© Springer Nature Singapore Pte Ltd. 2017
Xiaobing Fu and Liangming Liu (eds.)Advanced Trauma and Surgery10.1007/978-981-10-2425-2_12Early Prediction and Prevention of Trauma-Related Infection/Sepsis
(1)
State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, 400042, China
Abstract
According to the World Health Organization, trauma still stands for one of the leading causes of death around the world. Although the incidence of post-traumatic sepsis in the hospital has decreased in the past two decades, the mortality (between 19.5 and 23 %) of septic trauma patients is still high. Early prediction of the sepsis development can help the subsequent intervention and treatment for the patients and contribute to improving the outcome. This chapter is mainly divided into two sections, early prediction and prevention of trauma-related infection/sepsis. The methods for predicting sepsis in trauma patients are primarily using biomarkers (e.g., PCT, IL-10, PSP/reg, IL-1, NT-proCNP, Lactate clearance, mHLA-DR), patient demographics (e.g., age, gender, race) and injury characteristics (e.g., Injury severity, mechanism of injury, number of injuries, hypotension on admission). According to the new definition of sepsis, the prevention of trauma-related infection /sepsis correspondingly includes infection prevention (e.g., surgical managements, prophylactic antibiotics, tetanus vaccination, immunomodulatory interventions) and organ dysfunction prevention (e.g., pharmaceuticals, temporary intravascular shunts, lung-protective strategies, enteral immunonutrition, acupuncture). As a single method of prediction and prevention may not have the desired level of sensitivity and specificity for diagnostic and apotropaic purposes, a new combination of measures can be generated to improve posttraumatic diagnosis and outcome. Overall, more efficient and accurate ways to predict and prevent the trauma-related infection/sepsis should be developed.
Keywords
PredictionPreventionTraumaInfectionSepsis1 Early Prediction
Early prediction of the sepsis development can help the early intervention and treatment for the patients and contribute to improving the outcome. So far, the methods for predicting sepsis in trauma patients are mainly using biomarkers, patient demographics and injury characteristics. But the studies on verifying their predictive value are very few and the results are still controversial. More work should be done to explore more efficient and accurate ways to predict the posttraumatic sepsis.
1.1 Biomarkers
According to the Biomarkers Definitions Working Group, biomarker (biological marker) 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 [1]. In another word, Biomarkers are tools to measure biologic homeostasis that give standard to what is normal, and providing a quantifiable method for predicting or detecting what is abnormal [2]. The ideal biomarker for sepsis should have a high sensitivity allowing for early diagnosis, and would be specific for pathogenic microorganism in order to allow appropriate therapy [3]. It has been reported that more than 80 molecules have been proposed as useful biomarkers of sepsis [4], and to date, the number increases to 178 or more [5]. The validation of a biomarker needs three aspects of its performance: “(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” [6]. Here we list some representable candidates among the potential biomarkers of posttraumatic sepsis.
Procalcitonin (PCT)
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 the calcium homeostasis [7]. PCT has been proved to be an marker of bacterial infection and sepsis [8, 9], while PCT is released systemically from various kinds of cells outside the thyroid as a response to bacterial infection [10]. On the condition of systemic bacterial infection or by stimulation with endotoxin or proinflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin -6 (IL-6) and interleukin-1 (IL-1), PCT levels increase 1000 times within a few hours [11, 12]. The half-life about 22 h of PCT is another characteristic that it can be used as a biomarker for bacterial infection because its level show a rapid decrease when infection is resolved whereas many other inflammatory biomarkers still keep high levels during the acute-phase response [11]. For predicting posttraumatic 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 [13]. Continuous high levels or secondary increases of PCT are predictors of sepsis [10, 11, 14–19]. PCT as a biomarker is useful in predicting and early diagnosis of sepsis in trauma patients.
C-reactive Protein (CRP)
CRP belongs to acute phase protein family, and each one is made of five protomers of 206 amino acid residues, and belongs to the pentraxin family of calcium-dependent ligand-binding plasma proteins [20]. 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 kinds of systemic inflammation, including infections or trauma [20–22]. So it is a sensitive marker of inflammation and tissue damage. The half-life of CRP is 19 h [23]. Serum CRP is as a biomarker because of the rapid concentrations increasing in response to inflammation, the shorter half-life, and the wildly available inexpensive test. Many researchers have explored the predictive value of CRP for posttraumatic sepsis , but the results are unsatisfactory. Both prospective studies and retrospective studies have been reported no predictive power of CRP for sepsis in trauma patients [11, 13, 19, 24–27].
Interleukin-6 (IL-6)
IL-6 is a glycoprotein synthetized by various kinds of cells including T- and B-cells and endothelial cells. Other cytokines (IL-1, TNF) and viruses and bacterial components such as LPS induce the production of IL-6. IL-6 induces hepatic producing 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 [28]. Its release is triggered by tissue damage or infection. It is a cytokine involving in both pro-inflammatory and anti-inflammatory response [29]. IL-6 has a rapid onset, peaking within 2 h after the infectious stimulus [30]. The results of studies on the predict value of IL-6 for posttraumatic sepsis are controversial. Some studies have found that IL-6 is able to discriminate trauma patients prone to sepsis [15, 16], while others have shown no correlation between the IL-6 levels and sepsis development [26, 27, 31–34].
Interleukin-10 (IL-10)
IL-10 is a protein produced by T-lymphocytes, B-lymphocytes, macrophages, and dendritic cells (DC) [35]. It is an anti-inflammatory cytokine playing a role in counter inflammatory and autoimmune pathologies [36]. IL-10 down-regulates MHC class II and costimulatory molecule 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) and decreases cytokines production of Th-1 cells [35]. IL-10 peaks quickly in a few hours (4 h) following trauma, and the levels decreasing rapidly in all patients (the first day after trauma) [37, 38]. IL-10 levels have been shown significant higher in patients who develop sepsis at the point of admission [13, 37–40].
Neopterin
Neopterin is a pteridine produced by monocytes or macrophages upon stimulation with interferon-γ (IFN-γ) then released into body circulation [41]. It is helpful in diagnosis of bacterial, viral infections and systemic inflammation. In addition, increased levels of neopterin are associated with endothelial damage, organ dysfunction and sepsis [42]. Among the studies performed on predicting posttraumatic sepsis , neopterin levels have shown no statistical difference between patients who developed and not developed sepsis [26, 42–44].
Pancreatic Stone Protein/Regenerating Protein (PSP/Reg)
PSP/reg is a lectin-binding acute phase protein and was initially found in patients with pancreatitis [45]. PSP/reg acts as an acute phase protein causing the activation of leukocytes and can also be observed in other cells outside pancreas [16]. Its release is reduced by IL-6 following tissue injury [46]. PSP/reg levels can predict and distinguish no infection, local infection and septic complications in posttraumatic patients [16].
Interleukin-1 (IL-1)
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 [47]. Its effects on central nervous system cause fever, then the elevated temperature leads to an increased migration of leukocyte. Few literatures give the evidence of predictive power of IL-6 to sepsis after trauma except Menges et al. [39] has 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 is first identified in 1990. CNP participates in physiological processes such as bone growth, reproduction, nerve growth, and re-endothelialisation [48]. 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 [49]. 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 [49]. Results of a study show that the levels of circulating NT-proCNP can discriminate polytrauma patients without traumatic brain injury who develop sepsis from who do not [50].
Polymorphonuclear Elastase (PMNE)
In healthy adults, PMN is circulating in the resting state and it can be activated following major trauma [51]. PMN is the main effector cell of the inflammatory response posttrauma and it produces and releases toxic reactive oxygen species. PMN activation and inflammatory response post trauma may be reflected on serum elastase levels [51]. Some studies have proven the difference of PMN elastase between patients with and without infection or sepsis [31, 43], while some others have shown that it has no correlation with post-traumatic infective complications [26, 27].
Lactate Clearance
Persistent occult hypoperfusion is as a risk factor for infections following trauma [52]. And lactate clearance is proposed as a measure of early sepsis resuscitation effectiveness [53]. So lactate clearance can be a biomarker of sepsis. During the first 12–24 h, the lactate clearance is associated with the posttraumatic sepsis [15, 52].
IL-18
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 be high levels in sepsis patients compared to healthy people [54]. Mommsen et al. [42] has proposed IL-18 concentrations as early markers for posttraumatic complications such as sepsis and MODS .
Monocyte Human Leukocyte Antigen DR (mHLA-DR)
Human leukocyte antigen-DR (HLA-DR) protein is a member of the MHC class II system. HLA-DR is expressed in antigen presenting cells (APC) including monocytes, macrophages, dendritic cells, B lymphocytes [55]. Low expression of Human Leukocyte Antigen DR on circulating monocytes (mHLA-DR) is reported as an indicator to post trauma immunosuppression [55, 56]. And studies show that the decreased level in mHLA-DR is a biomarker of sepsis development after major trauma [57–59].
Other Biomarkers for Sepsis Following Trauma
Some potential biomarkers such as Toll-like receptor-9 (TLR-9) [60], PMN CD11b [33], Soluble FAS (sFAS) [31], L- and I-FABPs (small fatty acid binding proteins) [61], Group-specific component globulin (Gc-globulin) [62], kynurenine values and kynurenine-tryptophan ratios [63], shock index (SI) [64], Protein phosphatase type 2A (PP2A) [65], NT-proBNP level [66], the soluble thrombomodulin (s-TM) level [67] and serum S100 beta [68] also have been reported to have predictive abilities to post traumatic sepsis. TNF-α as an important cytokine has been proved to have no sufficiently predictive value of sepsis development after trauma [34].
Up to now, a lot of biomarkers have been proposed in the field of sepsis. But to the posttraumatic sepsis, there are only a few biomarkers proved to be useful. Among the biomarkers for sepsis following trauma, PCT is the most extensively investigated biomarker, and the results show the good application to predicting this complication. But to others, like CRP, though many studies have been performed on it, the results show no predictive power for patients in trauma. 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. Traumatic injuries cause the great changes in the immunological and neurohormonal environments and then affect the physiological processes. After trauma, the innate immune system is activated,then a lot of 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 the endothelium and tissue damage. To counter these disadvantages, anti-inflammatory cytokines such as IL-10 are released,leading to the immune suppression and increased risk to 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 protein such as PCT and CRP [69].
Most of these biomarkers illustrated above participate in the reaction of systemic inflammation. But post trauma physiological processes may become more complicated due to the immune function disorders causing by multiple trauma. For example, under the condition of abdominal or brain trauma, the kinetics of biomarkers can be changed [13]. So more tests should be performed to verify the predict value of the present biomarkers and find more biomarkers suitable to the traumatic sepsis.
1.2 Patient Demographics
Patient demographics including age, gender, and race are as risk factors associated with posttraumatic sepsis.
Older age is an independent risk factor for sepsis following trauma [70–73]. This may because the elderly trauma patients have decreased cardiopulmonary function, poor nutritional status, and susceptible to increased bleeding after injuries, and these factors may contribute to the disorder of physiological processes and immunologic function. In addition, the elder traumatic patients may have more preexisting diseases than the young patients, while the preexisting diseases is also as an risk factor of posttraumatic sepsis [74].
Some studies have proposed the male gender as a predictor for sepsis post trauma [17, 71, 72, 74, 75]. After trauma, the continuous increased cytokines and the subsequent immunosuppression make the body prone to sepsis. Study performed on animals shows that proestrus females are not immunodepressed compared with male and ovariectomized mice after trauma [76]. There are also tests results that estrogen produces beneficial effects on immune and cardiovascular function after trauma [77] by reducing the release of cytokine production such as TNF-α and maintaining the immune response [78]. So estrogen plays an important role in the gender dimorphism of posttraumatic sepsis.
African American race is reported as a risk factor of sepsis following trauma [72]. But there are not extensive researches done to investigate the role of racial or ethnic factors in posttraumatic sepsis . More researches should be warranted to explore the association between ethnicity and this complication.
1.3 Injury Characteristics
Injury severity, mechanism of injury, number of injuries, hypotension on admission and other injury characteristics are factors associated with posttraumatic sepsis.
Trauma can cause the 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 [79]. Different degrees of trauma severity may lead to the different influences in immune function. The main measures of injury severity are trauma scoring systems.
Among the various scoring systems, Injury Severity Score (ISS) and New Injury Severity score (NISS), members of anatomical scoring systems, are most widely used. The ISS is based on the Abbreviated Injury Scale (AIS) severity values, and it is first developed in 1974 [80]. 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 judge a same severity regardless of the injured body region [81]. The NISS is proposed by Osler et al. in 1997 to counter the limitations of ISS [82]. 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 ISS and NISS was associated with increased incidence of sepsis [70–74, 83].
Besides ISS and NISS, the Glasgow coma scale (GCS) which assess the level of clinical consciousness are also a predictor of sepsis [71, 74]. GCS is first described by Teasdale and Jennett in 1974 [84]. It is the sum of three 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 scores patient gets, the worse condition patient is. GCS belongs to physiological scoring systems [85].
The anatomy scoring systems such as ISS and NISS represent the physical degeneration of the body, and the physiological scoring systems such as GCS stand for the physiological impair caused by trauma. Compared to biomarkers, getting the indexes of these scoring systems are easier, earlier and cheaper.
Liang et al. [86] reported two novel formulae based on LD50 values of ISS and NISS were superior to PCT for prediction of sepsis in trauma patients. The performance of ISS/LD50ISS + SIRS score and NISS/LD50NISS + SIRS score were equivalent (area under the ROC curve (AUC) = 0.816 vs. 0.819, P > 0.05) and both performed better than PCT (AUC = 0.592, P < 0.05) in predicting posttraumatic sepsis. Overall, the two novel formulae ISS/LD50ISS + SIRS score and NISS/LD50NISS + SIRS performed well and both better than PCT in predicting sepsis following trauma. The value of the two formulae can be easily calculated in real-time and can identify the high-risk patients susceptible to sepsis . This method may become an effective way to guide the early assessment and treatment in trauma patients.
2 Prevention
The greatest danger after haemorrhage in trauma patients is sepsis. Sepsis 3.0 was put forward by Society of Critical Care Medicine, the chairman of the United States, Professor Craig Coopersmith on Chinese Medical Association (CMA) ninth intensive medical conference in 2015. The experts suggested the new definition of sepsis should take organ dysfunction (OD) as a core. Thus Sepsis 3.0 is composed of two parts (1) Infection; (2) Sequential Organ Failure Assessment (SOFA) ≥2, regardless earlier or later, as long as the two coexist and then diagnosed. According to the new definition of sepsis, the prevention of trauma-related infection/sepsis correspondingly includes infection (wound infection , nosocomial infection primarily) prevention and OD prevention.
2.1 Infection Prevention
Preventing infection following trauma basically involves preventing wound infection and nosocomial infection. Wound care methods commonly include surgical managements (disinfect, debridement, profuse irrigation and wound cleansing, negative-pressure wound therapy, wound drainage, appropriate wound closure etc.) and pharmaceuticals (prophylactic antibiotics, tetanus vaccination, immunomodulatory interventions, etc.) The prevention of nosocomial infection is another aspect. Immune dysregulation is a well described consequence of trauma, increasing the risk of nosocomial infection. Regional proper clinical protocols and hygiene are the correct methods in the accepted prevention principles. Here, we mention the following measures: chlorhexidine, hydrocortisone, detrusor botulinum toxin A injection, enteral nutrition and management of tube system etc. to prevent ventilator associated pneumonia (VAP), central line-associated bloodstream infection and urinary tract infection (UTI).
2.1.1 Surgical Managements
Hair Removal and Skin Disinfection
Hair is autologous source of wound contamination, and removing hair from the wound can avoid entangling during suture and closure [87]. The type and time of shaving has been revealed necessary in reducing the chance of infection. The infection rate of surgical wounds after electric clippers preparation of the skin is markedly lower than razor [88]. Moreover, shaving hair before wound repair is proved to be higher risk of surgical site infection than clipping hair immediately [89]. Although the antiseptic agents containing iodophor or chlorhexidine can suppress a broad spectrum of organisms and bacterial proliferation, they may damage the wound defenses and promote the development of infection [90]. Consequently, reasonable application of antiseptic agents into the wound should be considered.
Debridement
Wound debridement is the most common surgery used in conflict and civilian cases. First surgical treatment in war surgery at the first echelon hospital is debridement, without primary closure [91]. USA military recommends that repeat debridement and irrigation every 24–48 h before wound clean should be insist on [92]. Debridement can remove devitalized and severely contaminated tissues for preventing infection, and the basic principles of wound debridement are well accepted in field of surgical managements [93, 94]. However, Edlich et al. suggested that the less tissue debrided had been associated with lower wound infection. Thus, it is important to identify the definite limits of dead tissue, for instance, the “4C” guidelines (color, consistency, contraction, circulation) of muscle viability [87]. In the case of complex traumatic hand injuries, meticulous initial debridement of nonviable tissue and skeletal stabilization are paramount in preventing hand infection [95]. Multiple debridements will be necessary if significant contamination is present.
Mechanical Cleansing
Early and thorough irrigation following wound debridement is one of the important steps in basic principles of management of war wounds [91, 92]. Gentle irrigation with low pressure and normal saline will wash out any residual debris and clot and dilute any bacterial load, while high-pressure irrigation (7 psi, pounds per square inch) is applied to dirty or heavily contaminated wounds [91, 96]. Additionally, mechanical cleaning with high-pressure may effectively decrease the level of bacterial contamination and reduce the incidence of wound infection [87, 97].
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