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Chronic Critical Illness and Persistent Inflammation: What can we Learn from the Elderly, Injured, Septic, and Malnourished?

Nomellini, Vanessa*,†; Kaplan, Lewis, J.‡,§; Sims, Carrie, A.; Caldwell, Charles, C.

doi: 10.1097/SHK.0000000000000939
Review Articles

ABSTRACT Patients in the intensive care unit (ICU) who develop chronic critical illness significantly stress the clinical capacity and financial resources of healthcare systems. Although vast improvements have been made in critical care management, outcomes for this ICU subset remain poor. A hallmark for patients who progress to chronic critical illness is the development of persistent inflammation and immunosuppression. The risk factors associated with the development of chronic critical illness include increased age, medical comorbidities, severe injury, septic shock, and malnutrition. Interestingly, each of these clinical states bears strikingly similar immune defects, often resulting in the activation of a persistent inflammatory state. Strategies aimed at the prevention or early recognition of this state of immune compromise may help improve outcomes for these individuals and minimize the number who progress to chronic critical illness. This review explores the current knowledge regarding the immune defects associated with the development of persistent inflammation, the ways in which it can manifest clinically, attempted therapeutic interventions to date, and future insights into improving outcomes for this patient population.

*Division of Trauma, Critical Care, and Acute Care Surgery, Department of Surgery, University of Cincinnati, Cincinnati, Ohio

Division of Research, Department of Surgery, University of Cincinnati, Cincinnati, Ohio

Division of Traumatology, Surgical Critical Care, and Emergency Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

§Surgical Services, Corporal Michael J Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania

Address reprint requests to Vanessa Nomellini, MD, PhD, Division of Trauma and Critical Care, Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45229. E-mail:

Received 19 May, 2017

Revised 12 June, 2017

Accepted 26 June, 2017

The authors report no conflicts of interest.

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Advances in the care of critically ill patients over the past few decades have decreased the overall mortality for patients admitted to the intensive care unit (ICU). However, a certain subset of ICU patients progress to a state of chronic critical illness. These chronically ill patients require prolonged hospital stays, utilize the greatest share of hospital resources, and account for much of the morbidity associated with ICU care (1, 2). As a result of the complex management involved with the care of these patients, both in hospital and after discharge, their overall healthcare cost exceeds $20 billion annually (1). Despite rigorous care and intervention, about half of the patients with chronic critical illness die within 6 months of ICU discharge. For those that survive, at least 20% display significant physical and cognitive impairments 1 year after discharge with less than 10% ever returning home (1, 3, 4). Given the profound mental, physical, and financial burden associated with caring for these chronically ill patients in the ICU, continued efforts to identify therapies that improve outcomes in this population are crucial.

There are a number of identifiable risk factors associated with the development of chronic critical illness. The greatest risk factors tend to be the presence of multiple comorbidities and increased age (2). Interestingly, studies show that patients who progress to chronic critical illness often show signs of a persistent inflammatory response and a dysregulated immune system. Since inflammation is a major component of energy expenditure in the body, continued activation of this response leads to prolonged catabolism (5–7). This persistent catabolism renders patients vulnerable to substantial losses of lean body mass despite optimal nutrition, leading to profound weakness and functional deficits. This degree of weakness significantly affects a number of activities ranging from ventilator weaning to swallowing to performing simple activities of daily living. In addition, the chronic immune dysfunction associated with this state leads to recurrent nosocomial infections and impaired wound healing (8, 9). Moreover, chronic ICU care is associated with psychological distress and long-term neurocognitive dysfunction, signifying that this process can affect every organ system (3).

Decades ago, Moore et al. (10) revealed that the response to injury or infection is a bimodal phenomenon, whereby early mortality is related mostly to the degree of shock created by the acute event and late mortality is related to either organ dysfunction, secondary infection, or both. Since then, many have shown that progression to late multiple organ failure is associated with a dysfunctional immune system, marked by ongoing inflammation and dysregulated immune cell function. To better define this state of late multiple organ failure, Moore et al. created the term, persistent inflammation, immunosuppression, and catabolism syndrome (PICS) (4). While many agree about the clinical manifestations of this condition and the risk factors associated with it, predicting which individuals will progress to a state of PICS has been controversial. This makes it difficult to determine potential interventions to either prevent or mitigate its progression. This review examines the current knowledge regarding persistent inflammation, the various ways in which this can manifest clinically, and why so many therapeutic interventions have been unsuccessful. Furthermore, insights into this phenomenon may suggest future directions aimed at improving outcomes for this population. Prior to assessing our current knowledge of PICS, a number of gaps in knowledge and areas of controversy need to be addressed.

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While both innate and adaptive immune cells are involved in the inflammatory cascade to remove offending agents, they also have an important and synergistic role in resolving the inflammatory response and participating in tissue repair. This interplay between the innate and adaptive responses is crucial to generating an effective immune response (11). In the canonical response to injury or infection (Fig. 1), the release of local tissue factors initiates inflammation. These inflammatory mediators activate immune cells to hone to the site of insult, remove the offending agent, and potentially generate long-term memory to it. Once the source is controlled, the inflammatory response resolves, typically through apoptosis of immune cells. The ability for quick and effective control at the site of an insult provides compelling evidence for the protective role of the inflammatory response. On the other hand, excessive or prolonged inflammatory responses (Fig. 2) can lead to increased local tissue destruction and impaired cellular responses, leading to poor clinical outcomes (12). It is unclear whether this prolonged inflammation is primarily a sign of not achieving complete source control, an inability to turn off the response, or some combination of both. This response also tends to be associated with early lymphocyte depletion and immune cell exhaustion leading to global immunosuppression (13). The thresholds to define “prolonged” or “excessive,” however, are not clear. Therefore, more precise definitions of persistent inflammation are required prior to developing therapies to improve outcomes in this population.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Another concept not well understood is the exact threshold that determines when and how an immune response transitions from local to systemic. This is important because, once the response becomes systemic, the risk of developing subsequent organ failure increases significantly (14). The ability to predict how and when the response will systemically affect the host is necessary to understand the mechanisms involved in what we currently describe as a “dysregulated” response. Importantly, there has been a major paradigm change in the description of the systemic response to injury or infection, as initially described by Bone et al. (15). This has necessitated a shift in our understanding of the process of inflammation as a whole. The original theory was that the systemic inflammatory response syndrome (SIRS) initiates the response to injury or infection, characterized by the release of a cascade of pro-inflammatory mediators and activation of immune cells. The inflammatory mediators in SIRS allowed for the removal of invading pathogens or cellular debris. The killing mechanisms implicated in SIRS, however, are nonspecific and could cause local tissue destruction if left unchecked, leading to early death due to multiple organ failure. Once the SIRS response diminishes in this paradigm, there is a subsequent compensatory anti-inflammatory response syndrome (CARS) that not only downregulates the destructive mechanisms of innate immune cells, but also promotes tissue healing and repair (4, 16). If this phase becomes imbalanced or prolonged and certain signals are not turned off appropriately, patients are at risk of developing ongoing inflammation, which ultimately leads to lymphocyte depletion and immunosuppression. If the inflammatory response is either insufficient or too excessive in this model, both the responses activated simultaneously, creating a mixed antagonist response syndrome (17). Recent studies have challenged Bone's sequential articulation of inflammatory responses. Instead, it appears that the CARS-type response often occurs simultaneous to the SIRS-type response, providing a concurrent reaction to injury and infection from the onset of the insult (18). The mechanisms involved with maintaining the balance between the SIRS and CARS responses, however, are not clear. Therefore, future studies investigating which individuals do not resolve the inflammatory response and eventually progress to a state of immunosuppression are essential (2).

Finally, there is no consensus on whether PICS is a separate and distinct syndrome, part of a gradient of immune responses, a result of multiple clinical or sub-clinical insults, or one of many phenotypes yet to be defined. In addition, the role of other factors, such as race, gender, and genetic predisposition, has not been studied in the context of PICS. However, the decreased inflammatory response associated with estrogen has been shown to be protective (19, 20) and non-whites tend to experience worse outcomes in response to sepsis and trauma (21, 22). Since there are no clear criteria to diagnose someone with chronic critical illness or PICS, it is unclear who recovers, how they recover, and how long it can persist. In fact, many believe this state can persist long after discharge. Better characterization of this clinical state is therefore necessary prior to determining how to improve outcomes for this population.

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In states of persistent inflammation and immune suppression, the degree of insult seems to be the main determinant of the level of inflammation that occurs (23). For instance, with a small injury or infection, local activation of the inflammatory response occurs and resolves with clearance of cellular debris or pathogen eradication. With a moderate to severe injury, there is increased tissue damage that requires prolonged activation of the inflammatory response. In this scenario, the inflammatory response is often overwhelming and leads to the activation of a systemic response. This dysfunctional response is associated with mobilization of leukocytes into the periphery, a dysregulated release of pro- and anti-inflammatory cytokines, vascular compromise, imbalances in coagulation factors, and an excessive production of reactive oxygen species (24). When patients develop a systemic response to injury, this potentially leads to multiple organ failure and significantly increases the risk of death. The mechanisms behind this dysregulated response, however, are not well understood. Therefore, a better understanding of the subset of patients who develop a dysregulated response to injury or infection is imperative to improving outcomes. This section examines the various aspects of the dysregulated immune response that occur in states of persistent inflammation and immune suppression.

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Inflammatory mediator release

Conditions associated with persistent inflammation are typically associated with marked elevations in circulating levels of both pro- and anti-inflammatory mediators, such as interleukin-6 (IL-6) and IL-10. In these states, elevated cytokine levels tend to persist in circulation longer than individuals with a more efficient immune response (18, 25–29). In a landmark study of trauma patients, circulating levels of pro-inflammatory cytokines, IL-1 and IL-6, return to baseline within 7 to 14 days when patients are only mildly injured. In the more severely injured patients, however, circulating levels of these cytokines remain elevated beyond 28 days (18). Similar observations have been noted in septic patients, whereby the inflammatory response is greater and more prolonged in those with a more severe illness (2). Interestingly, elderly and malnourished patients exhibit elevated levels of circulating pro-inflammatory cytokines at baseline, even in the absence of injury, infection, or other comorbid conditions (25, 30). Other mediators significantly increased during conditions of excessive or persistent inflammation are inducible nitric oxide synthase leading to elevated nitric oxide release, prostaglandins, glucocorticoids, and catecholamines (26, 28). Elevated levels of each of these mediators have been shown to directly cause immune cell dysfunction (26).

It remains unclear whether one specific mediator or a medley of mediators are sensitive or specific enough to identify which patients will progress to PICS. IL-6 and IL-8 consistently seem to have the greatest sensitivity and specificity to prognosticate infection in critically ill patients in the ICU (31, 32). A number of studies have shown that certain genetic polymorphisms of cytokine genes are associated with worse outcomes in critically ill patients (33, 34) and with aging (35). In particular, individuals predisposed to generating higher levels of pro-inflammatory cytokines have decreased longevity and worse outcomes in response to an insult (36). None of these studies evaluates whether there are certain genetic predispositions to the development of chronic critical illness or PICS. While many biomarkers are associated with predictors of prolonged hospitalizations or increased infectious complications, perhaps measuring the absolute value of these markers does not accurately portray the course of the immune response. For instance, while elevated IL-6 correlates with worse outcomes in a number of clinical scenarios, it is unclear which is more harmful: the release of very high levels of IL-6 followed by a quick return to baseline or a protracted release of moderate levels of IL-6. Some have suggested that, rather than focusing on an absolute level of biomarker release, perhaps tracking the change in biomarker levels over time would allow one to predict a patient's course (11). Such studies could better identify which patients are at risk of developing prolonged critical illness and who would potentially benefit from early intervention.

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Defective cellular responses

Although activation of the inflammatory response is excessive or prolonged in conditions leading to persistent inflammation, the immune cells themselves appear markedly dysfunctional. In the normal inflammatory response, innate immune cells become activated upon recognizing pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) (29). PAMPs are peptides or DNA fragments derived from foreign pathogens at a site of infection, whereas DAMPs are released from host cells following tissue damage and are primarily implicated in the inflammatory response to injury. Pathogen-recognition receptors (PRRs) on the surface of innate immune cells then recognize these molecular fragments. The most commonly known group of PRRs is the toll-like receptor family (27).

Once the PAMPs or DAMPs bind to the PRRs, a series of host defense responses are activated. These responses include the elaboration of reactive oxygen species, the generation of reactive nitrogen species, and the phagocytosis of pathogens. In response to local tissue damage or infection, surrounding cells release chemokines to promote trafficking of additional immune cells toward the site of the insult. The robustness of this response is integral to the efficient and timely clearance of pathogens. Furthermore, the ability of innate immune cells to present antigens on their cell surface is imperative for activation and clonal expansion of T cells, which provide a complimentary pathway to eradicating pathogens and clearing damaged tissue.

In states of persistent inflammation, a number of genomic changes occur within immune cells (18). In addition, there is a significant reduction in the cell surface expression of PRRs on innate immune cells (37–40). As a result, the main downstream signaling pathways required to activate these cells, such as MyD88, p38 mitogen activated protein kinase, and NF-κB, are significantly attenuated (18, 27, 38, 40–43). Consequently, the essential innate immune cell functions—including pathogen eradication, cytokine production, chemotaxis, and antigen presentation—are significantly diminished (7, 26, 27, 29, 37, 38, 44–52). If the cells reach this point of suppression and an inflammatory source is not completely controlled or a secondary insult is encountered, the immune cells are unable to function properly. As a result, effective clearance of pathogens or injured tissue does not occur, thus predisposing the host to persistent inflammation.

Various states of systemic inflammation are also associated with a depletion of CD4+ and CD8+ T cells in the blood, bone marrow, spleen, and secondary lymphoid organs (53, 54). This loss is directly related to increased apoptosis of T cells. Therapies that prolong prosurvival signals for lymphocytes have demonstrated increased bacterial clearance in various models of infection (55). The significance of this suppressed adaptive response is exemplified in studies showing the reactivation of latent viruses that occurs even in nonimmunocompromised individuals suffering from prolonged inflammatory states (53, 56). While the respective roles of the innate and adaptive immune systems in the development of persistent inflammation are not clear, some show that a Gr-1+ CD11b+ suppressor cell population, termed myeloid-derived suppressor cells (MDSC), are significantly elevated in severe sepsis and other prolonged inflammatory states. These cells can significantly induce T-cell suppression, which decreases microbial clearance, and may be a contributing factor to persistent inflammation (57, 58).

Overall, an increased or prolonged release of immune mediators leading to the state of ongoing inflammation and immunosuppression is characterized by decreased activation of innate immune cells, as well as depletion and decreased activation of lymphocytes. This dysfunctional process leads to global immune suppression, resulting in decreased clearance of any remaining tissue debris or bacteria, generating a cycle that is difficult to resolve. It is unclear what determines which individuals will progress to this state; however, it is likely a combination of the size and type of the initial insult and the ability of the patient to respond, as determined by their genetics and current clinical state. Further investigation of the various states associated with the progression to PICS may help clarify this process.

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Those most at risk for progressing to a state of chronic critical illness are patients with multiple medical comorbidities, the elderly, those with severe injury or septic shock, and the malnourished (59). While these clinical states are seemingly unrelated, they can all present with prolonged states of inflammation. This section, as summarized in Figure 3, examines each of these clinical states and evaluates the divergent yet similar pathways to develop persistent inflammation and immune suppression.

Fig. 3

Fig. 3

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Advanced age is perhaps the most studied state of chronic inflammation. A number of diseases associated with aging, such as atherosclerosis, rheumatoid arthritis, osteoporosis, and cancer, are classically thought to be the etiology of the chronic inflammation seen in this population (25, 60). However, aging alone is associated with elevated levels of pro-inflammatory mediators in systemic circulation, even in the absence of illness or injury. This phenomenon has suitably been termed, “inflamm-aging” (60–62). Since these individuals exist in a state of chronic, low-grade inflammation already, the response to any secondary insult tends to be significantly diminished. This is thought to be the reason why the elderly are significantly more susceptible to infection and injury, even when they are thought to be healthy otherwise.

This chronic inflammatory state of the elderly is associated with a gradual accumulation of oxidative stress to DNA, proteins, and lipids, leading to alterations in overall cellular function over time (63, 64). Normally, cells can protect themselves against mild degrees of oxidant damage by activating catalase and superoxide dismutase to eliminate peroxide and superoxide, respectively (6). With excessive or prolonged stress, however, cells can be overwhelmed with oxidative stress. In addition, the ability to manage this overwhelming response is significantly decreased with aging due to a decrease in the endoplasmic reticulum stress response and decreased mitochondrial metabolism (63, 65). With an ongoing source of cellular damage, paired with an inability for the innate and adaptive immune system to function properly, the elderly are primed to remain in a persistent inflammatory state. For these patients, encountering even mild insults can be devastating.

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Severe trauma and septic shock

Many have corroborated that the more significant the insult in patients suffering from severe injury or septic shock, the greater the immune dysfunction (12, 26). In young, healthy patients with only mild injury or infection, activation of a robust inflammatory response, followed by rapid source control and resolution of the response, correlates with a relatively quick clinical recovery (18). In these patients, cell surface receptor expression and downstream signaling occur in a predictable and expected fashion (18). After a more severe insult, such as a large burn or significant traumatic injury, the immune system is tasked with a greater mission, potentially requiring increased or prolonged activation. Certainly, many factors contribute to poor outcomes in young patients with severe trauma or sepsis, such as dysregulation of the neuro-endocrine system, abnormal insulin utilization, and the secondary effects of multiple organ dysfunction. However, an uncontrolled inflammatory response is a major contributor to poor outcomes in this population as well (12, 26, 66). Without a definition of “excessive” inflammation in these patients, however, it is difficult to determine which individuals will progress to a persistent inflammatory state. More clear definitions of what threshold is “too excessive” for each individual patient may help determine which therapeutic interventions to employ throughout their clinical course.

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Nutritional states

Obesity is strongly associated with chronic, low grade inflammation which is thought to be an important underlying cause for obesity-related diseases, such as atherosclerosis, nonalcoholic steatohepatitis, and diabetes (67). The chronic inflammation noted in severe obesity is principally driven by the interplay of excess adipose tissue and the gut (67). However, severe protein-calorie malnutrition is also associated with immune dysfunction (39, 42, 45, 54). When further delineating between different classes of obesity, it appears that class 1 obesity (body mass index [BMI] between 30 and 34.9) yields the greatest survival benefit in sepsis compared with malnourished, nonobese, or morbidly obese individuals (68). Higher leptin levels in class 1 obese individuals are thought to confer this immune protection (69).

As opposed to the gradual accumulation of oxidative stress that occurs with aging or the acute stress that accompanies severe injury and septic shock, the mechanisms of persistent inflammation in malnutrition are even less understood. It is possible that the lack of substrate and cofactor availability during starvation leads to a decrease in the ability to perform cellular respiration, thus decreasing global cellular function (30). Others have suggested that, during starvation, disruption in the mucosal integrity and immunity of the gastrointestinal tract is the driving mechanism of systemic immune dysfunction (70–72). In this theory, mucosal disruption can lead to bacterial translocation, which alters systemic immune function. Consequently, when faced with an actual injury or infection, the response in these individuals is blunted. Regardless of the cause, defects in both the innate and adaptive immune systems can occur in malnourished individuals, as evidenced by poor wound healing, increased susceptibility to infection, decreased memory T-cell expansion, and anergy (53, 66). When studying the effect of nutritional states, however, it is imperative to differentiate the two extremes—malnourished versus BMI >35—since the mechanisms of immune dysfunction are different.

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Anti-inflammatory targets

There are a bewildering array of animal studies which suggest that blocking pro-inflammatory mediators diminishes the severity of the inflammatory response (73, 74). For example, administration of anti-IL-6 antibody, anti-TNFα antibody, antichemokine antibodies, IL-1 receptor antibody, or soluble TNF receptor in various animal models is associated with a significant reduction in the degree of systemic inflammation after either sepsis or injury (46, 75, 76). Modulation of bioactive lipid mediators through manipulation of the arachidonic acid pathway has also been examined. Specifically, treatment with nonsteroidal antiinflammatory drugs or inhibitors of prostaglandin in sepsis appears to confer a survival advantage in animal models (28, 77). Although many studies aimed at blocking inflammatory mediators have been attempted in humans, none of them has demonstrated a clinical benefit after injury or infection as they have in animal studies (78).

The administration of anti-inflammatory mediators to diminish a prolonged inflammatory response has also been studied, but this intervention also shows no clinical benefit. Preliminary animal studies offered great promise for the antithrombotic and anti-inflammatory protein, activated protein C, prompting the PROWESS trial in humans. In this trial, the administration of activated protein C in patients with severe sepsis or septic shock significantly improved mortality (79). However, subsequent studies failed to confirm the benefit of this modulator and instead suggested an increased bleeding risk. As a result, activated protein C as a treatment for sepsis was withdrawn from the market altogether (80).

Given that oxidative stress is associated with aging, severe injury, and sepsis, the administration of various antioxidants has also been extensively explored (81). The effects of antioxidants in aging show some benefit, but the results in sepsis or severe trauma have not been promising. In particular, selenium, zinc, vitamin A, vitamin C, and vitamin E have been studied in adult critically ill patients. It appears that, although there is significant depletion of these essential cofactors in the critically ill, supplementation alone does not affect overall outcomes or improve infectious complications and may even cause some harm (82).

Although targeting single mediators within the inflammatory response has largely been successful in animal models, this has not translated to durable success in human trials. Part of the reason for this lack of success is not only related to the inability to perfectly model these responses in the laboratory, but also because the redundancy in the inflammatory response prevents the ability to target one single molecule (83–85). Some also suggest that the trials evaluating the effect of anti-inflammatory agents were unsuccessful because they did not first evaluate the variability in individual responses (11, 86). Retrospective and confirmatory studies by Eichacker et al. indicate that anti-inflammatory agents minimally effect individuals who are at a high risk of dying. This study instead suggests that evaluating individual immune responses will allow us to risk-stratify patients and identify those who would actually benefit from anti-inflammatory agents. For instance, while elevated TNFα and IL-1β tend to correlate with worse outcomes in sepsis and injury, others have shown that not all septic patients have elevated levels of these cytokines in circulation (66). Therefore, administration of anti-TNFα or anti-IL-1β antibodies to all patients presenting with sepsis may not show significant clinical benefit. Future trials in which patients’ immune profiles are assessed prior to therapeutic intervention would be very impactful.

Another reason why administration of medications that block the inflammatory response has not shown clinical benefit is that conditions associated with ongoing inflammation exhibit decreased immune cell function. Therefore, administration of anti-inflammatory agents may further exacerbate this immunosuppressed state. On the other hand, attempting to reactivate immune cells to improve their function may provide some benefit. Restoration of HLA-DR expression on monocytes using interferon-γ, stimulating neutrophils with granulocyte colony-stimulating factor, restoring the ability for T and B cell proliferation with IL-7, or improving costimulation between T cells and antigen presenting cells significantly improves immune cell function (11, 87, 88). Regulatory immune cells are also being investigated as a way to manipulate the immune response as a therapeutic target (89). A host of regulatory cells have been investigated in these clinical fields, ranging from T- and B-regulatory cells to MDSCs (59). In theory, expanding MDSCs may help reverse the persistent inflammation that occurs after injury or sepsis by preventing excessive inflammation (90). However, MDSCs are also thought to suppress T-cell responses and may perhaps exacerbate the immunosuppression that occurs (4, 91).

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Modulation of endocrine responses to stress

Since stress is a potent activator of the hypothalamic-pituitary-adrenal axis, modulating hormonal pathways could theoretically counterbalance the inflammatory and catabolic state of critically ill patients. Although corticosteroids were previously recommended to reduce the inflammation of severe sepsis, large clinical trials have failed to show improved outcomes (92, 93). Currently, the Surviving Sepsis Campaign recommends using corticosteroids as an intervention in sepsis only when patients develop septic shock that is refractory to fluids and vasopressors (94). This subset of patients is in septic shock because of relative adrenal insufficiency leading to vascular collapse. Here, corticosteroid therapy acts to restore endogenous catecholamines, not necessarily to provide anti-inflammatory effects. In fact, the anti-inflammatory effects of corticosteroids in sepsis are potentially detrimental due to the increased risk of infectious complications that can occur.

The supplemental administration of oxandrolone, testosterone, or DHEA as methods to modulate the response to severe injury or sepsis also fails to improve outcomes (95–97). In fact, supplementation of aged or critically ill patients with certain anabolic hormones, such as growth hormone, does not improve muscle mass or strength and is associated with adverse side effects, such as increased insulin resistance and increased mortality (98, 99). The failure to achieve beneficial outcomes using anabolic hormones may be an age-related or injury-specific phenomenon, since oxandrolone improves muscle strength, preserves bone mineral content, and minimizes changes in height in pediatric burn patients (100).

Many studies show that females have a survival advantage in sepsis and trauma and that estrogen may be protective in these settings (19, 20). Therefore, administration of estrogen after severe injury or sepsis may be beneficial, regardless of patient gender. Topical estrogen accelerates cutaneous wound healing in aged humans by decreasing the inflammatory response (101). Others have shown that systemic administration of estrogen is particularly beneficial in aged animals after injury by acting as an anti-inflammatory agent (102). Trials examining the effect of estrogen in critically ill patients, however, have yet to be performed.

Lastly, since the ghrelin/leptin system has profound effects on the innate immune system, some have explored its effect on critically ill patients. Ghrelin and leptin are the main mediators of hunger and appetite, working in concert to regulate metabolism. Targeting this hormone pathway in critical illness has yielded mixed results (103, 104). Higher levels of leptin, as seen in mildly obese patients, seem to be protective in sepsis, leading to stabilization of body temperature, reduction in the overwhelming pro-inflammatory cytokine response, and improved survival (69). In other models of critical illness, ghrelin supplementation actually leads to improvement in systemic inflammation. In these studies, it is unclear whether ghrelin administration improves outcomes because of direct modulation of the inflammatory response or from the secondary benefits of improved enteral nutrition through stimulation of appetite (104). Further investigation on modulating this pathway is required to determine the mechanisms involved in injury or infection.

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Nutrition-based strategies

Early enteral nutrition may be one of the most potent strategies to improve outcomes after injury or infection. Administration of enteral nutrition is associated with a significant reduction in mortality, remote organ damage, and infectious complications after injury and sepsis compared with total parenteral nutrition in both animals and humans (105, 106). When the gastrointestinal tract is starved for multiple days, mucosal breakdown can occur, making the host vulnerable to the bacteria within the lumen of the gut (107). This breakdown decreases the natural defensins and other antimicrobial mediators within the lining of the gut, which weakens its innate defense system. This weakness is also associated with decreased lymphocytes in the lining of the gut, leading to increased susceptibility to systemic inflammation (107).

Initiation of enteral nutrition in the starved state results in almost immediate normalization of the gut mucosal barrier, restoration of mucosal immunity, and decreased neutrophil sequestration within the gastrointestinal tract (70, 107). In fact, early enteral nutrition has consistently demonstrated to improve outcomes after injury or sepsis (45, 70, 72, 106, 108, 109). Some have also shown that glutamine-enriched diets in severely injured and septic patients enhance the immune system by providing the small intestine with their primary source of energy. Accordingly, both the Society for Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition recommend a glutamine supplemented diet for enteral nutritional support in severely injured trauma and septic patients (110).

Since the inflammatory response is one of the most powerful modulators of energy expenditure, persistent inflammation is associated with a prolonged catabolic state (5–7). For those who are already malnourished, even mild challenges to the immune system may be devastating (111). However, restoration of immune function in the malnourished patient can occur by initiating early enteral nutrition. Importantly, neither aging, severe injury, nor sepsis demonstrate such rapid reversibility of a dysregulated inflammatory state. Therefore, establishing malnutrition as a model to investigate potential measures to abrogate PICS or chronic critical illness is essential.

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Exercise and resistance training

Employing early exercise and resistance training in critically ill patients is another adjunctive strategy that accompanies early enteral nutrition. Regardless of how it is clinically measured, frailty (and not age per se) serves as a robust predictor of mortality, ICU and hospital length of stay, readmission rate, and complication rate after major surgery or injury (112, 113). The persistent inflammation and accompanying catabolic state that characterizes chronic critical illness is thought to be responsible for the exaggerated loss of lean body mass and the concomitant development of clinical frailty (4, 25, 30). As such, early physical therapy and resistance training has been shown to impede frailty development and significantly improve outcomes for critically ill patients (114). In a landmark paper, patients who were mechanically ventilated in the ICU for greater than 72 h were randomized either to early mobilization with physical therapy or standard ICU therapy. Early mobilization resulted in decreased delirium, more ventilator-free days, and enhanced functional outcomes over the 28-day follow-up period (114). While the link between exercise and reduced inflammation has been recognized for some time, the effects of early mobilization and physical therapy on mitigating the development of immune dysfunction in critically ill patients have yet to be studied (115, 116).

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In summary, patients who progress to a state of persistent inflammation and immunosuppression, regardless of the etiology, demonstrate elevated pro- and anti-inflammatory cytokines and dysfunctional immune cells. In this pathologic state, patients are highly susceptible to further systemic insults and have a significantly prolonged recovery as well as an increased mortality. Interestingly, the immune dysfunction in severe injury or septic shock is quite similar to that demonstrated in aging and malnutrition. While the pathways leading to immune dysfunction in each of these states differ, clearly those who progress to a persistent inflammatory state have worse outcomes. Therefore, studying the pathophysiologic states of aging, sepsis, severe injury, and malnutrition in parallel may better predict those who will develop this persistent inflammatory state. Regardless of the cause, the definition of “persistent” or “excessive” inflammation, along with a more precise explanation for the development of PICS, is needed to better compare this group of patients to those with efficient resolution of their inflammatory response.

Given the observations that not all individuals respond to the same insult in a similar manner, perhaps individualized genomic or immune cell profiling may provide a more comprehensive analysis of the patient's clinical state to provide some insight into which treatment modalities could work best for them. This concept is not novel, in fact. Early studies of sepsis employed the idea of categorizing patient in terms of their Predisposition to having worse outcomes, Infection or injury type, the Response to the insult, and the Organ dysfunction that could increase the risk of complications further (117). This PIRO staging system was initially suggested as another tool for helping predict which septic patients would have poor outcomes. Given how cumbersome this score is to generate and the fact that more simplified scoring systems were generated, the PIRO staging system has fallen by the wayside. Perhaps studying the similarities and difference between aging, injury, infection, and malnutrition may uncover better strategies to risk stratify critically ill patients. With this risk stratification, clinical trials tailoring the therapy to the individual patient could significantly change outcomes and potentially advance our understanding of the response to significant injury or infection. Furthermore, with better definitions of “persistent” or “excessive” inflammation and immunosuppression, the ability to risk stratify patients will be even more robust. Further investigation into these mechanisms along with new insights from investigators evaluating the role of energy expenditure, mitochondrial dysfunction, and the effects of bioactive lipid molecules on immune cell signaling will be promising. In the meantime, multimodal regimens that include early enteral nutrition and mobilization are useful adjuncts to improving immune function in states of persistent inflammation.

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Immune suppression; persistent inflammation; PICS

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