We Have Met the Enemy, and He is Us: Why Do Hospitalized Trauma Patients Die?

We Have Met the Enemy, and He is Us: Why Do Hospitalized Trauma Patients Die?

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By: John C. Marshall, MD

Traumatic injuries resulting from motor vehicle crashes, falls, and war or urban violence are among the leading causes of preventable death in the world today. Trauma is responsible for more than 5 million deaths each year world-wide, disproportionally affecting the young and people from low income regions.1 Some of these deaths are a consequence of lethal and non-modifiable events – decapitation, rupture of the heart or a major blood vessel, devastating injury to the brain, etc. – however, advances in pre-hospital care and early resuscitation have enabled the survival of patients who previously would have died, and in the process, created new and potentially modifiable challenges for the attending clinician.

Devastating injuries to the brain or spinal cord account for a number of deaths amongst those patients who survive the initial traumatic event and are admitted to an intensive care unit (ICU). In the absence of neurologic injury, however, the leading cause of late death and disability following trauma is a process called Multiple Organ Dysfunction Syndrome (MODS). This is characterized by progressive, though potentially reversible loss of vital organ function involving the lungs, kidneys, and circulatory system. First described almost 40 years ago,2 MODS encompasses the body’s response to injury over time, and reflects the successes and failures of contemporary critical care.

MODS manifests differently in each organ. In the lung there is increased interstitial edema and an influx of activated neutrophils, resulting in impaired oxygen uptake into the blood, producing Acute Respiratory Distress Syndrome (ARDS) (Figure 1). In the kidney, a combination of altered blood flow, apoptosis of renal epithelial cells, and interstitial edema results in impaired excretion of fluids and solutes and a rising creatinine level. Dysfunction of the circulatory system is characterized by reduced peripheral vascular tone, increased endothelial permeability, and various degrees of myocardial depression, while hematologic dysfunction manifests in increased intravascular coagulation resulting in depletion of clotting factors, and leads to reduced platelet counts. Prognosis is directly related to the number of failing organs and the severity of derangement within each organ system (Figure 2).

Early studies of the development of MODS in patients following trauma focused on the role of occult infection, which often arises within the peritoneal cavity.3 With an evolving understanding of the biology of inflammation, it is apparent that although infection, along with tissue trauma or ischemia, can be the antecedent to MODS, the syndrome develops because of the systemic activation of an acute inflammatory response. The biologic processes underlying this response are complex, and the interested reader is referred to more detailed reviews. 4,5 Briefly however, conserved microbial products such as endotoxins, or certain intracellular molecules such as heat shock proteins, bind to pattern recognition receptors on host immune cells, predominantly monocyte/macrophages and neutrophils. These receptors target intracellular signalling pathways that lead to the repression or activation of thousands of different host genes,6 and to the cellular release of hundreds of biologically active mediator molecules that have both pro- and anti-inflammatory activity. These mediators then evoke cellular responses such as the generation of nitric oxide leading to relaxation of vascular smooth muscle and vasodilatation, expression of tissue factor on endothelial cells leading to intravascular coagulation, and activation of signalling pathways resulting in apoptosis of epithelial cells and lymphocytes.

The consequences of this process result in MODS. In the lung, for example, increased permeability of the pulmonary capillaries and alveolar epithelium results in interstitial edema while endothelial cell activation leads to microvascular thrombosis. Epithelial cell death or apoptosis increases, and activated neutrophils are recruited to the injured lung, exacerbating the local inflammatory injury. Fibrin deposition in the alveolar wall renders the normally delicate alveoli thick and less distensible (Figure 1). All of these processes lead to impaired oxygen uptake from the alveoli, and are responsible for the clinical changes known as the Acute Respiratory Distress Syndrome (ARDS).

The lung injury of ARDS and the generalized organ system dysfunction of MODS arise from more than the body’s response to the initial insult. Supportive care in the ICU can itself cause further inadvertent tissue injury. Plain radiographs of the lung of a patient with ARDS reveal diffuse patchy infiltrates – one of the defining characteristics of the syndrome (Figure 2a).  Computerized tomography of the lung, however, reveals consolidation in dependent lung zones resulting from the fact that patients are nursed supine in the ICU, and cystic changes in anti-dependent regions, a result of overdistention and rupture of alveoli by positive pressure ventilation (Figure 2b).  Recognition of the potentially modifiable component of ARDS that results from ICU care led to an alternate name for the syndrome – ventilator-induced lung injury, or VILI – and studies have shown that lung protective ventilatory strategies can attenuate organ injury and apoptosis,7 reduce the inflammatory response,8 and increase survival.9

Other examples of the inadvertent consequences of ICU support abound.  The administration of fluids in the setting of increased capillary permeability causes edema, and contributes not only to pulmonary dysfunction, but also to myocardial, renal, and central nervous system dysfunction.10  Sedation and analgesia predispose patients to muscle weakness and extend the time spent on the ventilator and in the ICU.  Total parenteral nutrition can induce liver injury, and the use of broad spectrum antibiotics promotes the emergence of resistant organisms, superinfections, and infections such as C. difficile colitis. Indeed MODS is the quintessential iatrogenic illness:  it only develops because medical intervention has succeeded in preventing a rapid death, but it evolves further because of the direct and indirect consequences of that intervention.11

The survival of severely injured trauma patients has improved dramatically over the past century.  This improvement is largely a consequence of advances in transport and regionalization of care of injured patients, of effective early resuscitation, of improved surgical management strategies including the wider adoption of damage control approaches, and of the development of effective means of organ system support in the ICU.  Further improvements will come from a recognition that the unsolved frontier lies within – from a better understanding of the endogenous host innate immune response that results in post-resuscitation organ injury, and of the iatrogenic consequences of medical care that exacerbate that injury.

References
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7.   Imai Y, Parodo J, Kajikawa O, de Perrot M, Fischer S, Edwards V, Cutz E, Liu M, Keshavjee S, Martin TR, Marshall JC, Ranieri VM, Slutsky AS (2003) Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 289: 2104-2112.
8.   Ranieri VM, Suter PM, Tortorella C, de Tullio R, Dayer JM, Brienza A, Bruno F, Slutsky AS (1999) Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome.  A randomized controlled trial. JAMA 282: 54-61.
9.   Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A, for the ARDS Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342: 1301-1308.
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11.   Marshall JC (2010) Critical illness is an iatrogenic disorder. Crit Care Med 38: S582-S589.