Current concepts of the inflammatory response after major trauma: an update

doi:10.1016/S0020-1383(02)00416-3

Injury

Volume 34, Issue 6, June 2003, Pages 397-404

https://doi.org/10.1016/S0020-1383(02)00416-3 Get rights and content

Abstract

During the past century explosive developments have taken place in the field of molecular medicine and genetics, vastly expanding our understanding of the normal physiological response to injury. We have been able to characterise specific molecular and cell biological processes and apply some of this knowledge to the treatment of multiply injured patients.

Despite the significant steps we have made, there still remains much work to be done in this area.

This review article highlights the current concepts of post-traumatic immunological changes and their impact in the management of trauma patients.

Introduction

Despite the advances made in injury prevention, pre-hospital care, critical care medicine, and various new therapeutic agents death after injury continues to occur in three phases 5. The first peak (45% of patients) represents the immediate effect of severe destructive injury with death usually occurring at the scene of the accident. The second peak is smaller (10%) and represents early deaths during the first day usually due to hypoxia, hypovolaemia or severe primary head injury. Immediate resuscitation and emergency surgery is primarily aimed at saving life by correcting the physiological defects that are present in this phase. The third peak (45%), days or weeks following injury represents the vast majority patients that reach hospital 5. These are patients who die on intensive care units, essentially of the after effects of head injury or of adult respiratory distress syndrome (ARDS) and multiple organ failure syndrome (MOF) 17., 26., 41.. This failure of all essential organ systems probably represents the widespread results of an uncontrolled immuno-inflammatory response 44.

The understanding of the host’s response to injury has increased greatly in recent years and is the topic of this review.

Section snippets

Pathogenesis of ARDS and MOF

Before referring to the immunological events occurring following trauma, it is essential to understand the pathogenesis of ARDS and MOF in these circumstances. MOF is characterised by generalised inflammation and tissue damage. In the early 1970s, Tilney et al. were given credit for first describing sequential failure of multiple organs in 18 consecutive patients with ruptured abdominal aortic aneurysm who required postoperative haemodialysis 62. These authors concluded that this was the result

Immune response following trauma

The immuno-inflammatory response is initiated in the immediate aftermath following trauma. Polymorphonuclear leukocytes (PMNs), the endothelium, macrophages and lymphocytes all become activated by the secretion of various mediators including cytokines and other molecules such as nitric oxide, platelet activating factor, reactive oxygen species, growth factors and eicosanoids 9. Furthermore, several physiological events occur centrally to regulate the injury sustained. The release of adrenaline

The role of cytokines

The alterations that take place in haemodynamic, metabolic and immune responses are mainly regulated by endogenous mediators referred to as cytokines. Trauma patients are a stew of pulsating cytokines, which serve as the language between activated cells in order to maintain total body homeostasis. These active biological autocoids are produced by diverse cell types at the site of injury and by systemic immune cells. Their rapid appearance after injury reflects active gene transcription and

Immune reactivity concepts

Multiple alterations in inflammatory and immunological functions have been demonstrated in clinical and experimental situations shortly after trauma and haemorrhage. Traumatic injury leads to systemic inflammation (systemic inflammatory response syndrome or SIRS) followed by a period of recovery mediated by counter-regulatory anti-inflammatory response (CARS) (Fig. 1) 38. Severe inflammation may lead to acute organ failure and early death after injury but a lesser inflammatory response followed

The first and second hit phenomena

Numerous studies have demonstrated that stimulation of a variety of inflammatory mediators takes place in the immediate aftermath following trauma. This response initially corresponds to the first hit phenomenon. In general, several authors have demonstrated the biological profile of the first hit in trauma patients and have shown a direct correlation between the level of the release of the inflammatory and anti-inflammatory mediators and the degree of injury 20., 25., 34..

The work of Obertacke

Immuno-suppression

Whilst, selective immunostimulation may play a critical part in the development of severe complications after injury, it is also clear that the governing effect of surgical or accidental trauma on immune function is suppressive. Following trauma, the production of immunoglobulins and interferon (IFN) fall and many patients become anergic as assessed by delayed hypersensitivity skin testing, being thus exposed to an increased risk of post-traumatic sepsis 35., 53.. Defects in neutrophil

Theories of abnormal immuno-inflammatory response

The mechanism by which the host response to trauma changes from normal to abnormal and cannot be compensated by the biological reserve of the patient is not understood fully. Theories have been proposed of mediator defects including cytokine excess, nitrous oxide overproduction and selective transcriptional failure. Probably the abnormal response involves of all three mechanisms.

Cytokine excess has been demonstrated in patients with sepsis and has been correlated with outcome. These cytokines

Markers of immune reactivity

A vast number of clinical trials have provided us with information of the multifaceted picture of the trauma patient in physiological crisis being at risk for the multiple organ dysfunction syndrome and combating for survival. Unfortunately, once multiple systems are dysfunctional the mortality rates remain as high as 50%, patient morbidity is severe and the health care costs are enormous. Although external support (ventilators, dialysis machines, inotropic drugs) is provided to all patients in

The importance of individual response and attempts at immuno therapy

Biological variation is increasingly offered as an explanation for why some patients develop serious post-traumatic complications and others do not, despite the same injury severity scores and similar risk factors 28. A genetic predisposition is suspected to be responsible for these differences in outcome, some individuals may just be pre-programmed to develop a hyper reaction to a given insult. Genetic polymorphism of the neutrophil receptor for immunoglobulin G, CD 16 has been reported and is

Hope for the future

Despite increasing knowledge of the mechanisms of cellular and molecular events that occurring during the inflammatory response, several approaches to inhibiting components of the mediator cascade in an attempt to improve the outcome following trauma and sepsis have not been successful. One reason these molecules have not been effective in clinical settings may be due to the difficulty in identifying the patients who might benefit from this type of therapy together with the critical delay

Conclusion

A series of inflammatory reactions is initiated shortly after major trauma. Uncontrolled or unbalanced responses may persist leading to SIRS and MOF. Inflammatory cells are recruited to the site of injury and elaborate cytokines which promote repair locally, but in severe injury may be released systemically and trigger remote inflammation. The search continues for suitable inflammatory markers, which could direct the appropriate timing of surgical intervention in high-risk patients. Knowing

References (68)

C.C. Baker et al.
Epidemiology of trauma deaths
Am. J. Surg.
(1980)
S.R. Baldwin et al.
Oxidant activity in expired breath of patients with the adult respiratory distress syndrome
Lancet
(1986)
W.G. Cheadle et al.
HLA-DR antigen expression on peripheral blood monocytes correlates with surgical infection
Am. J. Surg.
(1991)
E.G. Davis et al.
Microsatellite marker of interferon-gamma receptor 1 gene correlates with infection following major trauma
Surgery
(2000)
P.J. Guillou
Biological variation in the development of sepsis after surgery or trauma
Lancet
(1993)
C.E. Hack et al.
Increased plasma levels of IL-6 in sepsis
Blood
(1989)
F.A. Moore et al.
Evolving concepts in the pathogenesis of post-injury multiple organ failure
Surg. Clin. North Am.
(1995)
L.W. Norton
Does drainage of intra-abdominal pus reverse multiple organ failure?
Am. J. Surg.
(1985)
T. Taniguchi et al.
The ratio of interleukin-6 to interleukin-10 correlates with severity in patients with chest and abdominal trauma
Am J. Emerg. Med.
(1999)
L.M. Zheutlin et al.
Plasma elastase levels in the adult respiratory distress syndrome
Crit. Care Med.
(1986)

E. Abraham

Why immunomodulatory therapies have not worked in sepsis?

Int. Care Med.

(1999)

J. Andermahr et al.

Pneumonia in multiple injured patients: a prospective controlled trial on early prediction using clinical and immunological parameters

Inflamm. Res.

(2002)

B.O. Anderson et al.

Multiple organ failure: inflammatory priming and activation sequences promote autogenous tissue injury

J. Trauma

(1990)

K.M. Andrejko et al.

Intrahepatic STAT-3 activation and acute phase gene expression predict outcome following cecal ligation and puncture sepsis in the rat

Am. J. Physiol.

(1998)

A.M. Bowcock et al.

Rapid detection and sequencing of alleles in the 3′ flanking region of the interleukin-6 gene

Nucl. Acids Res.

(1989)

M.D. Cipolle et al.

Secondary organ dysfunction: from clinical perspectives to molecular mediators

Crit. Care Clin.

(1993)

P. Damas et al.

Cytokine serum level during severe sepsis in human IL-6 as a marker of severity

Ann. Surg.

(1992)

B. Eisman et al.

Multiple organ failure

Surg. Gynaecol. Obstet.

(1977)

W. Ertel et al.

Release of anti-inflammatory mediators after mechanical trauma correlates with severity of injury and clinical outcome

J. Trauma

(1995)

E. Faist et al.

Multiple organ failure in polytrauma patients

J. Trauma

(1983)

J.M. Fernandez-Real et al.

Interleukin-6 gene polymorphism and insulin sensitivity

Diabetes

(2000)

D. Fishman et al.

The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis

J. Clin. Invest.

(1998)

A.A. Fowler et al.

Adult respiratory distress syndrome: risk with common predisposition

Ann. Intern. Med.

(1983)

D.E. Fry et al.

Multiple system organ failure. The role of uncontrolled infection

Arch. Surg.

(1980)

P.V. Giannoudis et al.

Fatal systemic inflammatory response syndrome following early bilateral femoral nailing

Intensive Care Med.

(1998)

P.V. Giannoudis et al.

Stimulation of inflammatory markers after blunt trauma

Br. J. Surg.

(1998)

P.V. Giannoudis et al.

Stimulation of the inflammatory system by reamed and unreamed nailing of femoral fractures: an analysis of the second hit

J. Bone J. Surg.

(1999)

P.V. Giannoudis et al.

Serum CRP and IL-6 levels after trauma. Not predictive of septic complications

Acta Orthop. Scand.

(1998)

P.V. Giannoudis et al.

HLA-DR expression and intrapulmonary shunt following trauma

Shock

(1997)

P.V. Giannoudis et al.

Immediate IL-10 expression following major orthopaedic trauma: relationship to anti-inflammatory response and subsequent development of sepsis

Intensive Care Med.

(2000)

P.V. Giannoudis et al.

Molecular mediators and trauma: effects of accidental trauma on the production of plasma elastase, IL-6, ICAM-1 and e-selectin

Injury

(1996)

J.A. Goris et al.

Multiple organ failure

Arch. Surg.

(1985)

D.N. Granger et al.

The microcirculation and inflammation: modulation of leukocyte–endothelial cell adhesion

J. Leukocyte Biol.

(1994)

Harlan JM. Neutrophil-mediated vascular injury. Acta Med Scand 1987;(Suppl...

Cited by (185)

Effect of early hemostasis strategy on secondary post-traumatic sepsis in trauma hemorrhagic patients
2024, Injury
Fibrinogen and platelet, as the two main components of hemostatic resuscitation, are frequently administered in traumatic massive hemorrhage patients. It is reasonable to infer that they may have an impact on post-traumatic sepsis as more and more recognition of their roles in inflammation and immunity. This study aims to determine the association between the fibrinogen/platelet transfusion ratio during the first 24 h after trauma and the risk of the post- traumatic sepsis.
We analyzed the data from the National Trauma Data Bank (NTDB). Subjects included the critically injured adult patients admitted to Level I/II trauma center from 2013 to 2017 who received fibrinogen and platelet supplementation and more than 10 units (about 4000 ml) packed red blood cells (pRBCs) during the first 24 h after trauma. Two parts of analyses were performed: (1) multivariable stepwise regression was used to determine the variables that influence the risk of post-traumatic sepsis; (2) propensity score matching (PSM), to compare the influences of different transfusion ratio between fibrinogen and platelet on the risk of sepsis and other outcomes after trauma.
8 features were screened out by bi-directional multivariable stepwise logistic regression to predict the post-traumatic sepsis. They are age, sex, BMI, ISS_abdomen, current smoker, COPD, Fib_4h/24h and Fib/PLT_24h. Fib/PLT_24h was negatively related to sepsis (p < 0.05). A total of 1601 patients were included in the PSM cohort and grouped by Fib/PLT_24h = 0.025 according to the fitting generalized additive model (GAM) model curve. The incidence of sepsis was significantly decreased in the high Fib/PLT group [3.3 % vs 9.4 %, OR = 0.33, 95 %CI (0.17–0.60)]; the length of stay in ICU and mechanical ventilation were both shortened as well [8 (IQR 2.00,17.00) vs 9 (IQR 3.00,19.25), p = 0.006 and 4 (IQR 2.00,10.00) vs 5 (IQR 2.00,14.00), p = 0.003, respectively.
Early and sufficient supplementation of fibrinogen was a convenient way contribute to reduce the risk of sepsis after trauma.
Prediction models of methicillin sensitive Staphylococcus aureus ventilator associated pneumonia relapse in trauma and brain injury patients: A retrospective analysis
2021, Journal of Critical Care
To describe the incidence and risk factors of methicillin sensitive Staphylococcus aureus ventilator associated pneumonia (MSSA-VAP) relapse in trauma and non-traumatic brain injury patients.
Retrospective observational monocentric cohort study of consecutive ICU patients who developed a first episode of MSSA-VAP after trauma and non-traumatic brain injury. MSSA-VAP relapse encompass MSSA-VAP treatment failure (persistence or recurrence of MSSA) or other pathogen - VAP.
A total of 165 patients (71% of trauma and 29% of non-traumatic brain injury) with MSSA-VAP were included. MSSA-VAP relapse occurred in 54 (33%) patients, including 28 (17%) MSSA-VAP treatment failure and 46 (28%) other pathogen-VAP. Empirical first-line antibiotic therapy was appropriate in 96% of cases. In multivariate analysis, the presence of Streptococcus species (Odds ratio [OR] 7.37) and oropharyngeal flora (OR 3.64) as initial MSSA co-pathogen, suggested aspiration at the time of admission and independently predicted MSSA-VAP treatment failure. Initial Glasgow coma scale (OR 0.89), need for emergent surgery (OR 5.71) and the presence of an acute respiratory distress syndrome at the time of the first MSSA-VAP (3.99), independently predicted the onset of other pathogen – VAP.
Early and simple factors may help to identify patients with high-risk of MSSA-VAP relapse.
Fat embolism syndrome
2021, BJA Education
Can IL-6 predict the development of fat embolism in polytrauma? A rabbit model pilot experimental study
2020, Journal of Clinical Orthopaedics and Trauma
There are few studies in the literature that correlates the level of IL-6 with fat embolism syndrome (FES). But there is no conclusive correlative evidence of its specific relation to the establishment of FES. Also it is a proven fact that polytrauma due to its associated multiple long bone fracture and/or associated shock can predispose an individual to FES. By hypothesizing that polytrauma induces Fat Embolism in the animal; it was considered worthwhile to study the association of IL-6 in polytrauma induced Fat Embolism (FE) and to compare it with induced FE by injecting fatty acids in rabbits.
An animal study was conducted in 32 New Zealand white rabbits. The animals were divided into 3 groups: control, fat embolism and polytrauma group. We injected 6 ml of normal saline and 0.2 ml of linoleic acid in the control and fat embolism group respectively. In the polytauma group we created bilateral femur and tibial shaft factures which were stabilized with intramedullary K- wires. Blood was taken before and at 6, 12 and 24 h after the procedure to measure plasma IL-6 levels. The rabbits were euthanized at 24 h and lungs were removed and stained for fat globules.
All rabbits in the fat embolism group and around 72.22% rabbits in polytrauma group had fat embolism. The IL-6 levels were raised in all the groups reaching a peak at 6 h after procedure with a decline in the values at 12 h for polytrauma and fat embolism group. IL-6 in the control group was stationary after an initial raise at 6 h. There was no statistically significant difference seen among the groups (p value > 0.05) at 6 h.
IL-6 is not a specific marker to fat embolism per se or polytrauma who later develop complications like FES. Even though the recent literature says that IL-6 is an early marker of fat embolism, still the diagnosis of fat embolism syndrome is clinical only and can be supplemented by laboratory markers. None of the laboratory markers individually is good enough to predict the development of FES in an individual.
Elevations in Circulating sST2 Levels Are Associated With In-hospital Mortality and Adverse Clinical Outcomes After Blunt Trauma
2019, Journal of Surgical Research
Soluble suppression of tumorigenicity 2 (sST2), a decoy receptor for interleukin (IL)-33, has emerged as a novel biomarker in various disease processes. Recent studies have elucidated the role of the sST2/IL-33 complex in modulating the balance of Th1/Th2 immune responses after tissue stress. However, the role of sST2 as a biomarker after traumatic injury remains unclear. To address this, we evaluated serum sST2 correlations with mortality and in-hospital adverse outcomes as endpoints in blunt trauma patients.
We retrospectively analyzed clinical and biobank data of 493 blunt trauma victims 472 survivors (mean age: 48.4 ± 0.87; injury severity score [ISS]: 19.6 ± 0.48) and 19 nonsurvivors (mean age: 58.8 ± 4.5; ISS: 23.3 ± 2.1) admitted to the intensive care unit. Given the confounding impact of age on the inflammatory response, we derived a propensity-matched survivor subgroup (n = 19; mean age: 59 ± 3; ISS: 23.4 ± 2) using an IBM SPSS case-control matching algorithm. Serial blood samples were obtained from all patients (3 samples within the first 24 h and then once daily from day [D] 1 to D5 after injury). sST2 and twenty-nine inflammatory biomarkers were assayed using enzyme-linked immunosorbent assay and Luminex, respectively. Two-way analysis of variance on ranks was used to compare groups (P < 0.05). Spearman rank correlation was performed to determine the association of circulating sST2 levels with biomarker levels and in-hospital clinical outcomes.
Circulating sST2 levels of the nonsurvivor cohort were statistically significantly elevated at 12 h after injury and remained elevated up to D5 when compared either to the overall 472 survivor cohort or a matched 19 survivor subcohort. Admission sST2 levels obtained from the first blood draw after injury in the survivor cohort correlated positively with admission base deficit (correlation coefficient [CC] = 0.1; P = 0.02), international normalized ratio (CC = 0.1, P = 0.03), ISS (CC = 0.1, P = 0.008), and the average Marshall multiple organ dysfunction score between D2 and D5 (CC = 0.1, P = 0.04). Correlations with ISS revealed a positive correlation of ISS with plasma sST2 levels across the mild ISS (CC = 0.47, P < 0.001), moderate ISS (CC = 0.58, P < 0.001), and severe ISS groups (CC = 0.63, P < 0.001). Analysis of biomarker correlations in the matched survivor group over the initial 24 h after injury showed that sST2 correlates strongly and positively with IL-4 (CC = 0.65, P = 0.002), IL-5 (CC = 0.57, P = 0.01), IL-21 (CC = 0.52, P = 0.02), IL-2 (CC = 0.51, P = 0.02), soluble IL-2 receptor-α (CC = 0.5, P = 0.02), IL-13 (CC = 0.49, P = 0.02), and IL-17A (CC = 0.48, P = 0.03). This was not seen in the matched nonsurvivor group. sST2/IL-33 ratios were significantly elevated in nonsurvivors and patients with severe injury based on ISS ≥ 25.
Elevations in serum sST2 levels are associated with poor clinical trajectories and mortality after blunt trauma. High sST2 coupled with low IL-33 associates with severe injury, mortality, and worse clinical outcomes. These findings suggest that sST2 could serve as an early prognostic biomarker in trauma patients and that sustained elevations of sST2 could contribute to a detrimental suppression of IL-33 bioavailability in patients with high injury severity.
Molecular biology of acute and chronic inflammation
2019, Clinical Molecular Medicine: Principles and Practice
Inflammation is a natural response of tissues and organs following acute or chronic trauma, acute infection, or acute immune-mediated tissue damage. It is spontaneous and often positive and beneficial in response to acute injury or invading pathogen. The pathogenesis of acute and chronic inflammation includes complex molecular pathways involving several genes, genetic/genomic polymorphisms, peptides, and many other molecules. This chapter provides a clinically relevant overview on molecular complexities of inflammation.

View all citing articles on Scopus

View full text

ReviewCurrent concepts of the inflammatory response after major trauma: an update

Abstract

Introduction

Section snippets

Pathogenesis of ARDS and MOF

Immune response following trauma

The role of cytokines

Immune reactivity concepts

The first and second hit phenomena

Immuno-suppression

Theories of abnormal immuno-inflammatory response

Markers of immune reactivity

The importance of individual response and attempts at immuno therapy

Hope for the future

Conclusion

Am. J. Surg.

Lancet

Am. J. Surg.

Surgery

Lancet

Blood

Surg. Clin. North Am.

Am. J. Surg.

Am J. Emerg. Med.

Crit. Care Med.

Why immunomodulatory therapies have not worked in sepsis?

Int. Care Med.

Pneumonia in multiple injured patients: a prospective controlled trial on early prediction using clinical and immunological parameters

Inflamm. Res.

Multiple organ failure: inflammatory priming and activation sequences promote autogenous tissue injury

J. Trauma

Intrahepatic STAT-3 activation and acute phase gene expression predict outcome following cecal ligation and puncture sepsis in the rat

Am. J. Physiol.

Rapid detection and sequencing of alleles in the 3′ flanking region of the interleukin-6 gene

Nucl. Acids Res.

Secondary organ dysfunction: from clinical perspectives to molecular mediators

Crit. Care Clin.

Cytokine serum level during severe sepsis in human IL-6 as a marker of severity

Ann. Surg.

Multiple organ failure

Surg. Gynaecol. Obstet.

Release of anti-inflammatory mediators after mechanical trauma correlates with severity of injury and clinical outcome

J. Trauma

Multiple organ failure in polytrauma patients

J. Trauma

Interleukin-6 gene polymorphism and insulin sensitivity

Diabetes

The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis

J. Clin. Invest.

Adult respiratory distress syndrome: risk with common predisposition

Ann. Intern. Med.

Multiple system organ failure. The role of uncontrolled infection

Arch. Surg.

Fatal systemic inflammatory response syndrome following early bilateral femoral nailing

Intensive Care Med.

Stimulation of inflammatory markers after blunt trauma

Br. J. Surg.

Stimulation of the inflammatory system by reamed and unreamed nailing of femoral fractures: an analysis of the second hit

J. Bone J. Surg.

Serum CRP and IL-6 levels after trauma. Not predictive of septic complications

Acta Orthop. Scand.

HLA-DR expression and intrapulmonary shunt following trauma

Shock

Immediate IL-10 expression following major orthopaedic trauma: relationship to anti-inflammatory response and subsequent development of sepsis

Intensive Care Med.

Molecular mediators and trauma: effects of accidental trauma on the production of plasma elastase, IL-6, ICAM-1 and e-selectin

Injury

Multiple organ failure

Arch. Surg.

The microcirculation and inflammation: modulation of leukocyte–endothelial cell adhesion

J. Leukocyte Biol.

Review
Current concepts of the inflammatory response after major trauma: an update