Prediction of sepsis in trauma patients
© Author 2014
Received: 14 March 2014
Accepted: 10 June 2014
Published: 28 July 2014
Trauma is one of the leading causes of death worldwide. Approximately 39.5% of deaths occur in the hospital, and the mortality rate of delayed death caused by septic complications is still high. Early prediction of the development of sepsis can help promote early intervention and treatment for patients and contribute to improving patient outcomes. Thus so far, biomarkers, patient demographics and injury characteristics are the main methods used for predicting sepsis in trauma patients. However, studies that verify their predictive value are limited, and the results are still controversial. More work should be conducted to explore more efficient and accurate ways to predict post-traumatic sepsis.
KeywordsSepsis trauma infection prediction
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Diagnosis of the pathogen that causes sepsis requires bacterial culture, but it is often delayed due to long culture times (24 h to 48 h). Furthermore, a third or more of septic patients with infections have cultures that are negative for bacteria.[11,13–17] This may contribute to the high mortality. Identification of the factors associated with the development of post-traumatic sepsis may help in the early prediction of the occurrence of this complication so that timely interventions could be performed to improve the outcomes. Research on some factors, such as biomarkers, patient demographics and injury characteristics have revealed some elements that are predictable in post-traumatic sepsis. Here, we review these predictors and risk factors of post-traumatic sepsis.
According to the Biomarkers Definitions Working Group, a biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention. In other words, biomarkers are tools to measure biologic homeostasis that give standard to what is normal and provide a quantifiable method for predicting or detecting what is abnormal. The ideal biomarker for sepsis should have a high sensitivity allowing for early diagnosis and would be specific for pathogenic microorganisms to allow appropriate therapy. It has been reported that more than 80 molecules have been proposed as useful biomarkers of sepsis, and to date, the number has increased to 178 or more. To be considered a valid biomarker, 3 aspects must be present: (1) proving that the test truly measures a particular molecular species or its relevant biological activity; (2) proving that measurement of the biomarker discriminates patients with a disease from those who are without the disease; (3) proving that measurement of the biomarker can inform a clinical decision that can improve patient outcomes. Here, we list some representable candidates among the potential biomarkers of post-traumatic sepsis.
PCT is a precursor of the hormone calcitonin, which is codified by the CALC-I gene located on chromosome 11 and is produced and secreted by parafollicular C cells of the thyroid to sustain calcium homeostasis. PCT has been shown to be a marker of bacterial infection and sepsis[25,26] as PCT is released systemically from various types of cells outside the thyroid as a response to bacterial infection. On the condition of systemic bacterial infection or by stimulation with endotoxin or proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1, PCT levels increase 1,000 times within a few hours.[28,29] The half-life of PCT, approximately 22 h, is another characteristic that can be used as a biomarker for bacterial infection. Its levels show a rapid decrease when infection is resolved, whereas many other inflammatory biomarkers still have high levels during the acute-phase response. For predicting post-traumatic sepsis, studies have shown the rapid kinetics of PCT, with levels peaking at 24–48 h after trauma and rapid decrease in non-complicated patients, whereas with constant high levels in septic patients. Continuous high levels or secondary increases of PCT are predictors of sepsis.[27,28,30–34] PCT as a biomarker is useful in the prediction and early diagnosis of sepsis in trauma patients. Currently, PCT is already used in clinical practice, and it is used to guide antibiotic therapy in patients with lower respiratory tract infections or other infections such as fungal infections, postoperative fever and suspected bloodstream infections.
C-reactive protein (CRP)
CRP belongs to the acute phase protein family. Each one is made of 5 protomers of 206 amino acid residues, and belongs to the pentraxin family of calcium-dependent ligand-binding plasma proteins. CRP is mainly synthesized in the hepatocytes, and its transcription is reduced by the cytokine IL-6, which is predominantly released by macrophages in response to various types of systemic inflammation, including infections or trauma.[36–38] Therefore, it is a sensitive marker of inflammation and tissue damage. The half-life of CRP is 19 h. Serum CRP is used as a biomarker because of the rapid concentrations that increase in response to inflammation, the shorter half-life and the widely available inexpensive test. Many researchers have explored the predictive value of CRP for post-traumatic sepsis, but the results are unsatisfactory. Both prospective studies and retrospective studies have reported no predictive power of CRP for sepsis in trauma patients.[4,28,30–32,40–43]
IL-6 is a glycoprotein synthesized by various types of cells including T- and B-cells and endothelial cells. Other cytokines (IL-1, TNF-α), viruses and bacterial components, such as lipopolysaccharide (LPS), induce the production of IL-6. IL-6 induces hepatic production of acute-phase proteins such as CRP and complement factors, regulation of B- and T-lymphocytes, differentiation of cytotoxic T-cells, and an enhanced activity of natural killer (NK) cells. Its release is triggered by tissue damage or infection. It is a cytokine involved in both pro-inflammatory and anti-inflammatory responses. IL-6 has a rapid onset, peaking within 2 h after the infectious stimulus. The results of studies on the predictive value of IL-6 for post-traumatic sepsis are controversial. Some studies have found that IL-6 is able to discriminate trauma patients prone to sepsis[31,32] while others have shown no correlation between the IL-6 levels and sepsis development.[42,43,47–50]
IL-10 is a protein produced by T-lymphocytes, B-lymphocytes, macrophages and dendritic cells (DC). It is an anti-inflammatory cytokine playing a role in counter inflammatory and autoimmune pathologies. IL-10 downregulates MHC class II and co-stimulatory molecules B7-1/B7-2 expression on monocytes and macrophages, inhibiting their antigen-presenting function, and limits the synthesis of pro-inflammatory cytokines (IL-1, TNF-α) as well as decreases cytokine production of Th-1 cells. IL-10 peaks quickly, within a few hours (4 h) following trauma, and the levels decrease rapidly in all patients (the first day after trauma).[53,54] IL-10 levels have been shown to be significantly higher in patients who develop sepsis at the point of admission.[4,53–56]
Neopterin is a pteridine produced by monocytes or macrophages upon stimulation with interferon (IFN)-γ and is then released into body circulation. Neopterin is useful for the diagnosis of bacterial and viral infections and systemic inflammation. In addition, increased levels of neopterin are associated with endothelial damage, organ dysfunction and sepsis. Among the studies performed on predicting post-traumatic sepsis, neopterin levels have shown no significant difference between patients who developed and did not develop sepsis.[42,58–60]
Pancreatic stone protein/regenerating protein (PSP/reg)
PSP/reg is a lectin-binding acute phase protein and was initially found in patients with pancreatitis. PSP/reg acts as an acute phase protein causing the activation of leukocytes and can also be observed in other cells outside the pancreas. Its release is reduced by IL-6 following tissue injury. PSP/reg levels can predict and distinguish septic complications in post-traumatic patients.
IL-1 is an important mediator of innate immunity and inflammation. It can significantly lengthen the lifespan and activate the function of neutrophils and macrophages in response to infections. Its effects on the central nervous system cause fever, the elevated temperature leads to an increased migration of leukocytes. Few studies demonstrate evidence of the predictive power of IL-1 for sepsis after trauma, except Menges et al. who reported the positive correlation between IL-1 and sepsis.
Amino-terminal pro-peptide (NT-proCNP)
NT-proCNP is a part of the natriuretic peptide family and was first identified in 1990. CNP participates in physiological processes such as bone growth, reproduction, nerve growth, and re-endothelialization. ProCNP protein is a precursor of CNP. As a cleavage product of proCNP, Amino-terminal pro-C-type natriuretic peptide (NT-proCNP) is the N-terminal fragment of the C-type natriuretic peptide precursor. The amounts of NT-proCNP are equal to CNP in human plasma and NT-proCNP is considered to be a more reliable indicator of the extent of CNP synthesis. Results of a study show that the levels of circulating NT-proCNP can discriminate poly trauma patients without traumatic brain injury who develop sepsis from those who do not.
Polymorphonuclear elastase (PMNE)
In healthy adults, polymorphonuclear (PMN) circulates during the resting state and can be activated following major trauma. PMN is the main effector cell of the inflammatory response post-trauma and it produces and releases toxic reactive oxygen species. PMN activation and inflammatory response post-trauma may be reflected in serum elastase levels. Some studies have shown the difference in PMN elastase between patients with and without infection or sepsis[47,59], while others have shown that it has no correlation with post-traumatic infective complications.[42,43]
Persistent occult hypoperfusion is a risk factor for infections following trauma, and lactate clearance is proposed as a measure of early sepsis resuscitation effectiveness. Thus, lactate clearance can be a biomarker of sepsis. During the first 12–24 h, the lactate clearance is associated with post-traumatic sepsis.[31,68]
As a member of the IL-1 cytokine family, IL-18, which is produced by a variety of cells including Kuppfer cells, monocytes, dendritic cells (DC), macrophages, and so on, induces the production of IFN-γ and other cytokines. It is found to have high levels in sepsis patients compared to healthy people. Mommsen et al. has proposed IL-18 concentrations as early markers for post-traumatic complications such as sepsis and MODS.
Monocyte Human Leukocyte Antigen DR (mHLA-DR)
Human leukocyte antigen-DR (HLA-DR) is a member of the MHC class II system. HLA-DR is expressed in antigen presenting cells (APC) including monocytes, macrophages, dendritic cells and B lymphocytes. Low expression of HLA-DR on circulating monocytes (mHLA-DR) is reported as an indicator of post-trauma immune suppression. Studies show that the decreased level of mHLA-DR is a biomarker of sepsis development after major trauma.[72,73]
Other biomarkers for sepsis following trauma
Some potential biomarkers, such as Toll-like receptor (TLR)-9, PMN cluster of differentiation (CD) 11b, Soluble factor associated suicide (FAS) (sFAS), Group-specific component globulin (Gc-globulin), kynurenine values and kynurenine-tryptophan ratios, and the soluble thrombomodulin (s-TM) level, have also been reported to have predictive abilities for post-traumatic sepsis. TNF-α, an important cytokine, has been shown to have no sufficiently predictive value for sepsis development after trauma.
Evaluation of biomarkers of post-traumatic sepsis
Biomarkers of post-traumatic sepsis
kynurenine values and kynureninetryptophan ratio
Until now, many biomarkers have been proposed in the field of sepsis. However, there are only a few biomarkers that have been shown to be useful for predicting post-traumatic sepsis. Among the biomarkers for sepsis following trauma, PCT is the most extensively investigated biomarker, and the results show good application in predicting this complication. However, others, such as CRP, though many studies have been performed on it, show no predictive power for trauma patients. For some biomarkers such as IL-6 and PMNE, the results are controversial. There are also some biomarkers such as IL-1 and IL-18, that show the predictive value of sepsis post-trauma, but the studies are few and the results need further evidence to support this. Traumatic injuries cause great changes in the immunological and neurohormonal environments, which then affect physiological processes. After trauma, the innate immune system is activated, and many pro-inflammatory cytokines, such as TNF-α, IL-1 and IL-6 are released, leading to systemic inflammation. Activation of neutrophils and endothelial cells can cause endothelium and tissue damage. To counter these disadvantages, anti-inflammatory cytokines, such as IL-10, are released, leading to immune suppression and increased risk of secondary infections. The primary cytokines TNF-α and IL-1 can induce the release of following cytokines including IL-6 and IL-8. IL-6 again promotes the production of acute phase proteins such as PCT and CRP.
Most of the biomarkers illustrated above participate in the reaction of systemic inflammation. However, post-trauma physiological processes may become more complicated due to immune function disorders caused by multiple trauma. For example, in the condition of abdominal or brain trauma, the kinetics of biomarkers can be changed. Therefore, more tests should be performed to verify the predictive value of the present biomarkers and to find more biomarkers suitable to predict traumatic sepsis.
Some studies have proposed the male gender as a predictor for sepsis post-trauma.[6,7,33,78] After trauma, the continuous increase in cytokines and the subsequent immunosuppression make the body prone to sepsis. A study performed on animals showed that pro-estrus females are not immunode-pressed compared with male and ovariectomized mice after trauma. Other test results have demonstrated that estrogen produces beneficial effects on immune and cardiovascular function after trauma by reducing the release of cytokine production, such as TNF-α, and maintaining the immune response. Thus, estrogen plays an important role in the gender dimorphism of post-traumatic sepsis.
African American race is reported as a risk factor of sepsis following trauma. However, there has been no extensive research conducted to investigate the role of racial or ethnic factors in post-traumatic sepsis. More research is warranted to explore the association between ethnicity and this complication.
Injury severity, mechanism of injury, number of injuries, hypotension on admission, and other injury characteristics are factors associated with post-traumatic sepsis.
Trauma can cause deficits in the immune system by depressing the humoral and cell-mediated systems. After major trauma, the function of lymphocytes is depressed. The neutrophil chemotaxis is decreased and monocyte antigen-presenting capacity is impaired. There are also changes in complement components. Different degrees of trauma severity may lead to the different influences on immune function. The main measures of injury severity are trauma-scoring systems. Trauma scoring systems are divided into 3 categories: Anatomical scoring systems, physiological scoring systems and combined scoring systems.
The calculation of most trauma scoring systems is time consuming and complicated. However, among the various scoring systems, the Injury Severity Score (ISS) and the New Injury Severity score (NISS) can be rapidly calculated and are most widely used in predicting outcomes of trauma patients. The ISS and NISS are members of anatomical scoring systems. The ISS is based on the Abbreviated Injury Scale (AIS) severity values, and it was first developed in 1974. It is calculated as the sum of the squares of the highest AIS values from each of the three most severely impaired body regions. It has some limitations, for example, it does not represent multiple injuries in the same body region and it considers injuries with an equal AIS score to be the same severity regardless of the injured body region. The NISS was proposed by Osler et al. in 1997 to counter the limitations of the ISS. It is calculated as the sum of squares of the three most severe injuries, regardless of the body region injured. The ISS or NISS ranges from 1 to 75. Increasing injury severity measured by the ISS and NISS was associated with increased incidence of sepsis.[3,6,7,78,87]
In addition to the ISS and NISS, the Glasgow coma scale (GCS), which assesses the level of clinical consciousness is also a predictor of sepsis.[6,7] The GCS was first described by Teasdale and Jennett in 1974. It is the sum of 3 components that describes a patient’s best motor response, verbal response and eye opening to stimuli. It ranges from 3 to 15, and the lower score the patient receives, the worse condition the patient is in. The GCS belongs to physiological scoring systems.
The anatomy scoring systems such as the ISS and NISS represent the physical degeneration of the body, and the physiological scoring systems, such as the GCS, stand for the physiological impairment caused by trauma. Compared to biomarkers, obtaining the indices of these scoring systems is easier, earlier and cheaper. Further work may be needed to verify the accuracy of the scoring systems and to explore whether the combination of the two types of scoring systems can improve the predictive power for sepsis in trauma patients.
There are several injury characteristics reported as risk factors, such as number of red blood cell units transfused, hypotension on emergency department presentation and number of injuries. However, studies on these factors are not common.
Early prediction of sepsis development and early intervention for patients at risk can decrease the morbidity and mortality after trauma. The prediction of sepsis in trauma patients is still a challenge. Though approximately 180 biomarkers for sepsis have been reported, the studies performed on the biomarkers for post-traumatic sepsis are few and the results are controversial. Trauma can affect immunologic function, and injury characteristics, such as injury severity and the number of injuries, are risk factors that are associated with sepsis following trauma. To trauma patients, demographic variables, including age, gender and race are also risk factors. Obtaining the information of injury characteristics and patient demographics is earlier, easier and cheaper than biomarkers, but the connection between these factors and the pathophysiology of sepsis is yet to be identified or clarified. Additional work is needed to verify the predictors and find more efficient and accurate ways that can better predict sepsis in trauma patients.
This study was supported by grants from the key project of “twelfth five-year plan” for medical science and technology of PLA (No. BWS11J038).
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- NCIPC. Injury Response: Global Trauma Care. http://www.cdc.gov/traumacare/global_trauma.html.
- Baker CC, Oppenheimer L, Stephens B, Lewis FR, Trunkey DD. Epidemiology of trauma deaths. Am J Surg 1980;140:144–50.View ArticlePubMedGoogle Scholar
- Brattstrom O, Granath F, Rossi P, Oldner A. Early predictors of morbidity and mortality in trauma patients treated in the intensive care unit. Acta Anaesthesiol Scand 2010;54:1007–17.View ArticlePubMedGoogle Scholar
- Ciriello V, Gudipati S, Stavrou PZ, Kanakaris NK, Bellamy MC, Giannoudis PV. Biomarkers predicting sepsis in polytrauma patients: Current evidence. Injury 2013;44:1680–92.View ArticlePubMedGoogle Scholar
- Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013;369:840–51.View ArticlePubMedGoogle Scholar
- Wafaisade A, Lefering R, Bouillon B, Sakka SG, Thamm OC, Paffrath T, et al.; Trauma Registry of the German Society for Trauma Surgery. Epidemiology and risk factors of sepsis after multiple trauma: An analysis of 29,829 patients from the Trauma Registry of the German Society for Trauma Surgery. Crit Care Med 2011;39:621–8.View ArticlePubMedGoogle Scholar
- Osborn TM, Tracy JK, Dunne JR, Pasquale M, Napolitano LM. Epidemiology of sepsis in patients with traumatic injury. Crit Care Med 2004;32:2234–40.View ArticlePubMedGoogle Scholar
- Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al.; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013;39:165–228.View ArticlePubMedGoogle Scholar
- Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589–96.View ArticlePubMedGoogle Scholar
- BalcI C, Sungurtekin H, Gurses E, Sungurtekin U, Kaptanoglu B. Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit. Crit Care 2003;7:85–90.View ArticlePubMedGoogle Scholar
- Pittet D, Rangel-Frausto S, Li N, Tarara D, Costigan M, Rempe L, et al. Systemic inflammatory response syndrome, sepsis, severe sepsis and septic shock: Incidence, morbidities and outcomes in surgical ICU patients. Intensive Care Med 1995;21:302–9.View ArticlePubMedGoogle Scholar
- Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644–55.View ArticlePubMedGoogle Scholar
- Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence 2014;5:4–11.View ArticlePubMedGoogle Scholar
- Kim MH, Lim G, Kang SY, Lee WI, Suh JT, Lee HJ. Utility of procalcitonin as an early diagnostic marker of bacteremia in patients with acute fever. Yonsei Med J 2011;52:276–81.View ArticlePubMedPubMed CentralGoogle Scholar
- Mitaka C. Clinical laboratory differentiation of infectious versus non-infectious systemic inflammatory response syndrome. Clin Chim Acta 2005;351:17–29.View ArticlePubMedGoogle Scholar
- Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, et al.; Academic Medical Center Consortium Sepsis Project Working Group. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 1997;278:234–40.View ArticlePubMedGoogle Scholar
- Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al.; Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med 2006;34:344–53.View ArticlePubMedGoogle Scholar
- Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89–95.View ArticleGoogle Scholar
- Dalton WS, Friend SH. Cancer biomarkers — an invitation to the table. Science 2006;312:1165–8.View ArticlePubMedGoogle Scholar
- Schneider HG, Lam QT. Procalcitonin for the clinical laboratory: A review. Pathology 2007;39:383–90.View ArticlePubMedGoogle Scholar
- Marshall JC, Vincent JL, Fink MP, Cook DJ, Rubenfeld G, Foster D, et al. Measures, markers, and mediators: Toward a staging system for clinical sepsis. A report of the Fifth Toronto Sepsis Roundtable, Toronto, Ontario, Canada, October 25–26, 2000. Crit Care Med 2003;31:1560–7.View ArticlePubMedGoogle Scholar
- Pierrakos C, Vincent JL. Sepsis biomarkers: A review. Crit Care 2010;14:R15.View ArticlePubMedPubMed CentralGoogle Scholar
- Marshall JC, Reinhart K; International Sepsis Forum. Biomarkers of sepsis. Crit Care Med 2009;37:2290–8.View ArticlePubMedGoogle Scholar
- Muller B, White JC, Nylen ES, Snider RH, Becker KL, Habener JF. Ubiquitous expression of the calcitonin-i gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab 2001;86:396–404.PubMedGoogle Scholar
- Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: A systematic review and meta-analysis. Crit Care Med 2006;34:1996–2003.View ArticlePubMedGoogle Scholar
- Clec’h C, Ferriere F, Karoubi P, Fosse JP, Cupa M, Hoang P, et al. Diagnostic and prognostic value of procalcitonin in patients with septic shock. Crit Care Med 2004;32:1166–9.View ArticlePubMedGoogle Scholar
- Sakran JV, Michetti CP, Sheridan MJ, Richmond R, Waked T, Aldaghlas T, et al. The utility of procalcitonin in critically ill trauma patients. J Trauma Acute Care Surg 2012;73:413–418.View ArticlePubMedGoogle Scholar
- Castelli GP, Pognani C, Cita M, Paladini R. Procalcitonin as a prognostic and diagnostic tool for septic complications after major trauma. Crit Care Med 2009;37:1845–9.View ArticlePubMedGoogle Scholar
- Dahaba AA, Metzler H. Procalcitonin’s role in the sepsis cascade. Is procalcitonin a sepsis marker or mediator? Minerva Anestesiol 2009;75:447–52.PubMedGoogle Scholar
- Balci C, Sivaci R, Akbulut G, Karabekir HS. Procalcitonin levels as an early marker in patients with multiple trauma under intensive care. J Int Med Res 2009;37:1709–17.View ArticlePubMedGoogle Scholar
- Billeter A, Turina M, Seifert B, Mica L, Stocker R, Keel M. Early serum procalcitonin, interleukin-6, and 24-hour lactate clearance: Useful indicators of septic infections in severely traumatized patients. World J Surg 2009;33:558–66.View ArticlePubMedGoogle Scholar
- Keel M, Harter L, Reding T, Sun LK, Hersberger M, Seifert B, et al. Pancreatic stone protein is highly increased during posttraumatic sepsis and activates neutrophil granulocytes. Crit Care Med 2009;37:1642–8.View ArticlePubMedGoogle Scholar
- Oberholzer A, Keel M, Zellweger R, Steckholzer U, Trentz O, Ertel W. Incidence of septic complications and multiple organ failure in severely injured patients is sex specific. J Trauma 2000;48:932–7.View ArticlePubMedGoogle Scholar
- Wanner GA, Keel M, Steckholzer U, Beier W, Stocker R, Ertel W. Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients. Crit Care Med 2000;28:950–7.View ArticlePubMedGoogle Scholar
- Cho SY, Choi JH. Biomarkers of Sepsis. Infect Chemother 2014;46:1–12.View ArticlePubMedPubMed CentralGoogle Scholar
- Pepys MB, Hirschfield GM. C-reactive protein: A critical update. J Clin Invest 2003;111:1805–12.View ArticlePubMedPubMed CentralGoogle Scholar
- Biffl WL, Moore EE, Moore FA, Peterson VM. Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation? Ann Surg 1996;224:647–64.View ArticlePubMedPubMed CentralGoogle Scholar
- Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448–54.View ArticlePubMedGoogle Scholar
- Ventetuolo CE, Levy MM. Biomarkers: Diagnosis and risk assessment in sepsis. Clin Chest Med 2008;29:591–603, vii.View ArticlePubMedGoogle Scholar
- Castelli GP, Pognani C, Cita M, Stuani A, Sgarbi L, Paladini R. Procalcitonin, C-reactive protein, white blood cells and SOFA score in ICU: Diagnosis and monitoring of sepsis. Minerva Anestesiol 2006;72:69–80.PubMedGoogle Scholar
- Meisner M, Adina H, Schmidt J. Correlation of procalcitonin and C-reactive protein to inflammation, complications, and outcome during the intensive care unit course of multiple-trauma patients. Crit Care 2006;10:R1.View ArticlePubMedGoogle Scholar
- Egger G, Aigner R, Glasner A, Hofer HP, Mitterhammer H, Zelzer S. Blood polymorphonuclear leukocyte migration as a predictive marker for infections in severe trauma: Comparison with various inflammation parameters. Intensive Care Med 2004;30:331–4.View ArticlePubMedGoogle Scholar
- Flores JM, Jimenez PI, Rincon MD, Marquez JA, Navarro H, Arteta D, et al. Early risk factors for sepsis in patients with severe blunt trauma. Injury 2001;32:5–12.View ArticlePubMedGoogle Scholar
- Giannoudis PV, Hildebrand F, Pape HC. Inflammatory serum markers in patients with multiple trauma. Can they predict outcome? J Bone Joint Surg Br 2004;86:313–23.View ArticlePubMedGoogle Scholar
- Dvorak K, Dvorak B. Role of interleukin-6 in Barrett’s esophagus pathogenesis. World J Gastroenterol 2013;19:2307–12.View ArticlePubMedPubMed CentralGoogle Scholar
- Bloos F, Reinhart K. Rapid diagnosis of sepsis. Virulence 2014;5:154–60.View ArticlePubMedGoogle Scholar
- Paunel-Gorgulu A, Flohe S, Scholz M, Windolf J, Logters T. Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis. Crit Care 2011;15:R20.View ArticlePubMedPubMed CentralGoogle Scholar
- Giannoudis PV, Smith MR, Evans RT, Bellamy MC, Guillou PJ. Serum CRP and IL-6 levels after trauma. Not predictive of septic complications in 31 patients. Acta Orthop Scand 1998;69:184–8.View ArticlePubMedGoogle Scholar
- Giannoudis PV, Smith RM, Banks RE, Windsor AC, Dickson RA, Guillou PJ. Stimulation of inflammatory markers after blunt trauma. Br J Surg 1998;85:986–90.View ArticlePubMedGoogle Scholar
- Giamarellos-Bourboulis EJ, Mouktaroudi M, Tsaganos T, Koutoukas P, Spyridaki E, Pelekanou A, et al. Evidence for the participation of soluble triggering receptor expressed on myeloid cells-1 in the systemic inflammatory response syndrome after multiple trauma. J Trauma 2008;65:1385–90.View ArticlePubMedGoogle Scholar
- Couper KN, Blount DG, Riley EM. IL-10: The master regulator of immunity to infection. J Immunol 2008;180:5771–7.View ArticlePubMedGoogle Scholar
- Yao Y, Simard AR, Shi FD, Hao J. IL-10-producing lymphocytes in inflammatory disease. Int Rev Immunol 2013;32:324–36.View ArticlePubMedGoogle Scholar
- Neidhardt R, Keel M, Steckholzer U, Safret A, Ungethuem U, Trentz O, et al. Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients. J Trauma 1997;42:863–71.View ArticlePubMedGoogle Scholar
- Giannoudis PV, Smith RM, Perry SL, Windsor AJ, Dickson RA, Bellamy MC. Immediate IL-10 expression following major orthopaedic trauma: Relationship to anti-inflammatory response and subsequent development of sepsis. Intensive Care Med 2000;26:1076–81.View ArticlePubMedGoogle Scholar
- Menges T, Engel J, Welters I, Wagner RM, Little S, Ruwoldt R, et al. Changes in blood lymphocyte populations after multiple trauma: Association with posttraumatic complications. Crit Care Med 1999;27:733–40.View ArticlePubMedGoogle Scholar
- Sherry RM, Cue JI, Goddard JK, Parramore JB, DiPiro JT. Interleukin-10 is associated with the development of sepsis in trauma patients. J Trauma 1996;40:613–7.View ArticlePubMedGoogle Scholar
- Berdowska A, Zwirska-Korczala K. Neopterin measurement in clinical diagnosis. J Clin Pharm Ther 2001;26:319–29.View ArticlePubMedGoogle Scholar
- Mommsen P, Frink M, Pape HC, van Griensven M, Probst C, Gaulke R, et al. Elevated systemic IL-18 and neopterin levels are associated with posttraumatic complications among patients with multiple injuries: A prospective cohort study. Injury 2009;40:528–34.View ArticlePubMedGoogle Scholar
- Waydhas C, Nast-Kolb D, Jochum M, Trupka A, Lenk S, Fritz H, et al. Inflammatory mediators, infection, sepsis, and multiple organ failure after severe trauma. Arch Surg 1992;127:460–7.View ArticlePubMedGoogle Scholar
- Hensler T, Sauerland S, Lefering R, Nagelschmidt M, Bouillon B, Andermahr J, et al. The clinical value of procalcitonin and neopterin in predicting sepsis and organ failure after major trauma. Shock 2003;20:420–6.View ArticlePubMedGoogle Scholar
- Jin CX, Hayakawa T, Ko SB, Ishiguro H, Kitagawa M. Pancreatic stone protein/regenerating protein family in pancreatic and gastrointestinal diseases. Intern Med 2011;50:1507–16.View ArticlePubMedGoogle Scholar
- Dusetti NJ, Ortiz EM, Mallo GV, Dagorn JC, Iovanna JL. Pancreatitis-associated protein I (PAP I), an acute phase protein induced by cytokines. Identification of two functional interleukin-6 response elements in the rat PAP I promoter region. J Biol Chem 1995;270:22417–21.View ArticlePubMedGoogle Scholar
- Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: Back to the future. Immunity 2013;39:1003–18.View ArticlePubMedPubMed CentralGoogle Scholar
- Kuehnl A, Pelisek J, Bruckmeier M, Safi W, Eckstein HH. Comparative measurement of CNP and NT-proCNP in human blood samples: A methodological evaluation. J Negat Results Biomed 2013;12:7.View ArticlePubMedPubMed CentralGoogle Scholar
- Koch A, Zimmermann HW, Baeck C, Schneider C, Yagmur E, Trautwein C, et al. Serum NT-proCNP concentrations are elevated in patients with chronic liver diseases and associated with complications and unfavorable prognosis of cirrhosis. Clin Biochem 2012;45:429–35.View ArticlePubMedGoogle Scholar
- Bahrami S, Pelinka L, Khadem A, Maitzen S, Hawa G, van Griensven M, et al. Circulating NT-proCNP predicts sepsis in multiple-traumatized patients without traumatic brain injury. Crit Care Med 2010;38:161–6.View ArticlePubMedGoogle Scholar
- Bhatia R, Dent C, Topley N, Pallister I. Neutrophil priming for elastase release in adult blunt trauma patients. J Trauma 2006;60:590–6.View ArticlePubMedGoogle Scholar
- Claridge JA, Crabtree TD, Pelletier SJ, Butler K, Sawyer RG, Young JS. Persistent occult hypoperfusion is associated with a significant increase in infection rate and mortality in major trauma patients. J Trauma 2000;48:8–15.View ArticlePubMedGoogle Scholar
- Jones AE. Lactate clearance for assessing response to resuscitation in severe sepsis. Acad Emerg Med 2013;20:844–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Sedimbi SK, Hagglof T, Karlsson MC. IL-18 in inflammatory and autoimmune disease. Cell Mol Life Sci 2013;70:4795–808.View ArticlePubMedGoogle Scholar
- Lukaszewicz AC, Faivre V, Payen D. Is monocyte HLA-DR expression monitoring a useful tool to predict the risk of secondary infection? Minerva Anestesiol 2010;76:737–43.PubMedGoogle Scholar
- Gouel-Cheron A, Allaouchiche B, Guignant C, Davin F, Floccard B, Monneret G, et al. Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: A powerful association to predict the development of sepsis after major trauma. PLoS One 2012;7:e33095.View ArticlePubMedPubMed CentralGoogle Scholar
- Cheron A, Floccard B, Allaouchiche B, Guignant C, Poitevin F, Malcus C, et al. Lack of recovery in monocyte human leukocyte antigen-DR expression is independently associated with the development of sepsis after major trauma. Crit Care 2010;14:R208.View ArticlePubMedPubMed CentralGoogle Scholar
- Baiyee EE, Flohe S, Lendemans S, Bauer S, Mueller N, Kreuzfelder E, et al. Expression and function of Toll-like receptor 9 in severely injured patients prone to sepsis. Clin Exp Immunol 2006;145:456–62.View ArticlePubMedPubMed CentralGoogle Scholar
- Dahl B, Schiodt FV, Ott P, Wians F, Lee WM, Balko J, et al. Plasma concentration of Gc-globulin is associated with organ dysfunction and sepsis after injury. Crit Care Med 2003;31:152–6.View ArticlePubMedGoogle Scholar
- Logters TT, Laryea MD, Altrichter J, Sokolowski J, Cinatl J, Reipen J, et al. Increased plasma kynurenine values and kynurenine-tryptophan ratios after major trauma are early indicators for the development of sepsis. Shock 2009;32:29–34.View ArticlePubMedGoogle Scholar
- Ikegami K, Suzuki Y, Yukioka T, Matsuda H, Shimazaki S. Endothelial cell injury, as quantified by the soluble thrombomodulin level, predicts sepsis/multiple organ dysfunction syndrome after blunt trauma. J Trauma 1998;44:789–795.View ArticlePubMedGoogle Scholar
- Kisat M, Villegas CV, Onguti S, Zafar SN, Latif A, Efron DT, et al. Predictors of sepsis in moderately severely injured patients: An analysis of the National Trauma Data Bank. Surg Infect (Larchmt) 2013;14:62–8.View ArticleGoogle Scholar
- Knoferl MW, Diodato MD, Angele MK, Ayala A, Cioffi WG, Bland KI, et al. Do female sex steroids adversely or beneficially affect the depressed immune responses in males after trauma-hemorrhage? Arch Surg 2000;135:425–33.View ArticlePubMedGoogle Scholar
- Raju R, Chaudry IH. Sex steroids/receptor antagonist: Their use as adjuncts after trauma-hemorrhage for improving immune/cardiovascular responses and for decreasing mortality from subsequent sepsis. Anesth Analg 2008;107:159–66.View ArticlePubMedGoogle Scholar
- Knoferl MW, Angele MK, Diodato MD, Schwacha MG, Ayala A, Cioffi WG, et al. Female sex hormones regulate macrophage function after trauma-hemorrhage and prevent increased death rate from subsequent sepsis. Ann Surg 2002;235:105–12.View ArticlePubMedPubMed CentralGoogle Scholar
- Morgan AS. Risk factors for infection in the trauma patient. J Natl Med Assoc 1992;84:1019–23.PubMedPubMed CentralGoogle Scholar
- Kim YJ. Injury severity scoring systems: A review of application to practice. Nurs Crit Care 2012;17:138–50.View ArticlePubMedGoogle Scholar
- Baker SP, O’Neill B, Haddon W Jr., Long WB. The injury severity score: A method for describing patients with multiple injuries and evaluating emergency care. J Trauma 1974;14:187–96.View ArticlePubMedGoogle Scholar
- Balogh ZJ, Varga E, Tomka J, Suveges G, Toth L, Simonka JA. The new injury severity score is a better predictor of extended hospitalization and intensive care unit admission than the injury severity score in patients with multiple orthopaedic injuries. J Orthop Trauma 2003;17:508–12.View ArticlePubMedGoogle Scholar
- Osler T, Baker SP, Long W. A modification of the injury severity score that both improves accuracy and simplifies scoring. J Trauma 1997;43:922–926.View ArticlePubMedGoogle Scholar
- Harwood PJ, Giannoudis PV, Probst C, Van Griensven M, Krettek C, Pape HC, Polytrauma Study Group of the German Trauma Society. Which AIS based scoring system is the best predictor of outcome in orthopaedic blunt trauma patients? J Trauma 2006;60:334–40.View ArticlePubMedGoogle Scholar
- Jennett B, Teasdale G. Aspects of coma after severe head injury. Lancet 1977;1:878–81.View ArticlePubMedGoogle Scholar
- Middleton PM. Practical use of the Glasgow Coma Scale; a comprehensive narrative review of GCS methodology. Australas Emerg Nurs J 2012;15:170–83.View ArticlePubMedGoogle Scholar