Introduction
Sepsis is a syndrome that results from the interactions between the host and insults (pathogen, injury) leading to the production/release of biochemical mediators and the triggering of inflammatory cascades [
1]. Tissue damage and shock lead to the extracellular release of damage-associated molecular patterns (DAMPs), which evoke a systemic inflammatory response syndrome (SIRS) and hypoxia, reduce resistance to infection, and increase risk of sepsis [
2‐
4]. Moreover, microbial infection produces pathogen-associated molecular patterns (PAMPs) that drive septic inflammation. DAMPs and PAMPs share a number of conserved families of pattern recognition receptors (PRRs) including the prototypical PRR family, the Toll-like receptors (TLRs). Activation of TLRs on immune cells and endothelial cells leads to the release of pro- and anti-inflammatory mediators, which trigger excessive inflammation, sepsis and multiple organ failure (MOF) [
5,
6].
Intra-abdominal infection and injury are common causes of sepsis in surgical intensive care unit (ICU) patients, with high rates of mortality [
7‐
9]. Early diagnosis and treatment of infection in this group of patients is associated with improved outcome and reduced mortality. However, the clinical definitions of sepsis are nonspecific and often result in delay in diagnosis and therapy. One of the most challenging obstacles to the treatment of intra-abdominal infection and injury has been establishing the diagnosis and differentiating sepsis with bacterial infection from “sterile” SIRS [
10].
Given that both intra-abdominal infection and injury can incite hyperinflammatory status and sepsis, and the inflammatory response to injury is often clinically indistinguishable from sepsis, many studies have sought to identify biomarkers or mediators to aid in the diagnosis and management of sepsis [
11,
12]. The purpose of this scoping review was therefore to systematically review preclinical and clinical studies of inflammatory mediators in abdominal sepsis and injury in order to evaluate their ability to: (1) provide earlier diagnosis of SIRS, sepsis or severe sepsis, or predict complications or outcomes; (2) serve as therapeutic targets for randomized controlled trials (RCTs); (3) illuminate the mechanisms of pathogenesis of sepsis or injury-related organ dysfunction.
Methods
We developed a protocol according to the Arksey and O’Malley methodological framework for conducting scoping reviews with modifications [
13]. Scoping reviews entail the systematic selection, collection and summarization of existing knowledge in a broad thematic area for the purpose of identifying if there is sufficient evidence to conduct a full synthesis or further research is needed. Contrary to systematic reviews, in scoping reviews authors do not typically assess the quality of included studies or perform a meta-analysis [
13].
Search strategy
Two investigators (ZX, AWK) created a preliminary search strategy that was subsequently refined by a medical librarian with extensive systematic review experience (HLR). Relevant articles were identified by searching the following databases from the first date available until August 2014: Ovid MEDLINE; Ovid EMBASE; PubMed; Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. Combinations of the following search terms were used (see Table S1 in Additional file
1 for detailed search strategies): abdominal injuries, intraabdominal inflammation, intraabdominal sepsis, intraabdominal infections, intraabdominal hypertension, peritonitis, sepsis, septic shock, systemic inflammatory response syndrome, bacteremia, multiple organ failure, inflammation mediator, cytokine, interleukin, and biological markers. Appropriate wildcards were used in all searches to account for plural words and variations in spelling. Additional articles were identified by manually searching the bibliographies of those articles identified in the searches until December 2014.
Article selection
Two investigators (ZX, CW) independently screened the titles and abstracts of all identified citations. We included all articles that were original studies (controlled trials, cohort study, case series, case-control) assessing inflammatory or protein mediators in intra-abdominal sepsis or injury. Participants included patients (10 or more) admitted for surgery with peritonitis or abdominal injury, or animal models of abdominal sepsis/injury. Participants required measurement of mediator(s) from blood and/or peritoneal fluid for inclusion. Articles were excluded if not reporting original data, such as reviews, letters, and conference abstracts (no full text available). Disagreements between the two assessors were resolved by consensus.
Article review, data charting and reporting
The full texts of the remaining articles were independently reviewed by the same two authors. The two investigators extracted data independently using a predesigned electronic data extraction form. Assessors were not blinded to author or journal name [
14]. We extracted the following data from included studies: (1) study design and setting; (2) study participant characteristics, including age, primary patient diagnosis (for example, trauma, intra-abdominal sepsis, or source of infection), and severity of illness (for example, acute physiology and chronic health evaluation II (APACHE II) [
15], sequential organ failure assessment (SOFA) [
16], and injury severity score (ISS) [
17]; (3) severity of sepsis [
10]; (4) the number of participants, and intervention groups; (5) details of animal models; (6) details of reported mediators; and (7) the outcomes.
Results were first mapped based on their characteristics, such as study design, sample size, preclinical or clinical studies. Owing to the significant variability in study design, sample size, analytical technique and outcome measures, it was impossible to perform a full synthesis analysis of the findings. Therefore, studies were presented in tables based on thematic characteristics of the articles. In addition, the level of evidence for a mediator as a biomarker was discussed based on the “best-evidence synthesis” guideline used in review studies (see Table S2 in Additional file
2) [
18].
Risk of bias assessment
Risk of bias of clinical controlled studies was assessed using the guidelines proposed by the Cochrane Collaboration Back Review Group [
19,
20]. These guidelines assist in evaluating study patient participation and treatment allocation, outcome, and confounding factor measurement.
Discussion
This scoping review focused on examining the reported role of inflammatory and protein mediators in intra-abdominal sepsis or injuries. In surgical ICU patients, traumatic injuries and septic conditions can be simultaneously or subsequently present. Each can be associated with profound and dynamic production of bioactive mediators that are at the present poorly understood, particularly in terms of their kinetics and overall interaction with the host inflammatory response. This inflammatory response is a complex and multifaceted process. Traumatic injuries induce overwhelming reactions in the immunological and neurohormonal systems. Innate immunocytes are activated by hypoxia stress and endogenous signals (DAMPs) released by damaged tissues [
4,
6,
203]. These reactions are thought to represent attempts to adjust physiology for maintenance of homeostasis. These responses however often result in positive feedback loops leading to excessive cytokine production and uncontrolled inflammation. In the early phase following injury, the response is regulated by acute phase reactants, proinflammatory mediators (TNF-α, IL-1, -6, -8, -18), and the activation of endothelial cells (expression of P- and E-selectins, ICAM-1, VCAM-1), leading to a so-called “sterile” systemic inflammatory response or SIRS. At the same time, anti-inflammatory mediators (IL-10) are released in an attempt to balance the proinflammatory reaction. Polytrauma patients with excessive SIRS can not only progress to multiple organ damage and failure (MOF), but also develop persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which lead to infectious sepsis resulting in release of additional DAMPs and PAMPs, perpetuating a vicious cycle of inflammation [
4,
203]. Therefore, during this late phase post injury, trauma patients are prone to develop infective complications with high mortality rate. Injuries to the abdomen and visceral organs are common clinical scenarios, and are usually complicated with intra-abdominal sepsis [
123]. The objective of this scoping review was to search for current evidence of mediators as biomarkers and their roles in intra-abdominal sepsis or injury.
Although animal studies suggest that mediators play a critical role in both the pathogenesis and potential management in intra-abdominal sepsis/injury, the clinical evidence to support measuring mediators as biomarkers to discriminate SIRS from sepsis is conflicting.
Due to the heterogeneity of included studies, we discussed the overall results based on the “best-evidence synthesis” rating, which is widely used in narrative and systematic reviews [
18]. Moderate evidence supports utilizing serum CRP as a biomarker for diagnosing acute appendicitis with sepsis [
25,
26,
32,
47,
70]; or as a potential indicator for predicting complications (abscess, anastomotic leaks) after major abdominal surgery [
21,
92,
98,
103]. A normal CRP response to therapy, or absence of secondary rise after surgery, may help to exclude infection [
24]. It is important to note that no standard cutoff value was available, and some studies have reported negative results for using CRP as a biomarker [
64,
86,
96].
Furthermore, although the serum PCT value appears to predict severity of septic complications [
49,
64], it does not appear to be an ideal biomarker to discriminate SIRS from sepsis. Persistently high PCT levels appear to be associated with a significant increase in mortality in patients with sepsis [
77,
88,
93,
95]. The role of using serum PCT as a guide to monitor patients’ response to therapy remains to be determined [
74,
78].
Sepsis further increased IL-6 levels over the already elevated levels from the original injury. Although moderate level of evidence supports IL-6 to be a useful indicator for sepsis or severity [
48,
64,
87,
91], it is important to note that almost half of the studies for this cytokine do not support the use of IL-6 as a good sepsis biomarker. Currently, no evidence is available to support the use of TNF-α or other cytokines in diagnosing sepsis or predicting outcomes. Recent studies have reported endogenous DAMPs (mtDNA, HMGB1) released as a consequence of tissue injury or infection appear to be promising biomarkers [
3,
84,
85,
99,
105]; however, the evidence supporting their role is still limited.
It appeared to be futile to specifically target a single inflammatory or protein mediator in an effort to mitigate disease and improve outcomes. It is more likely that identifying promising biomarkers will only be possible when a number of mediators are analyzed as a profile [
204,
205].
It is currently unknown if the peritoneal cavity functions to restrain the inflammatory mediators or to act as a reservoir of mediators. Evidence has shown that peritoneal fluid functions as a priming and activating stimulus for neutrophils both in the peritoneum and in remote organs (lung, liver, kidneys) after injury, enhancing the incidence of MOF upon subsequent infection [
136,
163]. Moreover, early removal of peritoneal fluid appeared to reduce systemic inflammation and organ dysfunction [
123,
141,
153,
160,
190]. This notion supports the recent guidelines for management of intra-abdominal infections proposed by the World Society of Emergency Surgery [
206].
Finally, based on the evidence from animal models that injury followed by a second insult (infection, or ACS) substantially enhanced the inflammatory response and organ damage [
134,
136,
158,
163,
190], it is essential to avoid or timely intervene upon secondary insults for trauma patients to improve outcomes.
This review has limitations. First, despite the search of multiple databases using comprehensive search strategies with the assistance of a medical librarian, our search has excluded studies assessing extra-abdominal sepsis or injury. Moreover, limited abdominal trauma studies were available; the majority of which focused on surgical injuries. Importantly, the exclusion of studies assessing other kinds of sepsis can present a selection bias. Second, due to the inconsistencies in study design, it proved difficult to extract accurate data from all studies, even with the assistance of predefined data abstraction tools. Furthermore, only a small number of the included studies actually examined biomarkers for both sensitivity and specificity.
Competing interests
Professor Kirkpatrick received a research grant from Kinetic Concepts Inc., USA and afterwards consulted for Acelity Corp. AWK has received travel reimbursement to attend cadaver and research laboratories from the Life Cell and Innovative Trauma Care Corporations. The remaining authors have none to declare.
Authors’ contributions
ZX conceptualized the study, created the study design, conducted the literature search, collected data, drafted and revised the manuscript. CW participated in the study design, collected data, drafted and revised the manuscript. HLR participated in the study design, conducted the literature search and revised the manuscript critically for important intellectual content. DJR participated in the study design, performed data analysis, and critically revised the manuscript for important intellectual content. CGB participated in the study design, drafted and critically revised the manuscript for important intellectual content. CNJ participated in the study design, drafted and critically revised the manuscript for important intellectual content. AWK conceptualized the study, created the study design, drafted and critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.