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The Consequences of Aging On the Response to Injury and Critical Illness

Joseph, Bellal; Scalea, Thomas

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doi: 10.1097/SHK.0000000000001491
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Abstract

INTRODUCTION

According to the US Census Bureau, the coming decades are expected to bring about transformative changes to the demographic structure of the country's population. This includes the current, unprecedented expansion of the older adult subpopulation encompassing individuals aged 65 and older. Indeed, it is projected that there will be 38 million older adults by 2030, and about one in five Americans will be elderly by 2050 (1). This transformation alone will have a significant effect on the healthcare system. Multiple reports have highlighted increased healthcare utilization by geriatric patients (2), along with a sharp increase in the number of geriatric patients across the spectrum of care (3–5).

Advances in the medical management of chronic diseases and geriatric-specific syndromes have improved the overall independence, mobility, and lifestyle activity of the elderly. Ironically, however, the increased activity of older adults puts them at significant risk for a wide variety of injuries. Trauma, for instance, has become one of the leading causes of morbidity and mortality in the elderly (6). Not surprisingly, data from nationwide trauma registries reveal that around one in three trauma patients is elderly (7), and this number will increase over time.

Additionally, the intersection of aging and injury is often complicated. The elderly bring about a unique set of challenges to their course of management due to their wide array of comorbidities, geriatric-specific syndromes, and reduced physiological reserve (8, 9). Consequently, the understanding of risk stratification in an older adult has evolved beyond chronological age and now takes into consideration the physiological response to injury by assessing the patient's frailty status (10). Frailty is a comprehensive multidimensional phenotype characterized by age-associated depletion of physiological reserve leading to a state of augmented vulnerability to physical stressors and a diminished ability to recover from illnesses (11). It is well established in the literature that frail geriatric patients have suboptimal outcomes compared with their younger counterparts (even following seemingly minor injuries), and, as demonstrated in many studies, this translates to a higher rate of injury-related mortality (10–18). Although the exact reasons behind the inferior outcomes of geriatric trauma patients are not well defined, there has been much speculation about the role of chronological age, physiological age, the frailty syndrome, pre-existing medical conditions (5), and/or a combination of all of these factors. Likewise, there is a growing interest in the consequences of aging on the response to injury (19). Older adult patients have a senescent physiological response when compared with their younger counterparts; therefore, a better understanding of age-associated organ dysfunction is essential. Considering the aspects detailed above the current review aims to summarize and critically appraise current evidence regarding the influence of aging on the response to injury to produce a better understanding of why geriatric trauma patients have inferior outcomes following trauma.

Aging and trauma: the deconditioned patient

Older adult patients have an altered post-traumatic physiological response attributed mainly to a functional decline in organ systems (20) and a decrease in the number of functional cells. Aging is associated with a marked decline in the cardiopulmonary reserve, which is critical in the setting of trauma. Cardiac function declines by about 50%, and it co-occurs with reduced adrenergic sensitivity (21). As a result, the typical cardiovascular response to hypovolemia detected using the shock index may be masked (22). More specifically, the elderly may not be able to mount a compensatory tachycardic response or to increase their cardiac output. This is also accompanied by an overall increase in stiffness throughout the arterial system that increases left ventricular afterload, systolic blood pressure, and contributes to ventricular hypertrophy (21). Despite what seems to be an apparently normal blood pressure and heart rate, many older adult trauma patients still have evidence of tissue hypoperfusion, and their admission vital signs may not be predictive of shock states (23). The response to resuscitative interventions may also be altered due to the above-mentioned physiological derangements. Joseph et al. (24) recently conducted a 5-year review of the Trauma Quality Improvement Program created by the American College of Surgeons Committee on Trauma—they analyzed the factors that influence survival after an emergency resuscitative thoracotomy (ERT). Interestingly, one of the independent predictors of survival was being less than 60 years old. In addition, ERT was deemed to be futile in all patients older than 70 years of age (regardless whether their mechanism of injury was blunt or penetrating) and those older than 60 years of age with a blunt injury (24).

Older adults also have impaired pulmonary mechanics due to thoracic kyphosis, rib calcifications, and intercostal muscle atrophy. The chest wall is relatively less compliant, which reduces ventilatory capacity (25). In addition, the cough reflex is impaired along with the function of the mucociliary epithelium, which puts geriatric patients at substantial risk of hospital-acquired pneumonia, especially in critical care settings (26). Renal function in the elderly also decreases. Between the ages of 50 years and 80 years, the glomerular filtration rate decreases by a factor of two despite normal serum creatinine levels (27). The kidney's response to the compensatory effects of antidiuretic hormone and aldosterone is also blunted in the setting of hypovolemia (28). As a result, urine output may be maintained, but mask systemic hypoperfusion. The volume status of geriatric patients remains challenging to maintain. Age-related glomerulosclerosis places them at a higher risk of acute kidney injury along with the effect of injury-related nephrotoxins (29). At the same time, aggressive volume resuscitation can lead to fluid overload and hyperchloremic metabolic acidosis, both of which are associated with inferior outcomes and higher rates of mortality. There is a growing need to utilize cautious deresucitation in this age group to maintain normovolemia (30). The occurrence of acute kidney injury (AKI) in older adult patients is often iatrogenic, multifactorial, and similar to the risk factors in the general population (31). However, higher rates of AKI are observed in this age group likely due to the multifactorial nature of the insults along with a reduction in overall renal reserve. Harbrecht et al. (32) conducted a retrospective analysis of 836 elderly trauma patients > 75 years aiming to determine the incidence and risk factors of AKI in this age group. In their analysis, they reported an overall incidence of 8%. Multiple risk factors for AKI were reported including hypotension (systolic blood pressure < 90 mm Hg), higher injury severity scores, injuries with high bleeding potential such as chest, extremity, and pelvic injuries (32). Renal hypoperfusion in the elderly is associated with higher rates of progression to acute tubular necrosis especially in the setting of decreased cardiac output and hypovolemia (diuretics, laxatives, polypharmacy, and unconsciousness) (33, 34). The rate of recovery following AKI is also lower in older adult trauma patients as highlighted by a systematic review and meta-analysis (35). There is also emerging data on longer-term outcomes emphasizing a higher rate of progression to chronic kidney disease (36). Furthermore, the development of AKI is also associated with the need for long-term dialysis. According to the RENAL study, around 5.4% of patients who sustained an episode of AKI required long-term maintenance dialysis (37, 38). This was also corroborated by findings by Schiffl and Fischer (37). Studies with longer-term follow-up reported a wide range of results with an average long-term dialysis rate of 12.5% over a 10-year period (39).

Changes in the musculoskeletal system also predispose older adults to the occurrence of injuries. Sarcopenia leads to a progressive reduction in lean body mass (40). Moreover, skeletal degenerative changes and osteoporosis increase the risk of fractures, especially those involving the vertebrae, hip, and distal forearm (Fig. 1). The cervical spine range of motion is also affected, and this may be problematic for securing the airway during the primary survey (41).

Fig. 1
Fig. 1:
Older age and organ system changes.

Redefining vulnerability: the frailty syndrome

To better gauge the heterogeneous health condition of older adult patients regardless of age, the concept of frailty was introduced more than 20 years ago. Frailty is considered to be a multidimensional syndrome characterized by a depleted physiological reserve and diminished resistance to stressors (42). Multiple operational definitions of frailty have also been discussed in the literature, including characteristics such as diminished strength, endurance, and suboptimal physiological functioning that is associated with loss of independence and mortality (42). In trauma and acute care surgery, frailty has gained considerable attention due to its strong predictive ability to determine outcomes. Some frailty measurement tools have also been developed and validated on trauma patients. In 2014, Joseph et al. (12) developed and prospectively validated the Trauma Specific Frailty index (TSFI), which is a 15-variable score derived from the Canadian Study of Health and Aging Frailty Index (CSHA-FI) (Fig. 2) . The CSHA-FI is an extensive and time-consuming questionnaire that is difficult to implement in the acute setting of trauma. A comprehensive frailty assessment should take into account several factors that might affect the patient's physiological reserve, including comorbidities, nutritional status, and other functional aspects that make the patient vulnerable to injury (12). The literature has consistently described the association between frailty and adverse perioperative events (43–47). In a 2-year prospective cohort study of 250 geriatric trauma patients at a Level I trauma center, Joseph et al. (10) demonstrated that patients with frailty had a higher risk of in-hospital complications (cardiac, pulmonary, renal, hematological, infectious, and surgical). Additionally, frail patients had a higher likelihood of an adverse discharge disposition (that is, discharge to a skilled nursing facility instead of home) that reflects a decline in functional independence and the ability to perform activities of daily living (Fig. 3). Frail patients also had a higher rate of mortality following trauma (10, 48). At the same time, multiple reports have demonstrated that frail patients have higher rates of failure-to-rescue (14). From a critical-care point of view, the reported incidence of frailty among geriatric patients admitted to the intensive care unit (ICU) ranges from 23% to 41%. In a critical care setting, frail patients were reported to have increased rates of all postoperative complications—infectious complications (pneumonia, urinary tract infection, deep surgical site infection, and severe sepsis) ranked first, followed by respiratory (acute respiratory distress syndrome and unplanned intubation) and cardiovascular complications (cardiac arrest and myocardial infarction). Similarly, prolonged ventilation and postoperative renal failure are more common in frail patients (13). Published research findings clearly show that frail patients are less likely to be functionally independent after ICU discharge and that they will require some sort of home-based or institutional assistance (Table 1). Additionally, there is a linear increment in the rates of adverse outcomes with increasing degrees of frailty (Fig. 4) (13).

Fig. 2
Fig. 2:
Fifteen variable trauma-specific frailty index.
Fig. 3
Fig. 3:
The effects of frailty and dyshomeostasis on outcomes following trauma.
Table 1
Table 1:
Effect of frailty on outcomes following trauma
Fig. 4
Fig. 4:
Correlation between higher levels of frailty and adverse in-hospital outcomes.

Aging and the response to injury

Trauma exhibits an intricate biological response characterized by an increase in the baseline metabolic rate, protein catabolism (49), and an extensive cascade of inflammation described in the literature as the systemic inflammatory response syndrome (SIRS). The initial response to trauma is multisystemic, involving the hemostatic, inflammatory, endocrine, and neurological systems (49). Following the reperfusion of traumatized tissues, a state of immunoinflammatory activation occurs with the release of a wide range of different inflammatory factors. The injured cell releases endogenous damage-associated molecular patterns (DAMPs, alarmins) eliciting an immune response (50–52). Aging was recently reported to be associated with higher levels of circulating DAMPs (53, 54) especially in the immediate aftermath of trauma and such elevated levels are retained for a longer period given the lower rate of DAMP clearance. There are also multiple reports describing the altered metabolic profile following severe injury with accelerated lipolysis, proteolysis, and circulating biological matrix proteins that can have widespread systemic manifestations (55). Multiorgan failure in the postinjury period has also been linked to the state of immunoendocrine activation and the cascade of cellular and molecular derangements initiated by the injury (56, 57). All these factors were collectively referred to as persistent inflammation, immunosuppression, and catabolism syndrome as originally described by Moore et al. (57).

When age is factored into this intricate process, it adds a new level of complexity. Aging is characterized by a marked decline in cellular function leading to a diminished physiological reserve and, eventually, organ system dysfunction. This is expected to lead to an impairment in the adaptive and homeostatic mechanisms following injury that results in increased susceptibility to the stress of injury. Consequently, injuries commonly tolerated by younger patients can lead to disproportionally devastating outcomes in older adults. Studying a cohort of polytrauma patients, Frankenfield et al. (58) conducted one of the first investigations of the differences in the inflammatory/metabolic response to traumatic injury in older adults. After stratifying patients according to whether they were older or younger than 60 years, the authors reported a significantly higher rate of SIRS in the older (elderly) cohort compared with the younger group in the postinjury period. Even though the occurrence of tachycardia and leukocytosis did not differ between the groups, elderly individuals exhibited a lower number of fever episodes. The study also noted that the resting metabolic rate and oxygen consumption was markedly attenuated in the elderly. Despite similar carbohydrate intake through enteral or parenteral routes, hyperglycemia was more predominant in the elderly. There were also derangements related to the overall nitrogen balance because the elderly were more likely to be azotemic regardless of protein intake or renal function, which reflects accelerated protein catabolism. As expected, multiple organ dysfunction was the most common cause of death in the elderly group, as is commensurate with the findings of other studies. This could be attributed to the overall dyshomeostasis among older adults, which may lead to a dysregulated inflammatory and immunologic response to injury and infection (58).

Aging and immunesenescence

Aging has widespread effects on the physiology of the immune system (59). Through multiple morphological, cellular, and biochemical effects, aging eventually attenuates the ability to elicit a robust immune response leading to an overall decline in immune function (60). All these processes are collectively termed immunesenescence (61). Multiple reports highlight that age-related immune system remodeling affects both the innate and peripheral arms of the immune system. Aging is also associated with a marked decline in immune cell ontogenesis. The hematopoietic compartments of the bone marrow are gradually replaced by adipose tissue (62, 63) and this phenomenon has been linked to the age-related decline in growth hormone levels (64). Along with these morphological alterations, disturbances in the cytokine milieu have also been reported (65) and these changes contribute to a decline in hematopoietic stem cell output (66, 67). Furthermore, peripheral lymphoid tissues also undergo age-related architectural alterations. Studies performed on rat models revealed that aging is associated with a decrease in splenic cortex lymphocyte cellularity and the number of germinal centers (68). In a similar way, lymph node morphology has less paracortical and medullary zone formation (69). These changes indicate a decreased ability to provide the proper environment for immune responses to take place (70–72). Another important element of immunosenescence is the existence of a chronic sub-clinical systemic inflammatory state referred to as inflammaging (73–75). Relatively higher levels of inflammatory cytokines and reduced levels of anti-inflammatory cytokines characterize this cytokine imbalance (Fig. 5).

Fig. 5
Fig. 5:
Aging and the immune system.

Immunesenescence and the response to traumatic injury

Multiple reports emphasize the effect of inflammaging on clinical outcomes in older adult trauma patients (61). Even though elderly patients have relatively higher levels of pro-inflammatory cytokines which potentiate the immune response following trauma, the immune response is dysfunctional and has a lower overall efficacy. In this way, immunesenescence could contribute to increased susceptibility to nosocomial infections (76, 77) following trauma and this can lead to increased mortality and prolonged hospitalization. Prior reports have focused on the blunted microbicidal activity of neutrophils which is the first line of defense against infectious agents (78, 79). It was evident that the levels of microbicidal reactive oxygen species (ROS) were significantly lower in neutrophils isolated from older adults sustaining femoral neck fractures in comparison to their younger counterparts within 24 h of injury and 5 weeks postinjury. At the same time, ROS production was significantly lower in neutrophils isolated from older adult hip fracture patients who developed a postoperative infection in contrast to comparable patients with higher ROS levels (78, 79). Our understanding of the age-related immune cell alterations has evolved over the past decades (80, 81). Vanzant et al. (77) conducted a prospective cohort study of adult patients with severe blunt traumatic injury (injury severity score > 15) and subsequent hemorrhagic shock. They reported unique age-related genomic alterations in circulating neutrophils in patients above the age of 55 years relative to those below the age of 55 years. In healthy controls, gene expression changes in neutrophils are expected to return to their baseline state 4 days postinjury. While patients < 55 years demonstrated this expected pattern, neutrophils from patients > 55 years still demonstrated significant gene alterations when compared with healthy controls. The genes involved in these alterations were examined and were found to be related to decreased neutrophil chemotaxis (interleukin-8), up-regulation of myeloid derived suppressor cells (arginase 1), increased inflammation (matrix metalloprotease 8 and 9), and decreased innate and adaptive immunity (77). This unique neutrophil transcriptome response observed in this study is the product of trauma-induced immune activation superimposed on a background of age-related immunesenescence (61). Nacionales et al. (82) studied aged murine models of polytrauma who subsequently developed Pseudomonas pneumonia. They reported a significant impairment in the phagocytic and microbicidal activity of lung-resident neutrophils. These defects were attributed to aberrations at the level of the transcriptome with failure of adequate upregulation of the genes involved in phagocytosis (82). Additionally, it was observed that the number of short-term hematopoietic stem cells in the bone marrow was significantly lower in aged polytrauma mice with impaired proliferation of specific lineages (− sca-1+ c-kit+ cells).

Frailty and the altered inflammatory response

Our understanding of the inflammatory response to injury in these patients was further refined at the molecular level. Joseph et al. conducted a prospective cohort study of older adult trauma patients to analyze the association between the frailty syndrome and immune and endocrine derangements following trauma (83) reporting an altered inflammatory cytokine response (84–89) in older adult frail patients. A total of 100 older adult patients were recruited in the study and were stratified according to their frailty status as measured by the trauma adapted and validated TSFI. Frail patients had higher levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 compared with non-frail patients; however, there was no difference between the two groups regarding the serum levels of IL-2α. Examining endocrine biomarkers, frail patients had lower levels of anabolic hormones, insulin-dependent growth factor 1 (IGF-1), and growth hormone (GH) compared with non-frail patients. The association between frailty and immune and endocrine biomarkers observed was further verified after adjusting for baseline imbalances between the two groups, such as demographics, injury severity, mechanism, and comorbidities. The findings from this study are commensurate with our current understanding of immunoendocrine senescence and dyshomeostasis in frail patients, and they allow us to understand better the pathophysiology of frailty based on its unique molecular signature. The acute inflammatory response after trauma is therefore potentiated by frailty (83). In a meta-analysis of 35 studies, Soysal et al. (90) reported that frailty was consistently associated with higher levels of inflammatory cytokines including IL-6 and TNF-α. Similarly, Leng et al. (91) demonstrated a linear relationship between frailty and IL-6 in community-dwelling older adults. Lamparello et al. (92) analyzed the plasma of critically ill geriatric patients who suffered blunt trauma to study a wider spectrum of inflammatory mediators along with their temporal changes throughout the patients’ in-hospital stay. The researchers reported an exaggerated and sustained increases in alpha chemokines chemokines, including monokine induced gamma interferon and interferon gamma-induced protein. These markers play an important role in the recruitment of pro-inflammatory cells at the site of the injury, usually through a chemokine gradient. The fact that these chemokines were systemically elevated could be due to their overproduction and the failure of proper localization. This study also established an association between the trends in inflammatory markers and outcomes. These markers were associated with a prolonged ICU length of stay and a higher rate of nosocomial infections, especially in the setting of chronic immune dysfunction (93). The mechanisms that determine how an immune response disseminates systemically and becomes dysregulated are not yet fully elucidated (94–96).

One potential explanation behind the potentiated inflammatory response seen in older adult frail trauma patients could be related to an inability to resolve the pro-inflammatory response and this can be a result of derangements in the compensatory anti-inflammatory response system (CARS) (19, 97). The CARS is an intricate antagonistic pathway that downgrades the inflammation-associated destructive mechanisms to allow for tissue healing, repair, and regeneration (98–101). In this way, this pathway prevents immune cell depletion and subsequent immunosuppression. The mechanisms by which frailty contributes to an imbalance between ongoing inflammation and the CARS responses remain open to speculation.

Frail patients tend to have higher degrees of oxidative stress due to altered mitochondrial function (102). This redox imbalance generates higher levels of inflammatory cytokines (96, 103, 104) through the nuclear factor kappa B pathway (105, 106). Elderly patients have a limited ability to handle oxidative stress mainly due to the age-associated decline of the endoplasmic reticulum stress response and decreased mitochondrial metabolism. In the setting of cellular damage, both the innate and the adaptive immune system may not respond proportionally. As a result, the elderly remain in a persistent inflammatory state. For these patients, encountering even mild insults can be devastating In addition, frailty usually co-occurs with sarcopenia, which is another dimension of the frailty phenotype (107). The decrease in lean muscle mass occurs with adipose tissue replacement. Adipose tissues produce a wide variety of different pro-inflammatory cytokines contributing to a chronic inflammatory state (108, 109). We should also take into consideration the inflammatory burden attributed to pre-existing medical conditions that are usually highly prevalent in this age group. Diseases such as hypertension, coronary artery disease, and chronic obstructive disease promote the cycle of low-grade chronic inflammation (110–113). Persistent inflammation is a major element of excessive energy expenditure leading to prolonged catabolism (114–116) and worsening sarcopenia. Despite optimal nutrition, the degree of muscle weakness can have substantial impact on functional independence, enteral feeding, success of ventilator weaning (117), wound healing and regeneration (118, 119). The endocrine derangements described in this article are highly relevant to the setting of trauma. Frailty can blunt the neurohormonal response by disrupting the hypothalamic-pituitary-adrenal axis that is ubiquitously activated following injury (120–122). Multiple studies have described the low levels of IGF-1 and GH in frail patients (91). IGF-1 plays an important role in muscle repair, maintenance, and regeneration (123, 124). In this way, muscle mass recovery in frail patients is expected to be protracted and limited. Additionally, low levels of GH have been associated with impaired functional independence, higher rates of fall recurrence, and adverse discharge disposition. Geriatric trauma patients have a distinct immune response following trauma in comparison to their young counterparts. This is due to widespread alterations on multiple levels including cellular genomics, proliferation, and function. Immune gerontology remains an emerging area of research as more is understood about the impact of frailty and age on the immune response to injury. This information is of paramount importance to identify potential therapeutic strategies to mitigate the observed risks.

As the older adult segment of the population continues to expand, clinicians will encounter a progressively larger number of geriatric trauma patients. Therefore, an understanding of the unique anatomical and physiological aspects of the aging adult is essential for developing targeted interventions and improving overall outcomes. Early identification of the critically injured elderly patient, physiologically based resuscitation, and timely intervention for correctable injuries will optimize utilization of resources, decrease complications, and improve outcomes in this unique and vulnerable population.

CONCLUSION

Older adult patients have an altered post-traumatic physiological response attributed mainly to a decline in organ systems function. Compared with other forms of assessment, frailty is a comprehensive multidimensional phenotype that better captures the augmented vulnerability of the elderly due to impaired adaptive mechanisms that result in increased susceptibility to the stress of injury. Frailty dysregulates the inflammatory response following trauma and is associated with widespread dyshomeostasis effects involving multiple organ systems.

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Keywords:

Aging; frailty; geriatric; inflammation; physiological reserve; senescence; trauma specific frailty index

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