Angela Sauaia, Frederick A. Moore, and Ernest E. Moore
HISTORICAL PERSPECTIVE: EVOLVING CONCEPTS ON THE PATHOGENESIS OF MULTIPLE ORGAN FAILURE
Our increasing ability to keep severely injured trauma patients alive resulted in the clinical syndrome called postinjury multiple organ failure (MOF). As advances in prehospital and acute hospital care conquered “the golden hour” and the trimodal distribution of trauma deaths described in the 1970s and 1980s slowly flattened its first mode, MOF emerged as the leading cause of late trauma death.1–3
Much of advance in the treatment of trauma and shock has been stimulated by military experience.4 In World War I, soldiers’ death on battle was initially attributed to toxins released by dead or dying tissue (Table 61-1).5 Cannon et al, via their observations on the battlefield in 1917, expanded this concept to question the role of hypovolemia; however, it was not until the 1930s that reduced circulating blood volume was recognized as the cause of shock and mortality.6 Casualties in World War II were initially resuscitated with plasma and later with blood. This continued in Korea where blood and plasma were administered until blood pressure returned to normal. In addition to rapid transport for definitive care in field medical units, blood and plasma resuscitation improved battlefield survival but resulted in late deaths due to oliguric renal failure. In the 1960s, Shires et al. proposed that extracellular fluid deficits (third space losses) compounded traumatic shock and demonstrated in animals that survival improved with balanced salt solutions.7 Consequently, crystalloid resuscitation was added to blood and plasma resuscitation in the Vietnam War and resuscitation end points focused on maintaining adequate urine output. Helicopter evacuation also enabled rapid transport of casualties and the overall mortality rate decreased. Although late deaths from renal failure declined, a new entity termed “shock lung” emerged as the primary cause of late deaths.5 This new disorder became recognized in civilian trauma centers as the adult respiratory distress syndrome (ARDS).8 In the 1970s, subsequent improvements in advanced organ support such as mechanical ventilation (MV), vasoactive drugs, total parenteral nutrition, and hemodialysis armed physicians with better treatment to sustain the critically ill. Death from isolated pulmonary failure became rare, and a new syndrome of “multiple, progressive, or sequential systems failure” was recognized.9
TABLE 61-1 Historical Perspective of Postinjury Multiple Organ Failure
Eiseman et al. in Denver coined the term “multiple organ failure” in 1977, and provided the first clinical description of 42 patients with progressive organ dysfunction.10 During the late 1970s MOF was thought to be the “fatal expression of uncontrolled infection.”11 In addition, at this time, studies indicated that organ failure was a bimodal phenomenon with distinct patterns: rapid single-phase MOF due to massive tissue injury and shock or delayed two-phase MOF due to moderate trauma and shock followed by delayed sepsis.12,13 While infection remained a frequent cause of organ failure, by the mid-1980s it was convincingly shown that organ failure occurred in the absence of infection and the concept of “generalized auto-destructive inflammation” emerged.14,15
By the 1990s, noninfectious inflammatory models of MOF became the focus.16 In this conceptual framework, patients are resuscitated into a state of early systemic hyperinflammation, referred to as the systemic inflammation response syndrome (SIRS) (Fig. 61-1). A mild response is presumed to be beneficial and resolves in most patients as they recover. In the “one-event” model, a massive traumatic insult overwhelms the capacity of the patient to respond to resuscitation and precipitates organ failure. In the more common, alternative “two-event” model, patients who are initially resuscitated to a moderate response (primed) are vulnerable to a second (activating) event that can also precipitate hyperinflammation leading to early organ failure. The timing of the second hit may vary from occurring shortly after the first hit, where the two are indistinguishable, to a delay, where the second event is conspicuous 12–36 hours later. Patients who escape early MOF become susceptible to infection during the so-called compensatory anti-inflammatory response syndrome (CARS). If infected during this window, patients are at risk of developing late MOF. Other second hits include abdominal compartment syndrome (ACS), sepsis, fat embolus, MV, blood transfusions, long bone fixation, and secondary surgery.17
FIGURE 61-1 Pathogenesis of multiple organ failure.
More recently, a new model has emerged in which it is believed the injury triggers simultaneous, opposite responses: the proinflammation (SIRS) and the anti-inflammation (CARS) (Fig. 61-1).18 The term compensatory inflammation is in fact considered a misnomer as CARS appears to occur in response to the injury (not to SIRS). In this paradigm, the development of MOF is related to the intensity and the balance between these inflammatory responses to trauma. Severe SIRS, due to unbalanced early proinflammation, causes early MOF and can eventually result in a fulminant proinflammatory death. On the other hand, early anti-inflammation is directed at limiting proinflammation, creating a preconditioned state where the host is protected against second hits, and hastening the healing process. Anti-inflammation is also associated with apoptosis and depression in adaptive immunity. When countering unbalanced proinflammation, persistent anti-inflammation can result in severe CARS. This sets the stage for immunoparalysis, impaired wound healing, recurrent nosocomial infections, and late MOF, which can cause an indolent death.18
This new construct evolved from clinical observations and experimental studies at the bench level, and remains the foundation of contemporary MOF research. Research during the past decade has progressed toward further explaining these inflammatory mechanisms at the cellular and subcellular levels. New strategies to reduce secondary insults and to modulate the inflammatory responses in the early and late postinjury periods are currently undergoing intense clinical investigation. In sum, the presentation and outcome of postinjury MOF has changed considerably over the past 15 years. Yet, as we will describe in the next sections, MOF victims continue to suffer with high morbidity and long hospital stays and consume an inordinate amount of resources.
EPIDEMIOLOGY AND CLINICAL RELEVANCE
The epidemiological descriptions of MOF vary widely. The reported incidence of postinjury MOF varies from as low as single digit numbers to values approaching 40%, with case-fatality rates also varying within similarly large ranges.19 Recent studies have been inconsistent regarding changes in the incidence or the mortality associated with postinjury MOF, with some reporting no change in the incidence but a decreased mortality20 while others reporting both decreased incidence and mortality compared with historical controls.21 Reviews of patients prospectively included in our Denver MOF dataset showed a significant reduction in the incidence of MOF, with the most dramatic decrease being observed from 1998 to 2004, while MOF case-fatality rate has not shown a significant decrease.22
To determine whether the incidence reduction was due to a decline in disease severity of the patients admitted to our center, we examined changes in the major risk factors of postinjury MOF: age, Injury Severity Score (ISS), and number of RBC units transfused within the first 12 hours.23 Patients’ ISS and age increased over time while the proportion of patients requiring more than 6 U of RBC in the first 12 hours decreased after the implementation of a new protocol of judicious blood product utilization. The decrease in blood products use over time remained statistically significant after adjusting for age and ISS.22
In the early 1990s, about half of the MOF cases presented early (<3 days after injury) while the remaining cases presented later, most often around 7 days. This bimodal presentation pattern, first recognized by Faist et al. in 1983,13seems to be changing in recent years, with the second peak gradually leveling out (Fig. 61-2), possibly as a result of improved prevention and treatment of second insults.
FIGURE 61-2 Temporal distribution of MOF over time.
The risk factors for early MOF include an ISS >24, emergency department (ED) systolic blood pressure less than 90 mm Hg, blood transfusions >6 U within 12 hours of injury, and a lactate level >2.5 mmol/L measured between 12 and 24 hours after injury.24 Major infections are more likely to be a symptom that followed (sometimes worsening organ dysfunction) than a trigger that precipitated early MOF. Early MOF is typically associated with a higher incidence of heart failure than late MOF.
Late MOF (>72 hours postinjury), consistent with the distinct two-event construct, appears to be related to the increased risk of infection and systemic sepsis that is attributed to the relative immunosuppression associated with severe trauma. Independent risk factors for late MOF include age over 55 years, blood transfusion more than 6 U within 12 hours of injury, early base deficit more than 8 mEq/L in the first 12 hours postinjury, and a lactate level greater than 2.5 nmol/L measured between 12 and 24 hours postinjury.24 Although the risk factors for both early and late MOF included blood transfusion, base excess, and lactate levels, the shock indices were stronger risk factors for early MOF, whereas major infections were more frequently classified as triggers in patients who developed late MOF. Patients with late MOF also had a higher incidence of liver failure but a lower mortality (16%) than early MOF patients. Mortality is similar for early and late MOF as well as other adverse outcomes such as intensive care unit (ICU) length of stay and ventilation time.
Regarding individual organ patterns, the lung is virtually always the first organ to show evidence of dysfunction in the absence of preexisting disease.25 Lung dysfunction precedes heart dysfunction by an average of 
days, liver dysfunction by 
days, and kidney dysfunction by 
days. The number of involved organs and the severity of other organ dysfunction also seemed dependent on the severity of lung impairment. Of course, these conclusions are limited by our measurements of individual organ dysfunctions, that is, our measurements of lung dysfunction are far more sensitive to function changes than our measurements of liver or kidney function.
While MOF incidence seems to be decreasing, these patients continue to demand an excessive amount of hospital resources. Among MOF patients, the proportion of patients with less than 21 ventilator-free days (VFD) and less than 14 ICU-free days (IFD) has significantly increased steadily over the past decade from 90% to 100%. Indeed, from 1994 to 1998, there were 138 postinjury MOF patients in our ICU, who required 3,428 ICU days and 2,785 MV days. While from 1999 to 2003, there were less MOF patients (
, an 11% decrease), they required 3,548 ICU days and 2,812 MV days. In brief, despite reduction in incidence, MOF patients are responsible for an even larger amount of resources than in the past. Each MOF patient required a median number of 21 ICU days and 17.5 MV days from 1994 to 1998, while in the 1998–2003 period, the median number of ICU days was 26 and that of MV days was 21. Collectively, these numbers strongly support that despite a reduction in the MOF incidence, these patients still suffer through long hospital stays, have high morbidity, and consume an inordinate amount of resources.
PATHOPHYSIOLOGY
The First Hit: Initial Inflammatory, Hormonal, and Immune Responses to Trauma
The model of postinjury MOF, described in a previous section, was derived from a two-way translational model in which information was exchanged between epidemiological studies, predictive models, and basic investigations using in vivo and in vitro models. As mentioned above, severe trauma patients are resuscitated into an early state of systemic inflammation or SIRS. The American College of Chest Physicians and the Society of Critical Care Medicine defined SIRS as two or more of the following criteria26: (1) temperature <36.8°C or >38.8°C; (2) heart rate >90/min; (3) respiratory rate >20 breaths/min or PCO2 <32 mm Hg; and (4) WBC <4,000/mL or >12,000 mL or greater than 10% immature forms.
Figure 61-3 illustrates the current framework for the immunoinflammatory response to trauma. SIRS is the manifestation of the immunoinflammatory activation that occurs in response to ischemia–reperfusion (I/R) injury and released factors from disrupted tissue, that is, the damage-associated molecular patterns (DAMPs). In trauma, hemorrhagic shock following injury causes whole-body hypoperfusion, followed by subsequent reperfusion during resuscitation, which circulates cytokines, proinflammatory lipids, and proteins that prime polymorphonuclear neutrophils (PMNs) within 3–6 hours after injury.17 The CARS includes (a) apoptotic loss of intestinal lymphocytes and epithelial cells, (b) PMN and monocytic deactivation, (c) anergy characterized by suppressed T-cell proliferative responses, and (d) a shift from a THI to a TH2 phenotype.18 In the past, most studies attributed SIRS to hyperactivity of the innate immune system and CARS to dysfunction of the adaptive immune system, but recent evidence suggests that interactions between the innate and adaptive immune systems induce both SIRS and CARS and that the predominant mechanism for MOF is the balance between proinflammatory and counterinflammatory states.27
FIGURE 61-3 Immunoinflammatory response to trauma.
Role of the Gut
The gut is the last organ to have its circulation restored after ischemia, and is thought to play a pivotal role in the pathogenesis of postinjury MOF.18,28 Initially, the dominant hypothesis linking the gut to MOF was related to bacterial translocation: intestinal mucosa increased permeability allowed gut bacteria and/or endotoxin to be translocated to the circulation leading to sepsis and MOF. However, inconsistent results regarding the role of bacteria and endotoxin in the genesis of MOF led to experiments demonstrating that the mesenteric lymph acted as a bridge between the gut and the systemic circulation, allowing gut-derived inflammatory mediators and primed neutrophils to reach the systemic circulation. Via the thoracic duct, these mediators reach the pulmonary circulation and affect the lungs before any other organ, which is consistent with human studies demonstrating that postinjury respiratory dysfunction is an obligate event that precedes heart, liver, and kidney failure.29,30
Role of the PMN and Other Cells
PMN kinetics are different between MOF patients and non-MOF patients. Both groups develop neutrophilia at 3 hours postinjury; however, in patients who develop MOF there is a rapid neutropenia between 6 and 12 hours postinjury suggesting end-organ sequestration.31 PMNs marginated to end organs cause direct local cytotoxic cellular effects via degranulation, and the release of nitric oxide and reactive oxygen species. They also have remote systemic proinflammatory cytokine effects, releasing proinflammatory mediators including IL-8, IL-6, and TNF-α. In non-MOF, neutrophil priming and neutrophilia are not followed by neutropenia, and resolve over the next 36 hours without end-organ damage.32
Following trauma there is an immediate increase in adhesion molecules, including L-selectin and CD18, which allow PMNs to slow and roll along the endothelium and marginate out of circulation.17,33Antibodies directed against the CD11b/CD18 components of the adhesion receptor complex between leukocytes and endothelium significantly attenuate lung injury and prevent the neutropenia associated with tissue sequestration during sepsis, further supporting that adherence of neutrophils to endothelium is a critical step in local tissue injury.33
Circulating monocytes and tissue macrophages also become primed after severe injury and most authorities agree that microvascular endothelium has an integral role in postinjury priming of the innate inflammatory response.32Finally, other studies have demonstrated that the organ damage is also dependent on complement activation through the classical pathway mediated by natural IgM antibody produced by B1 lymphocytes.27
Cytokines
The hemodynamic, metabolic, and immune responses are mainly regulated by endogenous mediators referred to as cytokines, produced by diverse cell types at the site of injury and by systemic immune cells.33 Cytokines bind to specific cellular receptors resulting in activation of intracellular signaling pathways that regulate gene transcription and influence immune cell activity, differentiation, proliferation, and survival. They also regulate the production and activity of other cytokines, which may either augment or attenuate the inflammatory response. There is also significant overlap in bioactivity among different cytokines.33 Cytokines can be classified into proinflammatory (TNF-α, MIP, GM-CSF, IFN-Y, IL-1, IL-2, IL-6, IL-8, IL-17, etc.) and anti-inflammatory cytokines (IL-4, IL-10, IL-13), which downregulate synthesis of the proinflammatory cytokines.33
Recently, Jastrow et al. assessed the temporal cytokine expression (every 4 hours during 24 hours postinjury) during shock resuscitation in severely injured torso trauma patients.34 Median concentrations of IL-1 receptor antagonist (IL-1Ra), IL-8, eotaxin, granulocyte colony-stimulating factor (GCSF), granulocyte-macrophage colony-stimulating factor (CSF), inducible protein 10 (IP-10), monocyte chemotactic protein-1, and macrophage inflammatory protein-1 (MIP-1) were significantly greater in the MOF compared with those in the non-MOF subgroup at each time interval. Adams et al. demonstrated that IL-8 can activate PMNs via two different receptors, and differential early expression of these receptors may provide an explanation for why only selected patients develop MOF.35
The cytokine pattern after trauma also differs for patients developing early (less than 3 days) versus late (>3 days) MOF. Analysis of cytokine serum biomarkers revealed that whereas early onset MOF was associated with an initial peak of IL-6 and IL-8 followed by a comparatively rapid return to baseline values, late MOF was characterized by a significant secondary increase of the proinflammatory cytokines IL-6 and IL-8.36 Moreover, plasma levels of soluble tumor necrosis factor-alpha receptors (sTNF-R p55, sTNF-R p75) progressively increased during the 10-day observation period, and higher values were associated with lethal outcome.
Although inflammatory mediators’ levels vary greatly according to injury-related factors as well as the patient’s individual characteristics, most studies agree that the changes start very early postinjury. This underscores the importance of measuring inflammatory mediators very early and at short intervals after injury.27 Indeed, a recent German study including 58 multiple injured patients (ISS >16) found that IL-6, IL-8, and IL-10 differentiate patients with MOF (n = 43) and those without MOF (n = 15) within 90 minutes post trauma.37
PAMPS, Alarmins, and DAMPS
Pathogen-associated molecular patterns (PAMPs) are exogenous microbial molecules that alert the organism to pathogens and are recognized by cells of the innate and acquired immunity system, primarily through Toll-like receptors (TLRs), and activate several signaling pathways (e.g., NF-κB). A new awareness of the close relationship between trauma- and pathogen-evoked responses recently emerged and the term “alarmin” was proposed to differentiate the endogenous molecules that signal tissue and cell damage.38 Together, alarmins and PAMPs comprise the DAMPs. Alarmins are rapidly released after nonprogrammed cell death but not by apoptotic cells. They recruit and activate receptor-expressing cells of the innate immune system, and also promote adaptive immunity responses. An example of an alarmin is the high-mobility group box 1 (HMGB1), a nuclear protein which binds to nucleosomes and promotes DNA bending. HMGB1 has been associated with SIRS and end-organ damage in animals, and shown to be elevated in trauma patients more than 30-fold above healthy controls as early as 1 hour postinjury.38–40
A recent study by Zhang et al. showed that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. The authors suggest that since mitochondria are evolutionary endosymbionts derived from bacteria, the released MTDs have conserved similarities to bacterial PAMPs. Thus, these MTDs signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. This mechanism may provide the key link between trauma, inflammation, and SIRS.41
Toll-Like Receptors
TLRs are transmembranal proteins present in most body cell types, which form the major pattern recognition receptors that transduce signals in response to DAMPs.42 They were shown to participate in the recognition of endogenous alarmins released from damaged tissues after I/R injuries. Innate immune system responses are then initiated, including NF-αB activation, cell activation, and proinflammatory cytokine production.42 Inhibition of TLR2 or TLR4 seems to be beneficial in I/R injury in certain organs (hepatic, renal, cerebral, and heart) but not in gut I/R injuries. It is conceivable that because the gut mucosa is continuously exposed to local bacterial endotoxins, local TLRs are uniquely regulated to prevent persistent inflammatory activity. In spite of the distinct roles played by TR2 and TR4 in individual organs, our understanding of how the several TLR members interact among each other in I/R injuries is still limited, which may hinder the interpretation of interventions aimed at a specific TLR.42
Heat Shock Proteins (HSPs)
HSPs are a family of molecular chaperones (e.g., Hsp70 and Hsp90) necessary for the folding of newly synthesized proteins in the cell and also for the protection of proteins during exposure to stressful situations such as heat shock, which causes proteins folded previously to unfold.43 Extracellular HSPs can interact with several receptors (including TLRs), and have been implicated in inducing secretion of proinflammatory cytokines. However, highly purified HSPs do not show any cytokine effects suggesting recombinant HSP products may be contaminated with PAMPs that appear to be responsible for the reported in vitro cytokine effects of HSPs.43 Thus, the reported HSP’s role in antigen presentation and cross-presentation and in vitro cytokine functions may be attributable to molecules bound to or chaperoned by HSPs.
Complement
Complement system activation occurs immediately after trauma leading to production of biologically active peptides.28 Proinflammatory peptides include C3a, C3b, C4b (chemotaxis of leukocytes; degranulation of phagocytic cells, mast cells, and basophils; smooth muscle contraction and increased vascular permeability), and C5b-9 or membrane attack complex that leads to lysis of the target cells at the end stage of the complement activation cascade. Furthermore, complement activation results in the production of oxygen free radicals, arachidonic acid metabolites, and cytokines. Several studies suggest that complement activation, especially serum C3 and C3a levels, reflects severity and treatment of injury.28
Oxidative Stress
Oxidative stress occurs when the level of toxic reactive oxygen intermediates (ROIs) overcomes endogenous antioxidant defenses as a result from either oxidant production excess or antioxidant defense depletion.44 ROIs are normally generated by mitochondrial oxidation, metabolism of arachidonic acid, activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes, and activation of xanthine oxidase (XO) and play important roles in cellular homeostasis, mitosis, differentiation, and signaling.28 Excess ROI, however, causes direct oxidative injury to cellular proteins and nucleic acids, and cell membrane destruction by inducing lipid peroxidation.28,42,44
I/R injury leads to significant disturbances in the production of ROIs.28,42 During ischemia, hypoxemia leads to a shift from aerobic to anaerobic metabolism, with consumption of and decreased production of adenosine triphosphate (ATP). As ATP decreases, changes in cell membrane permeability result in intracellular Na+ increase causing cellular swelling and cell membrane damage. ATP reduction also alters cytosolic Ca2+ levels leading to phospholipase and protease activation and cell damage. Increased ATP hydrolysis is followed by rising levels of AMP and purine metabolites. As reperfusion increases O2availability, oxidation of purines produces urate and superoxide radicals, which can then produce the toxic hydroxyl radicals. In addition, superoxide radicals may be generated by a plasma membrane–associated NADPH oxidase system, which can be activated by macrophages, neutrophils, and other immunologic cells.45 ROI secreted from PMNs after I/R injury induces cytokines, chemokines (IL-8), HSP, and adhesion molecules (P-selectin, ICAM-1) leading to cell and tissue damage.28
Under normal conditions, NO production greatly exceeds O2− production in the endothelial cell (EC). However, with reperfusion, the balance between NO and O2− shifts in favor of O2−. The relatively low level of NO by constitutive endothelial nitric oxide synthase (NOS-I) reacts with the now abundant O2− to generate peroxynitrites, leaving little NO available to reduce arteriolar tone, prevent platelet aggregation, and minimize PMN adhesion to EC.46 In addition, NO seems to upregulate the production of proinflammatory cytokines.28 Thus, altering the redox state of the cell may contribute to the ongoing inflammatory cytokine production and progression to MOF.42 ROIs also play a role as second messengers in the intracellular signaling pathways of inflammatory cells, in particular, activation of NF-κB and activator protein 1 (AP-1), which can be activated by both oxidants and antioxidants depending on the cell type and on intracellular conditions.44
Endogenous antioxidant defenses, including enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and nonenzymatic (vitamins E and C, provitamin A, glutathione, bilirubin, urate) groups that combat oxidative stress, have been the focus of interventions to modulate the inflammatory response to critical illness, as detailed later.
Hormones
Traditionally, the injury stress response was viewed as a neuroendocrine reflex mediated via counterregulatory hormones (cortisol, glucagon, and epinephrine) that altered substrate metabolism while the body is in a state of repair. Adrenaline is released and suppresses insulin secretion but stimulates secretion of growth hormone and renin, proteolysis and glycogenolysis, enhancing hepatic-mediated gluconeogenesis.33 Glucagon is released by pancreatic islet cells that increase hepatic glucose production from substrate that arises from tissue catabolism. The liver produces acute phase reactants such as opsonins (CRP), protease inhibitors, hemostatic agents (fibrinogen), and transporters (transferrin).33
The hypothalamic–pituitary–adrenal (HPA) axis is activated during stress, stimulating the release of adrenal corticotropic hormone (ACTH) from the pituitary gland, which induces the release of cortisol from the adrenal cortex.47The HPA axis and the immune response are intrinsically linked in a negative feedback loop in which activated immune cells produce specific cytokines that activate the HPA axis increasing cortisol release that in turn suppresses the immune response and further cytokine release.47 Cytokines also act directly on the adrenal cortex and on glucocorticoid receptors (GR), present in most cells. In addition, different types of stress (sepsis, trauma, elective surgery) seem to be associated with the release of distinct mediators that may inhibit or stimulate cortisol production by acting on the HPA axis, adrenal cortex, and/or GR.
The HPA response is pivotal for survival as adrenal insufficiency (AI) increases the mortality of critically ill or injured patients.47 In the Section “Interventions,” we will return to this important topic in the treatment and prevention of MOF.
Less clear is the role of sexual hormones. Choudhry et al. in Alabama have studied extensively the influence of gender in the response to trauma and hemorrhage (TH) in animal models.48 They suggested that immune and cardiac dysfunctions after TH are depressed in adult males and ovariectomized/aged females, while both are maintained in castrated males and in proestrus females. The female reproductive cycle seems to be an important variable in the regulation of lung injury after TH.49 One of their most recent studies showed that enhanced hepatic heme oxygenase (HO-1) in proestrus- and estradiol-pretreated ovariectomized females modulates inflammatory responses and protects liver following TH.49
In contrast with the animal studies, clinical investigations have shown controversial results regarding a protective effect of female gender. In a 2006 study by the Alabama group, female polytrauma victims younger than 50 years with an ISS >25 suffered significantly less MOF and sepsis and had lower plasma cytokines compared with age-matched males.50 This study however included a relatively small number of women 
, of whom over half were older than 50 years of age; thus, a type II error in the postmenopausal women was possible. A more recent study by the “Inflammation and the Host Response to Injury Investigators” attempted to characterize the gender dimorphism after injury with specific reference to the reproductive age of the women (young, <48 years of age, vs. old, >52 years of age) in a cohort of 1,036 severely injured trauma patients.51 The independent protective effect of female gender on MOF rates remained significant in both premenopausal and postmenopausal women when compared with similarly aged men suggesting that factors other than sex hormones were responsible for the gender-based differences after injury.
The Second Hit
Abdominal Compartment Syndrome
A hallmark of the postinjury inflammatory state is generalized capillary leak and associated tissue edema. Historically, peripheral edema was considered to be a minimally significant consequence of fluid resuscitation. This view has changed with the resurgent interest in intra-abdominal hypertension that has accompanied the recent widespread application of damage control procedures (DCP). Increased intra-abdominal pressures (IAP) are accompanied by a host of physiologic derangements that include high ventilator pressures, decreased cardiac output, and impaired renal function, a constellation of signs that are named ACS. Usually associated with abdominal injuries (primary ACS), these effects can also be observed following extra-abdominal injury or following large-volume resuscitation for nontraumatic or nonsurgical conditions (secondary ACS).52
The incidence of ACS varies greatly according to the resuscitation strategy but is primarily dependent on the severity of injury and the degree of shock. Mesenteric I/R increases microvascular permeability causing bowel wall edema that can directly cause decreased bowel motility, decreased barrier function, and further capillary leak. Splanchnic hypoperfusion during shock is compounded by even mild increases in IAP (which can reduce the abdominal perfusion pressure) and low plasma oncotic pressure from crystalloid resuscitation (which worsens edema).52 As with any compartment syndrome, the increased pressure within the compartment rises above postcapillary pressure causing a functional venous and lymphatic obstruction. Under these conditions, the intestinal epithelium microvilli secrete fluid into the gut lumen. Transudation of free fluid into the peritoneal space also contributes to further IAP increases. The combination of bowel wall edema, intraluminal fluid secretion, and fluid accumulation in the peritoneal cavity further increases IAP and gut ischemia, which affects the inflammatory response as described above. While ACS physiologic effects usually reverse on decompression, the immunomodulatory effects may persist and trigger MOF.52
Both primary and secondary ACS can be predicted early. The independent predictors of primary ACS are the indicators of the damage control physiology (transfer to the operating room without further imaging, temperature <34°C, hemoglobin <8 g/dL, base deficit >8 mmol/L), whereas the secondary ACS predictors are markers of uncontrolled resuscitation (>7.5 L of crystalloids before ICU admission, no indication for lifesaving surgical intervention, relatively low urine output [≤150 mL/h] on ICU admission [considering the massive resuscitation]). Identification of these independent predictors led to earlier hemorrhage control in orthopedic trauma, abandoning crystalloid-based supranormal resuscitation goals, introduction of hemostatic resuscitation, and the early application of ICU resuscitation protocols.52 The current treatment of full-blown postinjury ACS is surgical decompression. Abdominal decompression may be performed in the ICU, especially in secondary ACS cases, whereas in primary ACS repeated hemorrhage control is usually required, preferably undertaken in the OR. After decompression, open abdomen management starts with the application of temporary abdominal closure followed by timely restoration of the abdominal wall.52
Blood Transfusions
The goals of transfusion in the injured patient are to maintain adequate oxygen-carrying capacity. However, there is abundant, solid evidence that blood transfusions are a risk factor for the development of MOF independent of shock or injury severity.53,54 Indeed, blood transfusions fit many of the criteria for causation, that is, strength of the association, temporal relationship (risk factor precedes outcome), dose–response relationship, consistency, and reproducibility. Early blood transfusion is indeed the most powerful independent risk factor for postinjury MOF.53 Reductions in blood transfusion in the resuscitation period correlate with improved outcome and less MOF.22 Blood products are immunoactive, contain proinflammatory cytokines and lipids, and have an early immunosuppressive effect predisposing the patient to CARS, infection, and late MOF.54
The age of transfused blood is also important, with progressive daily increases in proinflammatory cytokines in stored blood products. Transfusing packed red blood cells (PRBCs) stored >3 weeks in the first 6 hours postinjury are associated with a higher rate of MOF while PRBC units with shorter storage times are associated with decreased MOF prevalence and less morbidity and mortality.54 Leukodepletion does not remove the potential for blood to act as a second hit, as PRBCs contain proinflammatory cytokines, including IL-8 and IL-6. The mechanism was believed to be related to the generation of the proinflammatory agents PAF, IL-6, and IL-8 during storage. Later studies found that additional biologically active cytokines and lipid mediators (lysophosphatidylcholines) accumulate in stored blood and are capable of PMN priming.54 “Passenger leukocytes” present in stored blood have been implicated as pivotal components by the finding that prestorage leukoreduction decreases the PMN priming and transfusion-mediated lung injury in animal models.54 Proposed mechanisms include induction of T-cell anergy in the recipient, decreased natural killer cell function, altered ratio of T-helper to T-suppressor cells, and soluble proinflammatory cytokines produced by leukocytes during storage.54 Together, these effects can suppress the recipient immune system and promote a worse proinflammatory state leading to increased infection and complications.
Other blood-derived products (platelets, plasma, and coagulation factors) are also immunoactive and could act as second hits.17 Indeed, transfusion of fresh frozen plasma (FFP) is associated with MOF, especially among patients who received more than 6 U of PRBCs in the first 12 hours postinjury.55
Infections
Osler was the first to recognize in 1904 that “except on few occasions, the patient appears to die from the body’s response to infection rather than from the infection.”56 The association of infection and MOF was always strong. In the late 1970s, intra-abdominal abscess (IAA) was the inciting event in half of the cases.11 As a result of the appropriate use of presumptive antibiotics in patients sustaining abdominal trauma and prompt diagnosis of hollow viscus injury, the incidence of postinjury IAA decreased and its progression toward MOF was hindered. The epidemiology of postinjury infections changed and nosocomial pneumonia became the principal infection associated with MOF.
While CARS, the anti-inflammatory response, may be protective because it limits unnecessary (potentially autodestructive) inflammation, it is associated with relative immunosuppression predisposing the host to infections.57 Data from both clinical and animal studies suggest diminished production of proinflammatory type 1 and increased production of inhibitory type 2 cytokines by T cells. Monocytes/macrophages and suppressor T lymphocytes have been implicated to be key modulators that downregulate immune functions.57
Another area of research interest has been the potential role of persistent hypercatabolism in the development of infections.33 Although energy expenditure can increase dramatically following injury, the associated hypercatabolism is a critical metabolic alteration. If not supported by exogenous nutrients, the consequent obligatory protein turnover quickly erodes somatic protein stores and then the critical visceral mass. The resulting acute protein malnutrition causes well-documented adverse immunologic consequences and is a recognized cofactor for the development of postinjury infection.
Secondary Operation
The second operation can be considered a controlled traumatic event where surgical trauma takes the place of the initial injury. Additional stresses of secondary operations include higher intraoperative fluid consumption, hypothermia, hypotension, tissue hypoxia, and intraoperative blood loss.33
The timing of the second operation has been variously studied over the last decade mostly as related to operative fracture fixation. While early definitive fracture fixation decreases postinjury morbidity and improves recovery, it is not without consequences when performed within the priming window. A 2003 randomized controlled trial by Pape et al. demonstrated that early external fixation followed by delayed conversion to intramedullary instrumentation was associated with a decreased inflammatory response to the operative fixation.58 The same group compared the inflammatory response of injured patients with femoral shaft fracture who were divided into two groups according to their initial treatment: (1) damage control orthopedics (DCO) group if the femoral fracture was initially stabilized with an external fixator and (2) intramedullary nailing (IMN) group if they underwent primary IMN.59 Despite more severe injuries in the DCO group, patients had a smaller, shorter postoperative SIRS and did not suffer significantly more pronounced organ failure than the IMN group. DCO patients undergoing conversion while their SIRS score was raised suffered the most pronounced subsequent inflammatory response and organ failure. According to these data, DCO treatment was associated with a lesser SIRS than early total care for femur fractures.
Our group recently examined outcomes associated with early total care with IMN (ETC group) versus damage control external fixation (DCO group) for 462 multiple injured patients with femoral shaft fractures.60 Although minimal differences were noted between DCO and ETC groups regarding systemic complications, DCO was a safer initial approach, significantly decreasing the initial operative exposure and blood loss. Collectively, these findings strongly suggest that a secondary operation can act as an additional inflammatory insult and amplify the postinjury inflammatory response and precipitate MOF.
DEFINING MOF
Defining MOF given the absence of a definitive gold standard is a challenge.19 As a consequence, authors have used disparate definitions and the epidemiological descriptions of this condition vary widely. Indeed, the reported incidence of postinjury MOF varies from as low as single digit numbers to values approaching 40%, with case-fatality rates also varying within similarly large ranges.19 Some studies suggest that MOF is disappearing while other studies have not found a consistent change.19 These disparities are, in large part, due to the difficulty in defining and measuring MOF. The syndrome seems to fit well with Justice Stewart’s famous quote: “I may not be able to define it, but I know it when I see it.”
VALIDATION OF CURRENT SCORES
In the absence of a gold standard, validation must be done examining the association of different scores with objective adverse outcomes, reflecting clinical status (VFD, IFD, and death) and resource utilization (length of ICU stay [LOS] and MV days). VFD and IFD have been recently proposed as alternative outcomes for critically ill patients that account for patients who died early and consequently had shorter MV and ICU times.61 In addition, the validation process can be greatly enhanced if conducted on a homogenous population observed for an extended period of time, as in our long-term Denver MOF dataset. Started in 1992, this database contains prospectively collected clinical data on patients at risk for postinjury MOF for the first 28 postinjury days.19 To our knowledge, this is the longest, sustained prospective database on postinjury MOF using standardized data collection methods. Acutely injured patients admitted to the Rocky Mountain Regional Trauma Center surgical intensive care unit (SICU) at the Denver Health Medical Center (DHMC, a state-designated Level I trauma center verified by the American College of Surgeons Committee on Trauma) are studied prospectively. The analytic dataset of 1,480 patients from 1992 to 2004 is summarized in Table 61-2. Our population consisted of mostly young, healthy males, with moderate to severe injuries, mostly due to blunt force in motor vehicle accidents. Mortality and number of VFD days were low, but health care resource utilization was high with over one third of these patients requiring longer than 14 admission days in the surgical ICU (LOS) and/or over 7 days of MV. (Data from additional 1,000 patients admitted since 2005 are still being examined for accuracy and processed into analytic files.) Patients fitting the following criteria are entered in the dataset:
TABLE 61-2 The Denver MOF Dataset: Characteristics of a Trauma Patient Population at Risk for MOF Admitted from 1992 to 2004
1. ISS greater than 15: patients with this level of injury or worse are all likely to be admitted to the ICU, minimizing selection bias.
2. Survival longer than 48 hours from injury: our studies demonstrate that physiologic derangements prior to 48 hours are not indicative of MOF, but rather reflect the primary injury or inability to respond to resuscitation.62
3. Admission to DHMC within 48 hours of injury: due to delay in admission, early risk factors shown to be associated with MOF were not observed or recorded.
4. Age greater than 15 years: it has been demonstrated that MOF presents differently among children, and that the currently used organ dysfunction measures may not be appropriate to the pediatric population; thus, children are not included in this analysis;63 we are however including children in a specific section of the MOF dataset, which will be used to adapt current scores to pediatric use.
In addition, we exclude patients with isolated head injuries because these patients tend to have a lower MOF incidence with distinct presentation, risk factors, and outcomes when compared with torso injury patients. Patients with burn and/or hanging injuries are also excluded, as they are most often treated primarily at other centers and their risk factors for MOF are different from torso blunt and penetrating injuries. Daily physiologic and laboratory data are collected through day 28.
MOF Scores
We focused our validation on two widely used scores: the Marshall MOD score (Marshall score) and the Denver MOF score (Denver score), developed by our group. For other scores, the reader is referred to the excellent review by Baue.64 The Denver score, first proposed in 1991, originally included eight organ systems, (cardiovascular, pulmonary, renal, hepatic, gastrointestinal, hematologic, central nervous system [CNS], and metabolic). The score was later revised and gastrointestinal, hematologic, CNS, and metabolic failures were excluded since their addition did not improve the characterization of MOF. In brief, the Denver score grades on a scale from 0 to 3 the dysfunction of four systems (pulmonary, renal, hepatic, and cardiac), evaluated daily throughout the patient’s ICU stay with the total score ranging from 0 to 12 (Table 61-3).
TABLE 61-3 Denver Postinjury Multiple Organ Failure Score
The Marshall score was developed in 1994 and validated based on probability of subsequent mortality in a sample of 692 patients from a Canadian ICU.65,66 It grades dysfunction from 0 to 4 and evaluates the same four systems as the Denver score, plus the dysfunctions of the hematologic and neurologic systems (Table 61-4).
TABLE 61-4 Marshall Multiple Organ Dysfunction Score
MOF Classification in the Denver MOF Dataset
There were 1,389 patients with complete data in the Denver MOF dataset to calculate both scores (95% of the 1,440 total sample). Tables 61-5 and 61-6 show the risk factors and outcomes distribution stratified by MOF classification. Patients could be classified into one of the following four potential scenarios:
Or:
• Scenario a: classified as “MOF” by both scores
• Scenario d: classified as “no MOF” by both scores
• Scenario b: classified as “MOF” by Denver score but as “no MOF” by Marshall score
• Scenario c: classified as “no MOF” by Denver score but as “MOF” by Marshall score
TABLE 61-5 Risk Factors of Patients Identified as Having or Not MOF Based on the Denver and Marshall MOF Scores
TABLE 61-6 Adverse Outcomes of Patients Identified as Having or Not MOF Based on the Denver and Marshall MOF Scores
Patients in scenarios a and d were those for whom both scores agreed in the classification while scenarios b and c represented the discordant classification. Three major groups of patients emerged: (1) patients classified by both scores as MOF comprised a severe injury group of patients with high rates of risk factors, mortality, and utilization, (2) patients classified as “no MOF” by both scores constituted a mild injury group for whom risk factor rates, utilization, and mortality were all low, and (3) patients for whom the scores disagree in the MOF classification represented a moderate injury group with medium risk factor rates, medium utilization, and low mortality.
Validation of the Scores Using Receiver Operating Characteristic (ROC) Curves
ROC curves were developed during World War II to determine if a blip on a radar screen represented a ship or an extraneous noise. The radar receiver operators used this method to set the threshold for military action. In medicine, ROC curves have gained increasing popularity as a method to evaluate measurements. For every possible boundary between “positive” and “negative,” the ROC plot shows the trade-off between sensitivity (ability to detect disease) and specificity (ability to detect lack of disease). ROCs, by convention, plot the sensitivity in the Y axis and (1-specificity) in the X axis. The best cutoff for a measurement, that is, the cutoff that has the best combination of sensitivity and specificity, is the data point located at the left uppermost position in the ROC curve. In addition, the area under the ROC (AUR) may be used as a measurement of the overall performance of the measurement.
To validate the MOF scores, we compared their ROC curves for the outcomes (death, VFD <21 days, LOS >14 days, and MV >7 days) as shown in Figures 61-4 to 61-7. Overall, both scores were associated with areas ≥80 (ideal value = 100). The AUR for the Denver score was slightly greater than that for the Marshall score regarding prediction of death, VFD, and MV. The differences, however, were not significant.
FIGURE 61-4 ROC curves for the Denver and Marshall MOF scores showing prediction of postinjury mortality.
FIGURE 61-5 ROC curves for the Denver and Marshall MOF scores showing prediction of postinjury ventilator-free days shorter than 21 days.
FIGURE 61-6 ROC curves for the Denver and Marshall MOF scores showing prediction of postinjury mechanical ventilation longer than 7 days.
FIGURE 61-7 ROC curves for the Denver and Marshall MOF scores showing prediction of postinjury ICU stay longer than 14 days.
INTERVENTIONS
Preventing the onset of MOF through therapies directed at modulating SIRS or blocking CARS is likely to offer more practical benefit to injured patients than efforts to treat MOF once established, when the treatment is largely supportive.27
Protective Resuscitation Techniques
Certain resuscitative strategies protect against distant organ injury after periods of gut I/R.29 Resuscitation with isotonic crystalloids proposed in the late 1960s contributed to a decrease in mortality and acute renal failure, but was implicated in the emergence of ARDS as a major source of morbidity and mortality in the ICU. There is still controversy about the use of isotonic crystalloids compared with colloids. The multicenter, randomized, double-blind SAFE trial showed no difference in mortality, single organ failure, and MOF between the groups receiving saline and the group receiving albumin.67 A preplanned subgroup analysis of trauma patients, however, seemed to favor the use of crystalloids, although the difference was not significant at the 95% confidence level (relative risk, 1.36, 95% confidence interval, 0.99–1.86, 
). In fact, when patients with brain injury were excluded, no difference was detected (death rate in both groups = 6.2%, relative risk, 1.0, 95% confidence interval, 0.56–1.79, 
). A recent Cochrane systematic review (published in 2007 and updated in 2009 without any change in conclusions) compared colloids with crystalloids and showed no difference in mortality of trauma patients. The lack of a survival advantage combined with the higher costs of colloids favors the use of crystalloids in trauma resuscitation.
A systematic review (published in 2004 and updated in 2007) comparing hypertonic with isotonic crystalloid solutions for the resuscitation of patients with trauma or burns or those undergoing surgery did not provide enough data to determine there was a difference in outcomes.68 The authors, however, pointed out that confidence intervals were wide and recommended further trials were needed. Hypertonic resuscitation (hypertonic saline and 6% Dextran 70) was compared with lactated Ringer’s solution (LRS) in adult, blunt trauma patients by Bulger et al. in a recent randomized clinical trial.69 The study, stopped for futility after the second interim analysis, demonstrated no significant difference in ARDS-free survival (hazard ratio, 1.01; 95% confidence interval, 0.6–1.6). There was improved ARDS-free survival in the subset requiring massive transfusion (hazard ratio, 2.2; 95% confidence interval, 1.1–4.4), suggesting a benefit may exist in patients at highest risk of ARDS.69 However, this large multicenter clinical trial was subsequently reactivated, and the preliminary results do not indicate a clinical benefit. In addition to more efficient volume restoration, hypertonicity has an effect on multiple immune response functions, which may someday translate to improved outcome in select populations.70 Similarly, low-dose albumin was shown to protect against shock-induced lung, EC, and red blood cell injury, as was the intraintestinal administration of a pancreatic protease inhibitor.29
Judicious Use of Blood Transfusions
Judicious use of blood products seems to prevent MOF. A 12-year analysis of our MOF dataset suggests that reduction of blood use was implicated in the decreased incidence of MOF in our trauma center.22Current transfusion guidelines support the safety of restrictive transfusion practices in trauma patients.71,72 Other techniques to reduce the deleterious effects of PRBCs are washed PRBCs and prestorage leukoreduction. Despite the beneficial effects of washed PRBC units, the preparation time, the lack of apparatus to wash units in many blood banks, and the short outdate of washed units (24 hours) make them impractical in the trauma setting.54 Prestorage leukoreduction may reduce biologically active lipids in stored PRBC; however, trials have shown modest or no improvement in outcomes.54,71
Finally, blood substitutes have offered promising results in trauma populations. Only two hemoglobin substitutes have been used extensively in injured patients, the diaspirin cross-linked hemoglobin from the Baxter Corporation and polymerized, pyridoxylated human hemoglobin (PolyHemeTM) from Northfield Laboratories.54 Our experience in the trauma setting with PolyHemeTM suggests it provides an immunologic advantage relative to blood in the injured patient by diminishing PMN priming and decreasing IL-6 and IL-8.54,73 In a recent clinical trial, patients resuscitated with PolyHeme, without stored blood for up to 6 U in12 hours postinjury, had outcomes comparable with those for the standard of care. Although there were more adverse events in the PolyHeme group, the benefit-to-risk ratio of PolyHeme was favorable when blood was needed but not available.74 In a recent meta-analysis of blood substitutes, the authors concluded that these products were associated with an increased risk of mortality and myocardial infarction.75 However, because the authors included studies on such diverse populations, the results of the meta-analysis were questionable.76 In fact, in studies with trauma patients, the associations were not significant.
Fracture Management
The benefits of early definitive fracture stabilization include early patient mobility, improved pulmonary toilet, and a decrease in systemic inflammation, thromboembolic events, morbidity, mortality, and hospital resource utilization. However, this is not without a price, as operative fracture fixation exposes the patient to an additional inflammatory insult that can precipitate MOF. Consequently, the concept of damage control surgery was extended to major fracture initial management in the severely injured. Damage control external fixation (DCO) is performed in coordination with acute resuscitation and hemodynamic stabilization, and it allows fracture stabilization with minimal blood loss and anesthesia time.58,77 The principle is to provide early fracture stabilization by external fixation as a bridge to definitive fracture care once the patient is more physiologically appropriate. Conversion of external fixation to intramedullary implantation is associated with reduced procedure-related inflammatory response compared with early primary femur fracture fixation.58 When compared with early total care, the damage control approach with delayed conversion to definitive care has been shown to decrease the initial operative time and intraoperative blood loss without increasing the risk of procedure-related complications such as infection and nonunion, and may improve overall survival.77 A recent study examining acute patient outcomes associated with early total care with IMN (ETC group) versus DCO group for multiple injured patients with femoral shaft fractures showed comparable outcomes between the two methods, suggesting that DCO is a safer initial approach, decreasing the initial operative exposure and blood loss, both potential insults that can trigger MOF.60
Protective Lung Ventilation
In addition to direct injury and secondary inflammatory-mediated injury discussed below, the lung is also subject to ventilator-induced lung injury. While the mechanical ventilator is an indispensable therapy for lung failure, the administration of positive pressure ventilation can result in lung injury that is functionally and histologically identical to that seen in ARDS. Conversion from negative pressure ventilation to positive pressure ventilation is associated with unequal distribution of tidal volumes to the heterogeneously involved lung parenchyma. Areas of low compliance (as seen in pulmonary contusion, edema, or infection) force tidal volumes to areas of high compliance resulting in increased alveolar pressures, overdistension, and injury to uninvolved lung tissue. Mechanical injuries to the lung (barotraumas, atelectrauma, volutrauma) initiate a local inflammatory reaction and biotrauma with release of inflammatory mediators from damaged cells, recruitment of PMNs to the site of injury, and local inflammatory reaction mediated by circulating leukocytes. Mechanical stresses on the living cell are translated into intracellular inflammatory signal transduction and the combination of mechanical damage from positive pressure ventilation and the inflammation increases pulmonary dysfunction.78
The effects of ventilator-induced lung injury extend beyond the lung. Impaired oxygen delivery amplifies post-traumatic I/R injury. Mechanical disruption of normal lung defense mechanisms increases the infectious potential and the risk of pulmonary sepsis. Inflammatory cytokines generated in the lung spill over into the systemic circulation and have the capacity to increase the inflammatory state (priming) and promote remote organ dysfunction via direct cell signaling (activation). Lung tissue that has undergone a prior stress such as direct injury or I/R is particularly sensitive to further ventilator- induced lung injury.79
Clinical evidence of the contributing effects of MV on the incidence of MOF was demonstrated in the ARDS Network lung-protective ventilation (LPV) trials.80 A 2007 Cochrane Library systematic review showed that day 28 mortality was significantly reduced by LPV (relative risk, 0.74; 95% confidence interval, 0.61–0.88).81 Current evidence supports PLV as the standard therapy for patients at risk for ARDS.
Adrenal Insufficiency and Cortisol Replacement Therapy
Serum cortisol levels in polytrauma patients have been shown to be 30 μg/dL or greater for at least a week.47 Adrenal insufficiency (AI: random serum cortisol <25 μg/dL or stimulation test increase <10 μg/dL), seems to be a frequent occurrence in trauma patients, that if left untreated is associated with increased mortality.82,83 Recent data from our MOF database showed that the relationship between cortisol levels and postinjury MOF is complex with both low and high cortisol values being associated with higher risk of MOF.84 The major limitation of these retrospective reviews, however, is related to patient selection bias, as only patients in whom AI is suspected have cortisol measurements and/or stimulation tests. An RCT in trauma patients is urgently needed to better define whether AI is a risk factor for, or a symptom of, postinjury MOF, and the role of administration of cortisol postinjury.
Despite controversies, a recent task force from the Society of Critical Care Medicine and the European Society of Intensive Care Medicine appraised the current evidence and delivered general recommendations regarding AI and cortisol replacement therapy in critically ill patients.85 Although the recommendations did not specifically address trauma patients, it is reasonable to assume that AI behaves similarly in trauma as in other SIRS-inducing conditions. The task force recommended that AI should be suspected in hypotensive patients who have responded poorly to fluids and vasopressor agents, who present a delta serum cortisol of <9 μg/dL after adrenocorticotrophic hormone (250 μg) administration or a random total cortisol of <10 μg/dL. Although the task force supported the use of stimulation tests in AI diagnosis, the sole use of a random cortisol level has been shown to be sufficient and rarely discordant with the results of the stimulation tests.47,84 In patients most likely to benefit from treatment with glucocorticoid (vasopressor-dependent septic shock and patients with early severe ARDS, i.e., PaO2/FiO2 of <200 and within 14 days of onset), the task force recommended that the decision to treat with corticosteroids be based on the clinical criteria and not on the results of adrenal function. Glucocorticoids should be tapered down slowly, and reinstitution should be considered if there are signs of sepsis, hypotension, or worsening oxygenation.
The dose of corticosteroid should be sufficient to downregulate the proinflammatory response without causing immunodeficiency and impaired wound healing. Therapy with high-dose corticosteroids (>1,000 mg per day of hydrocortisone or equivalent) has not improved outcomes and was associated with higher complication rates.47 The use of extended course, stress-dose corticosteroids (200–350 mg/dL of hydrocortisone or equivalent) in critically ill patients has been associated with improved outcomes (reduction in mortality, length of stay, and MV requirements). A note of caution on the use of etomidate as an anesthetic induction agent in critically ill patients: this agent has been associated with inhibited cortisol production for up to 48 hours, and to be an independent risk factor for death.47
Insulin and Glycemic Control
While glycemic control (≤180 mg/dL) is undoubtedly important, tighter glucose control (81–108 mg/dL) in critical care patients has had conflicting results.86–88 The recently published NICE-SUGAR study89demonstrated an increased death risk associated with intensive glucose control compared with more conventional glycemic goals. Interestingly, in this study, trauma patients were one of two subgroups to exhibit the opposite trend, albeit not statistically significant. A review of our Denver MOF database to evaluate our glucose control protocol is underway, but our preliminary findings are as follows. After exclusion of diabetes patients, there was a significant dose response between mean level of glucose and mortality. Over half of these patients maintained mean levels of glucose <160 mg/dL, with only 22% maintaining mean levels <130 mg/dL. Mean number of required insulin units was also consistently higher among nonsurvivors than among survivors suggesting that the difficulty to achieve normoglycemia (and possibly insulin resistance) may be associated with higher risk of death. We are now evaluating these findings among patients for whom cortisol was measured.
In addition to its role in glucose control and induction of anabolic processes, one must account for the immunomodulatory effects of insulin, which can attenuate SIRS and modulate the proliferation, apoptosis, differentiation, and immune functions of monocytes/macrophages, neutrophils, and T cells associated with severe trauma, burn injury, or sepsis.90
Immunonutrition
Two aspects are relevant in immunonutrition: the delivery route (enteral vs. parenteral) and the diet composition.18 Although controversy exists concerning the safety of feeding the hypoperfused small bowel, evidence supports that early enteral nutrition (EEN) is not only feasible but also associated with decreased incidence of nosocomial infections.18 EEN effects go far beyond mere nourishment; rather EEN induces a complex immunologic response.91 EEN supports the function of the mucosal-associated lymphoid tissue (MALT) that produces 70% of the body’s secretory IgA.92 Naive T and B cells target and enter the gut-associated lymphoid tissue (GALT) where they are sensitized and stimulated by antigens sampled from the gut lumen and thereby become more responsive to potential pathogens in the external environment. These stimulated T and B cells then migrate via mesenteric lymph nodes and the thoracic duct and into the vascular tree for distribution to GALT and extraintestinal sites of MALT. Lack of enteral stimulation (i.e., use of TPN) causes a rapid and progressive decrease in T and B cells within GALT and simultaneous decreases in intestinal and respiratory IgA levels. Previously resistant TPN-fed lab animals, when challenged with pathogens via respiratory tree inoculation, succumb to overwhelming infections. These immunologic defects and susceptibility to infection are reversed within 3–5 days after initiating EN.92 Indeed, feeding the gut in critically ill patients has been shown to reverse shock-induced mucosal hypoperfusion and impaired intestinal transit as well as attenuate gut permeability defects and lessen the severity of CARS.18
Regarding content, to be effective, immunonutritional therapies must ameliorate cellular defense, oxidative stress, and mitochondrial function without increasing SIRS. Previous systematic reviews of immunomodulating diets (IMD) have shown a positive, albeit modest effect in decreasing mortality, infections, and length of stay in trauma patients.93,94 These analyses are hindered by the different content of the studied diets. This remains a major issue in IMD: which nutrients to include? In which dose? In which combination?
Specifically regarding the inclusion of antioxidants, supplementation of Se and Zn has shown that early provision of micronutrients improves recovery in trauma and burns.95 Se is important in thyroid hormone activity and its supplementation achieves a more rapid correction of the low triiodothyronine (T3) concentrations, a characteristic post-traumatic thyroid alteration.95 The IV route seems the only way to deliver the doses required to obtain a clinical effect. There is some evidence suggesting that Zn supplementation during the immediate postinjury period is associated with improved neurologic recovery after severe closed head injury.95 The evidence, however, seems to favor using a combination of several antioxidants.45
Intraluminal glutamine seems to have several beneficial effects: (1) reverses shock-induced splanchnic vasoconstriction; (2) preferred fuel source for the gut and lymphocytes; (3) promotes protein synthesis in the gut mucosa; (4) precursor for the antioxidant glutathione and nucleotides (required for rapid cellular proliferation of enterocytes and lymphocytes under stress); (5) protection against oxidant- and cytokine-induced apoptosis (a prominent event in severe CARS); and (6) induction of antioxidant enzymes.18 Indeed, the Houston group has been exploring enteral administration of glutamine in the setting of gut hypoperfusion. Their preliminary results in a small trial with 20 shock resuscitation patients showed that enteral glutamine administered during active shock resuscitation and through the early postinjury period is safe and enhances gastrointestinal tolerance. The results of the REDOXS study, designed to evaluate the effect of multiple antioxidants (Se, Zn, β-carotene, vitamins E and C) combined with high-dose glutamine on mortality in a large-scale randomized trial in critically ill patients, will provide important information on the value of this combination.45
The inclusion of arginine in IMD has been under debate because its use has been associated with gut barrier dysfunction and enhanced early inflammation.18 In addition, arginine is a substrate for inducible nitric oxide synthase (iNOS), which can be pathologically activated if the patient develops septic shock. Recent work by the Pittsburgh group, however, has shown that trauma patients exhibit a dramatic increase in arginase activity leading to arginine deficiency, which depresses T-cell immunity.96 Thus, the role of arginine in IMD for trauma patients needs to be further investigated.
TLR-Directed Interventions
Because TLR activation leads to an intense and immediate inflammatory reaction in response to I/R injury, targeting TLRs may be a promising intervention strategy to reduce MOF.42 Yet, because TLR activation occurs through a variety of mechanisms, generating full antagonists is technically difficult. The development of eritoran, a potent and full antagonist of LPS at TLR4, is a significant advance and offers hope that other TLR-selective antagonists may become available in future years.
Continuous Renal Replacement Therapy (CRRT)
In addition to the conventional aim of replacing renal function in acute kidney injury (AKI), CRRT may be used to modulate SIRS in sepsis.97 With the intention of influencing circulating levels of inflammatory mediators such as cytokines and chemokines, the complement system, as well as factors of the coagulation system, several modifications of CRRT have been developed over the last years. These include high-volume hemofiltration, high-adsorption hemofiltration, use of high cutoff membranes, and hybrid systems such as coupled plasma filtration absorbance. One of the most promising concepts may be the development of renal assist devices using renal tubular cells for implementing renal tubular function into CRRT.
Immunostimulating Factors
In the immunodepression stage of the inflammatory response to injury, it may be useful to enhance immune function to prevent infections that can act as second insults. Although still in its infancy, therapy with immunostimulating factors seems promising. GM-CSF was tested in small trauma populations and shown to counteract trauma-induced monocyte function depression while IFN-γ had the capacity to enhance HLA-DR on B and T lymphocytes.98,99
In conclusion, MOF remains the leading cause of late death among trauma patients. While new therapies seem to have reduced its incidence, its morbidity and mortality remain high. Indeed, despite being fewer, MOF patients are spending even more hospital resources. The latest framework to explain MOF is based on the balance between the initial inflammatory response to injury and the compensatory anti-inflammation that follows.
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