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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.

Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells whose numbers dramatically increase in chronic and acute inflammatory diseases, including cancer, autoimmune disease, trauma, burns and sepsis. Studied originally in cancer, these cells are potently immunosuppressive, particularly in their ability to suppress antigen-specific CD8 + and CD4+ T-cell activation through multiple mechanisms, including depletion of extracellular arginine, nitrosylation of regulatory proteins, and secretion of interleukin 10, prostaglandins and other immunosuppressive mediators. However, additional properties of these cells, including increased reactive oxygen species and inflammatory cytokine production, as well as their universal expansion in nearly all inflammatory conditions, suggest that MDSCs may be more of a normal component of the inflammatory response ("emergency myelopoiesis") than simply a pathological response to a growing tumor. Recent evocative data even suggest that the expansion of MDSCs in acute inflammatory processes, such as burns and sepsis, plays a beneficial role in the host by increasing immune surveillance and innate immune responses. Although clinical efforts are currently underway to suppress MDSC numbers and function in cancer to improve antineoplastic responses, such approaches may not be desirable or beneficial in other clinical conditions in which immune surveillance and antimicrobial activities are required.

OBJECTIVE To determine the incremental hospital cost and mortality associated with the development of postoperative acute kidney injury (AKI) and with other associated postoperative complications. SUMMARY BACKGROUND DATA Each year 1.5 million patients develop a major complication after surgery. Postoperative AKI is one of the most common postoperative complications and is associated with an increase in hospital mortality and decreased survival for up to 15 years after surgery. METHODS In a single-center cohort of 50,314 adult surgical patients undergoing major inpatient surgery we applied risk-adjusted regression models for cost and mortality using postoperative AKI and other complications as the main independent predictors. We defined AKI using consensus RIFLE criteria. RESULTS The prevalence of AKI was 39% among 50,314 patients with available serum creatinine. Patients with AKI were more likely to have postoperative complications and had longer lengths of stay in the intensive care unit and the hospital. The risk-adjusted average cost of care for patients undergoing surgery was $42,600 for patients with any AKI compared to $26,700 for patients without AKI. The risk-adjusted 90-day mortality was 6.5% for patients with any AKI compared to 4.4% for patients without AKI. Serious postoperative complications resulted in increased cost of care and mortality for all patients, but the increase was much larger for those patients with any degree of AKI. CONCLUSIONS Hospital costs and mortality are strongly associated with postoperative AKI, are correlated with the severity of AKI, and are much higher for patients with other postoperative complications in addition to AKI.

BACKGROUND Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long term consequences. In cancer, increased myeloid-derived suppressor cells (MDSCs) induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis. Based on our chronic sepsis animal models, we hypothesized that after sepsis in humans, MDSCs will be persistently increased, functionally immunosuppressive, and associated with adverse clinical outcomes. METHODS Blood was obtained from 74 patients within 12 hours of severe sepsis/septic shock (SS/SS), and at set intervals out to 28 days, as well as in 18 healthy controls. MDSCs were phenotyped for cell surface receptor expression and enriched by cell sorting. Functional and genome-wide expression analyses were performed. Multiple logistic regression analysis was conducted to determine if increased MDSC appearance was associated with in-hospital and long-term outcomes. RESULTS After SS/SS, CD33+CD11b+HLA-DR−/low MDSCs were dramatically increased out to 28 days (p<0.05). When co-cultured with MDSCs from SS/SS patients, antigen-driven T-cell proliferation and TH1/TH2 cytokine production were suppressed (p<0.05). Additionally, septic MDSCs had suppressed HLA gene expression and upregulated ARG1 expression (p<0.05). Finally, SS/SS patients with persistent increased percentages of blood MDSCs had increased nosocomial infections, prolonged ICU stays, and poor functional status at discharge (p<0.05). CONCLUSION After SS/SS in humans, circulating MDSCs are persistently increased, functionally immunosuppressive, and associated with adverse outcomes. This novel observation warrants further studies. As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after SS/SS to improve currently observed dismal long-term outcomes.

We constructed an automated predictive analytics framework for machine-learning algorithm with high discriminatory ability for assessing the risk of surgical complications and death using readily available preoperative electronic health records data. The feasibility of this novel algorithm implemented in real time clinical workflow requires further testing.

Dysregulated host immune responses to infection often occur, leading to sepsis, multiple organ failure, and death. Some patients rapidly recover from sepsis, but many develop chronic critical illness (CCI), a debilitating condition that impacts functional outcomes and long-term survival. The “Persistent Inflammation, Immunosuppression, and Catabolism Syndrome” (PICS) has been postulated as the underlying pathophysiology of CCI. We propose that PICS is initiated by an early genomic and cytokine storm in response to microbial invasion during the early phase of sepsis. However, once source control, antimicrobial coverage, and supportive therapies have been initiated, we propose that the persistent inflammation in patients developing CCI is a result of ongoing endogenous alarmin release from damaged organs and loss of muscle mass. This ongoing alarmin and danger-associated molecular pattern signaling causes chronic inflammation and a shift in bone marrow stem cell production toward myeloid cells, contributing to chronic anemia and lymphopenia. We propose that therapeutic interventions must target the chronic organ injury and lean tissue wasting that contribute to the release of endogenous alarmins and the expansion and deposition of myeloid progenitors that are responsible for the propagation and persistence of CCI.

IMPORTANCE-Surgeons make complex, high-stakes decisions under time constraints and uncertainty, with significant effect on patient outcomes. This review describes the weaknesses of traditional clinical decision-support systems and proposes that artificial intelligence should be used to augment surgical decision-making.OBSERVATIONS-Surgical decision-making is dominated by hypothetical-deductive reasoning, individual judgment, and heuristics. These factors can lead to bias, error, and preventable harm. Traditional predictive analytics and clinical decision-support systems are intended to augment surgical decision-making, but their clinical utility is compromised by time-consuming manual data management and suboptimal accuracy. These challenges can be overcome by automated artificial intelligence models fed by livestreaming electronic health record data with mobile device outputs. This approach would require data standardization, advances in model interpretability, careful implementation and monitoring, attention to ethical challenges involving algorithm bias and accountability for errors, and preservation of bedside assessment and human intuition in the decision-making process.