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Review
. 2012 Jun;72(6):1491-501.
doi: 10.1097/TA.0b013e318256e000.

Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care

Lori F Gentile  1 , Alex G Cuenca, Philip A Efron, Darwin Ang, Azra Bihorac, Bruce A McKinley, Lyle L Moldawer, Frederick A Moore
Affiliations
Review

Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care

Lori F Gentile et al. J Trauma Acute Care Surg. 2012 Jun.

Abstract

Surgical intensive care unit (ICU) stay of longer than 10 days is often described by the experienced intensivist as a "complicated clinical course" and is frequently attributed to persistent immune dysfunction. "Systemic inflammatory response syndrome" (SIRS) followed by "compensatory anti-inflammatory response syndrome" (CARS) is a conceptual framework to explain the immunologic trajectory that ICU patients with severe sepsis, trauma, or emergency surgery for abdominal infection often traverse, but the causes, mechanisms, and reasons for persistent immune dysfunction remain unexplained. Often involving multiple-organ failure (MOF) and death, improvements in surgical intensive care have altered its incidence, phenotype, and frequency and have increased the number of patients who survive initial sepsis or surgical events and progress to a persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Often observed, but rarely reversible, these patients may survive to transfer to a long-term care facility only to return to the ICU, but rarely to self-sufficiency. We propose that PICS is the dominant pathophysiology and phenotype that has replaced late MOF and prolongs surgical ICU stay, usually with poor outcome. This review details the evolving epidemiology of MOF, the clinical presentation of PICS, and our understanding of how persistent inflammation and immunosuppression define the pathobiology of prolonged intensive care. Therapy for PICS will involve innovative interventions for immune system rebalance and nutritional support to regain physical function and well-being.

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Conflict of interest statement

Conflict of Interest Statement: No conflict of interests have been declared.

Figures

Figure 1
Figure 1. The Evolving Clinical Epidemiology of Multiple Organ Failure and PICS
Summary of the evolution of clinical management of MOF and shock secondary to trauma and sepsis beginning with the emergence of MOF in the 1970s, through today’s currently proposed phenotype PICS.
Figure 2
Figure 2. Mortality Rate for Severe Sepsis-Septic Shock and Trauma-The Methodist Hospital (TMH) Surviving Sepsis Campaign and the Glue Grant Experiences
A. Yearly mortality rate (2006–2009) for patients treated for severe sepsis-septic shock in The Methodist Hospital SICU compared with Surviving Sepsis Campaign (SSC) guideline-based performance improvement initiative and National Surgical Quality Improvement Program (NSQIP) data. In 2006 (before initiation of sepsis protocols), mortality rate in TMH SICU was 34%. In 2007 (as sepsis screening and our sepsis protocol were implemented using a paper protocol (PP)), mortality rate decreased to 24%. In 2008 (using the PP), mortality rate was 23%. In 2009 (with implementation of computerized sepsis protocol (CP)), mortality rate decreased to 14%. For comparison, 31% mortality rate was reported in the eighth quarter of the SSC PI initiative and 34% as reported in a recent NSQIP analysis. Reprinted with permission from Journal of Trauma. B. The overall mortality rate for blunt trauma from the Glue Grant study cohort decreased during the study period from 22% in the first two years to 11% in the last two years (p<0.01), as guidelines were implemented and compliance increased. Reprinted with permission from Annals of Surgery.
Figure 3
Figure 3. Evolution the of SIRS-CARS model
A. The traditionally accepted SIRS-CARS phenomenon holds that mortality from severe sepsis and injury is a consequence of an overabundant and dysregulated early innate immune response from the over production of proinflammatory mediators and cytokines, leading to endothelial injury, tissue damage, inadequate perfusion and MOF, ultimately leading to death. In patients who survive this early SIRS event, a compensatory anti-inflammatory responses (CARS) including suppression of adaptive immunity results. Additional insults such as nosocomial infection can cause a late “second-hit” that may lead to recurrent SIRS. B. Recently, the Glue Grant showed that based on leukocyte genomic expression patterns, there is a simultaneous induction of innate (both pro- and anti-inflammatory genes) and suppression of adaptive immunity genes, and that there is minimal genomic or clinical evidence for a “second-hit” phenomenon. Reprinted with permission from Journal of Experimental Medicine.
Figure 4
Figure 4
Emergency myelopoiesis and expansion of the MDSC population in sepsis Changes in the early populations of hematopoietic stem cells and multipotent progenitors, the progenitors for MDSCs are shown. Although expansion of the MDSC population can be explained in part by increased myelopoiesis, defects in the maturation and differentiation of these populations also contribute to its expansion and MDSCs immature phenotype. Reprinted with permission from Molecular Medicine.
Figure 5
Figure 5. Persistent inflammation – immune suppression catabolism syndrome and the Cellular Constituents Which Contribute to its Development
After the initial, simultaneous SIRS-CARS responsse, many patients linger in the ICU with manageable organ dysfunctions, but do not meet established criteria for late MOF. Clinically, these patients exhibit ongoing protein catabolism with poor nutritional status, poor wound healing and recurrent infections. Additionally, they have persistent low grade inflammation with defects in innate and adaptive immunity including macrophage paralysis, persistent increased MDSC populations, and decreased effector T cell number and function. These patients are ultimately discharged to long term acute care (LTAC) facilities, rarely rehabilitate or return to functional life and usually suffer prolonged decline and indolent death.
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