Elsevier

The Lancet

Volume 384, Issue 9952, 18–24 October 2014, Pages 1455-1465
The Lancet

Series
The systemic immune response to trauma: an overview of pathophysiology and treatment

https://doi.org/10.1016/S0140-6736(14)60687-5Get rights and content

Summary

Improvements in the control of haemorrhage after trauma have resulted in the survival of many people who would otherwise have died from the initial loss of blood. However, the danger is not over once bleeding has been arrested and blood pressure restored. Two-thirds of patients who die following major trauma now do so as a result of causes other than exsanguination. Trauma evokes a systemic reaction that includes an acute, non-specific, immune response associated, paradoxically, with reduced resistance to infection. The result is damage to multiple organs caused by the initial cascade of inflammation aggravated by subsequent sepsis to which the body has become susceptible. This Series examines the biological mechanisms and clinical implications of the cascade of events caused by large-scale trauma that leads to multiorgan failure and death, despite the stemming of blood loss. Furthermore, the stark and robust epidemiological finding—namely, that age has a profound influence on the chances of surviving trauma irrespective of the nature and severity of the injury—will be explored. Advances in our understanding of the inflammatory response to trauma, the impact of ageing on this response, and how this information has led to new and emerging treatments aimed at combating immune dysregulation and reduced immunity after injury will also be discussed.

Introduction

According to WHO, trauma accounts for 10% of deaths and 16% of disabilities worldwide—considerably more than malaria, tuberculosis, and HIV/AIDS combined.1 The proportion of deaths that are due to injury is rising worldwide, so that road traffic accidents alone are projected to be the fifth largest cause of death by 2030.2 The peak age group of patients with traumatic injuries is in the second decade of life; however, older trauma victims have become more frequent as populations age. For reasons that will be discussed subsequently, they have higher mortality even after adjustment for comorbidity and extent of injury.

Without medical care most people with a severe bodily injury will bleed to death. This began to change in the 16th century when French military surgeon Ambroise Paré first ligated arteries during amputation. Care improved gradually over the ensuing centuries and then more rapidly after the outbreak of World War 2. Most patients who would previously have died now survive as a result of advances in the management of haemorrhage. The control of haemorrhage and coagulopathy after major trauma has been reviewed recently in The Lancet.3 Topics such as methods to stop bleeding, selection of blood products, finding the balance between underperfusion and overperfusion, and antifibrinolytic and procoagulation therapy were covered. However, many survivors of massive haemorrhage now go on to develop multiorgan failure often accompanied by sepsis.4 Multiorgan failure and sepsis are a result of the systemic response to severe injury, which compounds the original injury (figure 1). Patients who experience severe trauma are now able to survive because of advances in the control and correction of massive blood loss. Thus, responses that were once protective after mild or moderate trauma are now exaggerated and destructive following massive trauma that is now survivable. Increased understanding of the biology of organ damage has spawned a new generation of proposed treatments for major trauma.5, 6 In our Review, we are concerned with the phase of injury in which the immediate threat of exsanguination has been averted, but the patient remains at risk of multiorgan failure and sepsis. Furthermore, we will review possible causes for the substantially worse prognosis experienced by older patients with traumatic injuries, independent of injury severity.

Key messages

  • Victims of trauma frequently survive the initial insult owing to rapid volume replacement and haemostasis; however, they are at risk of multiorgan failure as a result of an over-exuberant, systemic inflammatory response

  • The systemic response not only aggravates the initial organ damage caused by shock, but also reduces the body's ability to fight infection; this process can lead to an increased risk of sepsis, which, in turn, triggers a further vicious cycle of inflammation, immunoparesis, and infection

  • Recent laboratory research has improved our understanding of the complex interaction between the haemostatic, inflammatory, endocrine, and neurological systems; new therapeutic targets such as microvesicles, extracellular DNA, and non-protein mediators have been discovered

  • The aim of treatment is to reduce inflammation without aggravating immunoparesis; most randomised controlled trials assessing treatments targeting systemic immune responses in trauma were inadequately powered and inconclusive; many trials of promising treatment strategies, including statins, immunonutrition, and those targeting neutrophil function, are ongoing

  • The beneficial effects of tranexamic acid demonstrated in the CRASH-2 trial might be attributed not only to its antifibrinolytic effect, which reduces bleeding, but also to its immunomodulatory effect

  • The use of antibiotic prophylaxis, avoidance of starch for fluid resuscitation, and limited use of red-blood-cell transfusions are supported by several studies that include evidence from patients with major trauma

  • Priorities for future research include the use of a systems biology approach for identification of the most propitious therapeutic targets, nesting studies of biological mechanisms within clinical trials, and judicious selection of results from trials in intensive care and general surgery to support studies in patients with traumatic injuries

The systemic response to severe injury involves interactions across the haemostatic, inflammatory, endocrine, and neurological systems, aggravating initial damage caused by hypoperfusion (shock) and reperfusion (figure 1). Endothelium activated by exposure to inflammatory cytokines becomes more porous, allowing mediators of tissue damage to gain access to the intercellular space. The systemic responses to major trauma are associated with a lowered ability to fight infection, leading to sepsis and further activation of the destructive inflammatory response.

Severe injury is associated with the systemic inflammatory response syndrome (SIRS).7 This response starts within 30 min of a major injury, and is an inflammatory response to blood loss and tissue damage rather than infection.

SIRS results from the release of endogenous factors termed damage-associated molecular patterns (DAMPs) or alarmins7, 8 after tissue injury.9 They are secreted by activated immune cells such as neutrophils8 or released from necrotic cells.10 Peptides and mitochondrial DNA released during necrosis provoke a particularly vigorous foreign body reaction, probably because they are ultimately derived from intracellular bacteria. DAMPs directly activate several immune cells, including neutrophils and monocytes, via cell-surface DAMP receptors.8 DAMPs are also potent activators of complement, leading to rapid generation of C3a and C5a.11, 12, 13 Activation of complement and of inflammatory cells triggers the production and release of inflammatory mediators such as interleukins, thereby generating the systemic response seen in SIRS.14 Many therapies to prevent multiorgan failure are directed at targets on the SIRS pathway.

The immune system contains a series of feedback loops to restore homoeostasis. SIRS is associated with a compensatory anti-inflammatory response characterised by raised levels of anti-inflammatory cytokines (eg, interleukin 10 and transforming growth factor-β) and cytokine antagonists (eg, interleukin 1Ra).15 Dependent on the balance of proinflammatory and anti-inflammatory factors, the response might return to baseline or progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS) with an increased risk of multiorgan dysfunction and sepsis.16 The risk of such a sustained inflammatory response increases with age for a given severity of trauma.17

Paradoxically, heightened non-specific immunity in SIRS is accompanied by suppression of the body's ability to mount a defence against invading pathogens. The result is increased susceptibility to infection and sepsis, with the invading microbes further stimulating immune cells via their pathogen-associated molecular patterns (eg, lipopolysaccharide). A vicious cycle ensues, with SIRS resulting in inflammation and immunoparesis, which, in turn, leads to sepsis with further inflammation and risk of multiorgan failure (figure 2). The inflammatory response also includes rapid activation of the complement system—initial activation is followed by consumption and a subsequent imbalance in the components of the complement cascade,11 which is one of many factors that reduces the ability of the body to defend against microorganisms.

According to the cell-based theory of coagulation, activated platelets provide a surface that promotes interaction of clotting factors in the development of a clot.18 Platelets activated by trauma and coagulation release proinflammatory mediators that excite the immune system,19 thereby promoting SIRS. Activation of the immune system increases platelet activity, generating a self-perpetuating cycle.19 Platelets form leucocyte–platelet aggregates, which are potent activators of immune cells and cause endothelial cell damage.20 Platelets21 and neutrophils22 are also major sources of microvesicles and exosomes, which express surface markers and can contain various molecules (including cytokines, miRNA, metabolites, and lipids)23 that propagate SIRS. These molecules might prove to be useful targets for treatment. The humoral elements of the coagulation and complement pathways act together to initiate the inflammatory response, with C3a, C5a, and fibrin all known to be neutrophil chemoattractants.13 Plasmin, an important antifibrinolytic molecule, also stimulates the complement cascade.

High concentrations of proinflammatory cytokines increase the activity of neutrophils causing them to migrate across damaged endothelium and become sequestrated in so-called bystander organs.24 Here, the destructive armamentarium of the neutrophil, including proteases (eg, neutrophil elastase) and reactive oxygen species, are deployed against healthy tissue. This process exacerbates inflammation and leads to the development of localised organ damage, such as that seen in acute respiratory distress syndrome. Neutrophils have been shown to release their DNA to trap and kill pathogens extracellularly.25 However, this benefit is to some extent negated by histones in the DNA net acting as DAMPs to initiate further inflammation. Importantly, although neutrophils are initially activated as a result of SIRS, their bactericidal function is markedly impaired in the days that follow.26 This decrease might be compounded by release of immature banded neutrophils expressing low levels of the Fcγ receptor CD16 into the circulation.27 Several treatment strategies have been targeted at reduction of the cascade of events triggered by activated neutrophils.

Cortisol released in response to injury is profoundly anti-inflammatory, inhibiting the activation of innate and adaptive immune cells, and inducing apoptosis in lymphocytes. Furthermore, cortisol strongly induces the release of neutrophils from the bone marrow and from the marginated pool within tissues.28 Activation of the hypothalamus-pituitary-adrenal axis usually leads to concomitant release of dehydroepiandrosterone (DHEA) and its sulphated ester DHEAS. However, following trauma, DHEAS levels fall and cortisol steroidogenesis predominates.29 The resulting increased cortisol:DHEA ratio is associated with increased infection rates after trauma.30 Supplementation with DHEA reduced sepsis-related mortality in animals,31 and provides a promising hypothesis for clinical studies.

Over the past decade, kinetics and amplitude of acute inflammatory responses have been shown to also be regulated by non-protein effectors, including lipid mediators (eg, protectins, maresins, resolvins,32 and microRNAs). The discovery that some lipids (eg, resolvins and maresins) reduce the acute inflammatory response has led to intervention studies with fish oil supplementation to modulate immune response after trauma (discussed later). Several trials are underway to assess the role of statins and dietary modifications as anti-inflammatory agents in trauma (appendix p4 and p6).

The interaction between the brain and nervous system is bidirectional; the traumatised brain exacerbates both SIRS and immunoparesis through parasympathetic and sympathetic pathways, respectively.33, 34 Furthermore, the complement system has been shown in human and experimental traumatic brain injury models to be an early mediator of post-traumatic neuroinflammation and secondary neuronal damage, ultimately leading to behavioural, emotional, and cognitive problems.35 The brain is also affected by a purely somatic injury. Endothelial damage as a result of raised proinflammatory cytokines and shock reduces the integrity of the blood–brain barrier.36 Not only does this reduced integrity allow humoral mediators of inflammation to enter the brain parenchyma, but it also permits migration of monocytes which then take on the morphological appearance of microglial cells.37 Receptors for proinflammatory cytokines are highly expressed in the hippocampus,36 a structure involved in memory consolidation and neuroplasticity, and chronic inflammatory cell activation in this organ may lead to irreversible cognitive decline, especially in elderly people.

Elderly people have a significantly worse prognosis after trauma independent of the nature or severity of their injury, and despite adjustment for comorbidities.38, 39 The association between age and outcome of injury is potentially confounded, even after risk adjustment, by factors that contribute to the risk of sustaining an injury in the first place. However, such residual confounding is unlikely to explain the extent of the association between age and mortality which varies 3–4-times between the second and ninth decade of life.40, 41 Similar age effects are seen in animals.42 A biological definition of ageing is the increase in frailty of an organism with time that reduces its ability to deal with stress. It can be conceptualised as a reduction in the range of stress over which the body can maintain its milieu intérieur. Although the precise mechanisms that relate age to survival of the stress of trauma are not fully elucidated, several plausible hypotheses have been proposed.42 Elderly people are known to have a low-grade inflammatory state at baseline, termed inflammageing.43 When injury occurs, the SIRS response can be exaggerated in old people, perhaps because the body has been primed by elevated baseline levels of cytokines, or as a result of their reduced ability to produce anti-inflammatory cytokines such as interleukin 10.17 Moreover, the capacity to respond to pathogens is more severely suppressed owing to the age-related decline in both the non-specific (innate) and specific (adaptive) immune pathways; a deterioration known as immunosenescence.43, 44 A raised cortisol:DHEAS ratio is seen in all patients after trauma, but the age-related loss of DHEA and DHEAS (adrenopause) could exacerbate this increase contributing to immunoparesis in older trauma patients.30

Although no consensus has been reached,45 large retrospective studies have reported male sex, in addition to old age, as a major risk factor for pneumonia and sepsis after major trauma.46 This finding might be the result of oestrogen modulation of proinflammatory and anti-inflammatory pathways.45

Section snippets

Classification of interventions in the postresuscitation phase

To identify interventions used in the postresuscitation phase, we systematically searched for relevant randomised controlled trials (RCTs) and reviews of RCTs, and selected articles with clinical endpoints (appendix p 2).47 Treatment strategies to prevent multiorgan failure following acute resuscitation can be categorised as those that aim to modulate SIRS, stimulate natural immunity, and prevent microbial proliferation.

Interventions to modulate SIRS

Numerous interventions have been postulated to attenuate or truncate

Future research

Owing to our increased understanding, the pathway between injury and organ damage can be mapped in increasing detail. This mapping has resulted in a growing list of therapeutic targets—recent additions include non-protein molecules and cellular fragments such as exosomes. However, clinical trials with adequate statistical power to show worthwhile reductions in mortality following acute trauma are not trivial undertakings; the CRASH 2 trial, which showed a reduction in mortality of nearly 10%,

Search strategy and selection criteria

We aimed to produce a usable and accessible document through compilation of evidence from multiple systematic reviews of interventions according to the Cochrane guidelines.47 We searched Medline and Embase for reports published in English between Jan 1, 2008, and Dec 5, 2013, related to trauma and injuries (full search terms are listed on appendix p 2). We scrutinised abstracts and identified systematic reviews of trials with clinical endpoints. We also searched for studies on trauma care in

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