

Sepsis and trauma are both leading causes of death in the United States and represent major public health challenges. Murine models have largely been used in sepsis and trauma research to better understand the pathophysiological changes that occur after an insult and to develop potential life-saving therapeutic agents. Mice are favorable subjects for this type of research given the variety of readily available strains including inbred, outbred, and transgenic strains. In addition, they are relatively easy to maintain and have a high fecundity. However, pharmacological therapies demonstrating promise in preclinical mouse models of sepsis and trauma often fail to demonstrate similar efficacy in human clinical trials, prompting considerable criticism surrounding the capacity of murine models to recapitulate complex human diseases like sepsis and traumatic injury. Fundamental differences between the two species include, but are not limited to, the divergence of the transcriptomic response, the mismatch of temporal response patterns, differences in both innate and adaptive immunity, and heterogeneity within the human population in comparison to the homogeneity of highly inbred mouse strains. Given the ongoing controversy, this narrative review aims to not only highlight the historical importance of the mouse as an animal research model but also highlight the current benefits and limitations of the model as it pertains to sepsis and trauma. Lastly, this review will propose future directions that may promote further use of the model.

Objective To determine the incidence and risk factors of chronic critical illness (CCI) after severe blunt trauma. Design Prospective observational cohort study (NCT01810328). Setting Two Level-1 trauma centers in the United States. Patients 135 adult blunt trauma patients with hemorrhagic shock who survived beyond 48-hours after injury. Interventions None Measurements and Main Results CCI was defined as an ICU stay lasting ≥14-days with evidence of persistent organ dysfunction. Three subjects (2%) died within the first seven-days, 107 (79%) exhibited rapid recovery and 25 (19%) progressed to CCI. Patients who developed CCI were older (55 vs 44-years-old; p=0.01), had more severe shock (base deficit −9.2 vs −5.5, p=0.005), greater organ failure severity (Denver MOF score, 3.5±2.4 vs 0.8±1.1, p<0.0001) and developed more infectious complications (84% vs 35%, p<0.0001). CCI patients were more likely to be discharged to a long-term care setting (56% vs 34%, p=0.008) than to a rehabilitation facility/home. At four-months, CCI patients had higher mortality (16.0% vs 1.9%; p<0.05), with survivors scoring lower in general health measures (p<0.005). Multivariate analysis revealed age ≥55-years, systolic hypotension ≤70-mmHg, transfusion ≥5-units packed red blood cells within 24-hours, and Denver MOF score at 72-hours as independent predictors of CCI (AUC 0.87, 95% CI [0.75, 0.95]). Conclusions While early mortality is low after severe trauma, CCI is a common trajectory in survivors and is associated with poor long-term outcomes. Advancing age, shock severity and persistent organ dysfunction are predictive of CCI. Early identification may facilitate targeted interventions to change the trajectory of this morbid phenotype.

Early host recognition of microbial invasion or damaged host tissues provides an effective warning system by which protective immune and inflammatory processes are initiated. Host tissues responsible for continuous sampling of their local environment employ cell surface and cytosolic pattern recognition receptors (PRRs) that provide redundant and overlapping identification of both microbial and host alarmins. Microbial products containing pathogen-associated molecular patterns (PAMPs), as well as damage-associated molecular patterns (DAMPs) serve as principle ligands for recognition by these PRRs. It is this interaction which plays both an essential survival role in response to infection and injury, as well as the pathologic role in tissue and organ injury associated with severe sepsis and trauma. Elucidating the interaction between ligands and their respective PRRs can provide both a better understanding of the host response, as well as a rational basis for therapeutic intervention.

IntroductionSepsis is a common, costly and morbid cause of critical illness in trauma and surgical patients. Ongoing advances in sepsis resuscitation and critical care support strategies have led to improved in-hospital mortality. However, these patients now survive to enter state of chronic critical illness (CCI), persistent low-grade organ dysfunction and poor long-term outcomes driven by the persistent inflammation, immunosuppression and catabolism syndrome (PICS). The Sepsis and Critical Illness Research Center (SCIRC) was created to provide a platform by which the prevalence and pathogenesis of CCI and PICS may be understood at a mechanistic level across multiple medical disciplines, leading to the development of novel management strategies and targeted therapies.MethodsHere, we describe the design, study cohort and standard operating procedures used in the prospective study of human sepsis at a level 1 trauma centre and tertiary care hospital providing care for over 2600 critically ill patients annually. These procedures include implementation of an automated sepsis surveillance initiative, augmentation of clinical decisions with a computerised sepsis protocol, strategies for direct exportation of quality-filtered data from the electronic medical record to a research database and robust long-term follow-up.Ethics and disseminationThis study has been registered at ClinicalTrials.gov, approved by the University of Florida Institutional Review Board and is actively enrolling subjects. Dissemination of results is forthcoming.