The Effect of Aging Physiology on Critical Care

Introduction

The number of older adults, defined as individuals ≥65 years old, are rapidly increasing in the United States and are projected to reach 84 million by the year 2050 ¹. Although there is a difference between chronological and physiological aging ², older adult populations tend to have a weaker physiological phenotype compared to a younger population ³. In addition, older adults account for nearly 50% of intensive care unit (ICU) admissions and 60% of all ICU days. ^4,5

One of the main biological processes of systemic deterioration that contributes to development of organ dysfunctions in aging are immunosenescence (age associated gradual deterioration of protective immunity) and inflammaging (chronic subclinical systemic inflammation). Both of these detrimental processes lower the efficacy of the immune system, leading to higher vulnerability to infections and susceptibility to inflammatory conditions ^6,7, and thus higher susceptibilities for critical illness and dismal outcomes. ⁸ Other cellular processes like elevated oxidative stress and apoptosis, as well as declines in autophagy are hallmarks of the aging deterioration process that contribute to susceptibility to infections and worse outcomes in critical illness. ^9–12

Reactive oxygen species are produced in the normal aging process at the cellular level in all systems as mediators of cell differentiation and growth, and are scavenged by anti-oxidant enzymes in order to maintain homeostasis. ^13,14 The aging process is associated with a less efficient free radical scavenging process and over-production of free radicals elevating oxidative stress, cell damage and death – necrosis. ^15,16 Aging is also associated with a higher level of apoptosis, programmed death and decline in autophagy, a cellular process where dysfunctional and cytotoxic parts of the cell are digested and removed by lysosomes. ^17,18 These detrimental processes contribute to the development of comorbidities in older adults such as cardiovascular disease, neurodegenerative diseases, physical disability and cancers.

The main purpose of this review is to briefly summarize the age-specific changes in the main physiologic systems (Figure 1) that occur in critically ill older adults that can have implications in clinical management. Special considerations for clinical management of older patients in the ICU need to be considered ^3,5 due to different physiological and biological profile especially when considering the management of sepsis and trauma, that may result in a relatively new phenotype, prevalent in older critical illness survivors, classified as chronic critical illness (CCI). ¹⁹

Figure 1.

Summary of the effect of aging on various physiologic systems.

Brain

Aging is associated with neurodegeneration, neuroinflammation and decreased perfusion of the cerebrovascular circulation that contributes to cognitive decline, dementia and Alzheimer’s Disease.²⁰ Inter-personal degrees of alterations in the brain are highly variable, but the largest changes are observed in the frontal and temporal cortex. The frontal cortex is responsible for attention and memory, and also speech production.²¹ The temporal cortex is involved in auditory and visual recognition such as language recognition.²² Older adults with pre-existing cognitive impairment are more susceptible to an amplified burden of critical illness leading to delirium in the ICU.²³ Delirium is an acute state of confusion that affects majority of older patients and develops within hours or days after the ICU admission and leads to alterations in consciousness and cognition.²⁴ A medical team should distinguish between delirium and dementia or other psychiatric disorders, and implement reduction of factors that triggered delirium and apply medication treatment for those at risk of harming themselves.²⁵

Cardiovascular

Advanced age is associated with a change in cardiac structure such as a loss in the number of myocytes, increased arterial wall thickness, increase in collagen deposition and reduced vascular compliance.^26,27 These changes contribute to the higher prevalence of cardiovascular disease (CVD) in older adults such as hypertension, atrial fibrillation, heart failure, myocardial infarction, stroke and peripheral arterial disease. ^28,29 However, the addition of the stress of critical illness accentuates the cardiac dysfunction in the elderly requiring special consideration in hemodynamic support in the ICU.³⁰

Coronary artery flow is also diminished in the elderly population, which is secondary to increased prevalence of coronary artery disease, increased arterial wall thickness, and increased pulse pressure. ^31,32 During critical illness, these changes lead to increased risk for cardiac ischemia in the elderly. ³³ Finally, increased age is also an independent risk factor for the development of arrhythmias as a result of the conduction system dysfunction caused by an increase in collagen, inflammation and fat deposition as well as decreased myocyte number. ^34–37 New onset atrial fibrillation secondary to acute critical illness is more common in the elderly and is associated with increased mortality in the ICU. ³⁸

During aging, cellular loss and increases in myocardial collagen deposits lead to a decreased response to β-adrenergic stimulation. ^39,40 This translates to a decreased heart rate response to stressors. ⁴¹ Therefore, the aging heart relies on increasing preload and stroke volume for increase in cardiac output, which makes this population sensitive to hypovolemic states. ^26,42 In addition, these changes lead to a diastolic dysfunction, secondary to impaired early left ventricular filling and decreased ventricular compliance.⁴³ Therefore, the critical care practitioner must pay special attention to volume resuscitation in the older adult population. ²⁶ A small amount of hypovolemia can compromise cardiac function, while a small amount of hypervolemia can precipitate pulmonary edema. ²⁶ Bedside transthoracic echocardiography (TTE) has become a very important non-invasive tool and is now routinely used for assessing the cardiac function and hemodynamic evaluation that is utilized in clinical management decisions in older ICU patients.^44,45

Pulmonary

Age-related changes in chest wall rigidity and lung parenchyma contribute to decreased respiratory reserve in older adults as well as many ICU related respiratory complications in elderly patients. Chest wall compliance can decrease up to 30% by the age of 75 year old and respiratory muscle strength can decline near 50% in older patients, both ultimately resulting in decreased chest wall expansion. ^4,46 The diaphragm also flattens and becomes less efficient. ^47–49 Full airway expansion cannot occur unless the geriatric patient is in the standing position, which is difficult to achieve in the ICU setting, resulting in a propensity for atelectasis. ^48,50 Geriatric patients who are dependent on mechanical ventilation have to work harder because of the diaphragm muscle weakness and decreased chest wall compliance, which can result in difficulties weaning from a ventilator. ⁵¹

Aging is also associated with a decreased host response to hypoxemia and hypercapnia. ⁵² Therefore, with decreased respiratory reserve, older patients are likely to appear normal during respiratory decline and can decompensate very quickly. ⁴ Decreased alveolar fluid anti-inflammatory proteins and decreased ability for airway clearance resulting in a higher risk of developing pneumonia. ^53–55 Pneumonia is associated with more complications, frequently requires ICU admission, mechanical ventilation and can lead to death in older adults. ^56–58 Although the treatment is the same regardless of age, consideration of the above physiology can aid the intensivist in adjuvant treatment and even prevention of pneumonia in their older patients.

Renal

Normal aging is associated with nearly a 45% decrease in glomerular filtration rate secondary to a 50% decrease in renal blood flow and loss of functional parenchyma ^59,60. Also, with aging there is an impaired ability to regulate sodium and hydrogen ions, and thus, a decreased ability to manage acid-base status. ⁶¹ There is also impaired ability to maximally dilute or concentrate urine that is exacerbated under stress conditions. ⁶² This renal dysfunction is partially responsible for the inability of older adults to respond to hypovolemia. ⁶¹ Additionally, older adult’ kidneys have a decreased filtering ability, and this requires careful consideration for drug levels that are renally excreted and those that can cause nephrotoxicity such as vancomycin, amphotericin B, nonsteroidal anti-inflammatory drugs, or aminoglycosides. ^63,64

Age greater than 65 years is an independent risk factor for acute kidney injury (AKI). The cause of this in critically ill aged patients is usually multifactorial with ischemia, hypovolemia, drug or contrast induced nephrotoxicity, and/or acute urinary obstruction often co-existing. ^64–66 Pre-existing cardiovascular and chronic kidney disease, as well as iatrogenic injury from contrast exposure and various drugs, are among the common causes of AKI in critically ill patients. ⁶⁷ Also, renal recovery rates are significantly lower in older patients. ⁶⁶ A recent study suggests that early initiation of renal replacement therapy was associated with increased renal recovery, attenuated kidney-specific and non-kidney organ injury, and decreased risk of all-cause mortality. ⁶⁸ However, prevention of AKI remains the most important factor in management. ⁶⁵ Intensivists should maintain appropriate blood pressure and volume status and limit drug and imaging contrast toxicity to reduce increased morbidity and mortality associated with AKI in older patients. ⁶⁹ Additionally, intensivists should keep in mind that since older patients have lower muscle mass ^70,71 and creatinine is formed almost exclusively in the muscles⁷², creatinine is a less reliable biomarker of baseline renal function and the development of AKI in this population. ⁷³

Gut/Intestine

The intestinal microbiome consists of trillions of organisms and its metabolites, and plays an important role in maintaining the immune system homoeostasis. ⁷⁴ Importantly, microbiome alterations occur with normal aging as well as contributing to maintaining chronic low-grade inflammation (inflammaging) and immunosenescence. Thus, the microbiome is thought to be involved in the risk for and the development of chronic diseases, as well those conditions associated with these chronic diseases and aging (e.g. sepsis). ^75,76

Sepsis is thought to lead to a complete ‘collapse’ of the intestinal microbiome, with an accompanying emergence of a ‘pathobiome’, both of which contribute significantly to the pathology of sepsis. ⁷⁷ In particular, during aging and in response to critical illness, the gut microbiome loses its microbial diversity. This includes the disappearance of microbes that represent an important part of the microbiota of healthy individuals with anti-inflammatory properties, as well as those producing short-chain fatty acids (SCFAs) from digested fibers, essential metabolites for cellular energy production. ^74,78

The aging-related gut microbiome dysbiosis and pathobiome in critical illness have been linked to peripheral organ dysfunctions such as brain, liver, kidney, cardiovascular system, pancreas and skeletal muscle.⁷⁶ Therefore improving the gut microbiome may be a target to prevent aging-related comorbidities and lowering the susceptibility of these individuals to infections and improving their outcomes to critical illness. ⁷⁶ For example, gut microbiota can be modulated by supplementing specific beneficial microbial communities deficient in disease states with prebiotics and probiotics as well as fecal microbiota transplantation (FMT).^79,80 FMT is thought to supply under-represented microorganisms with probiotics or increasing the diversity of the microbiome and decreasing the pathobiome. Recolonizing particular microbes and the whole microbiota of the older adult host holds promise as approaches to prevent and treat age-related pathological conditions. ⁷⁸

Skeletal Muscle

Gradual loss of muscle mass, strength and function with aging is natural, but the clinically significant loss of muscle mass and function could be considered as a disease. ⁸¹ Sarcopenia is described as a progressive skeletal muscle disorder characterized by decrease in muscle size, fiber composition, number of motor units, and increase of intramuscular fat fibrotic tissue and is associated with increased likelihood of adverse outcomes including falls, fractures, physical disability and mortality ⁸². Age-related contributing factors to the development of sarcopenia are denervated motor units resulting from disuse atrophy, malnutrition, hormonal changes, and increased of inflammation and oxidative stress. ⁸²

Acute and chronic immune host dysregulation and systemic inflammation contribute to rapid loss of skeletal muscle and lead to the intensive care unit- acquired weakness (ICU-AW). The main risk factors contributing to the development of ICU-AW include the severity of critical illness, immobilization, hyperglycemia, and the use of some medications, including steroids and neuromuscular agents. ⁸³ The pathophysiology of sepsis-induced myopathy involves: mitochondrial dysfunction leading to a bioenergetic failure, oxidative stress and inflammatory cell infiltration protein catabolism, mainly related to an activation of the ubiquitin-proteasome pathway, muscle fibrosis and satellite cell loss and dysfunction. ^84–86 Satellite cells are progenitor cells that differentiate to myoblasts and fuse to myofibers as part of muscle regeneration. ⁸⁷ Loss and dysfunction of satellite cells in response to critical illness impairs the regenerative capacity of muscle and ameliorates weaning from the intensive care unit (ICU). ^87,88

Given the acute and chronic muscle wasting and impaired regeneration, clinical management should include early post-discharge rehabilitation and nutritional strategies to stimulate anabolic processes and muscle regeneration. Consideration should be given to a high protein diet paired with resistance exercise training, as this therapy combination has been shown to reverse sarcopenia. ^89,90

Implications for Clinical Management of Older Trauma Patients

Geriatric trauma accounts for a third of all trauma health care costs in the United States ⁹¹. Elderly trauma patients present with worse injuries, have longer hospital stays, and have three times higher mortality rate than young trauma patients. ⁹² One study demonstrated that geriatric trauma patients that present with severe injuries (ISS>15) and low systolic blood pressure had an odds of 2.16 for mortality compared to young patients with the same injury severity. ⁹³ In a different multi-center cohort study, advanced age was found to be strongly associated with poor outcomes such as severe organ failure, secondary infectious complications, intensive care utilization, ventilator days, and poor discharge disposition or loss of independent living status (long-term acute care facility, skilled nursing facility, hospice etc.). ⁹⁴ Additionally, elderly trauma patients older than 74 have a 1.67 odds of mortality compared to trauma patients 65–74 years old. ⁹³

Falls are the most common mechanism of injury in geriatric trauma patients. ⁹⁵ In fact, same level falls are responsible for more severe injury (30-fold) and for an increased cause of death (10-fold) in older adult patients compared to younger cohorts. ^96,97 Motor vehicle accidents are the second most common mechanism of injury and the leading cause for mortality in geriatric trauma patients. ^98,99

The association of advancing age with increasing frailty has been described as a main contributor to increased risk of short and long term poor outcomes after trauma. ^100–102 Frailty syndrome is defined as a “decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems, and causing vulnerability to adverse outcomes” and can be found in over a third of geriatric trauma patients. ^{100,102–104} Diminished reserves and decreased ability to compensate, as described above, leads to significant morbidity and mortality even with minor injuries after trauma. ^97,105–107 Diminished respiratory reserve and diminished response to hypoxia and hypercapnia pose a challenge for management of the geriatric patient after chest trauma. ¹⁰⁸ Additionally, traditional physiological parameters of Systolic Blood Pressure (SBP) 90 or Heart Rate (HR) > 120 do not accurately reflect clinical decline for elderly trauma patients. ^109,110 Therefore, CDC guidelines recommend transport to trauma center for patients ≥ 65 with SBP 110. ¹¹¹

Implications for Clinical Management of Older Sepsis Patients

Sepsis is the leading cause of death in US hospitals with studies estimating over 5 million deaths per year worldwide. ^112,113 There has been an improvement in mortality over the last three decades. ^114–117 The reduction in short term mortality can be largely credited to the improvements in sepsis screening, evidence-based resuscitation strategies, and standardized critical care, starting with the “Surviving Sepsis Campaign” in 2004. ¹¹⁸ These improvements include increased compliance with evidence-based strategies including early fluid administration, broad-spectrum antibiotic therapy, and vasopressor support to restore end-organ perfusion. ^119–122 However, older adults continue to have increased susceptibility and mortality to sepsis. ¹²³ One single center study revealed that critically ill patients ≥55 years with sepsis have greater organ dysfunction, 8-fold higher hospital mortality and even higher six month mortality secondary to persistent immunosuppression and catabolism. ¹²⁴

This predisposition to sepsis in older patients can be partially explained by the aged immune systems inability to mount an effective immune response to pathogens. This is in part due to inflammaging and immunosenescence. ^82,125–127 Studies in aged humans and mice reveal that the immune dysfunction associated with aging extends to both innate and adaptive immunity. ^128–130 The aging bone marrow has been noted to produce fewer well-functioning innate cells (e.g. granulocytes, macrophages and dendritic cells) and more immature, less effective myeloid-derived suppressor cells (MDSCs). ¹³¹ MDSCs are immature myeloid cells that have the ability to suppress acute inflammatory responses, including lymphocyte proliferation, and resolve inflammation. ^132–134 Sepsis induces emergency myelopoiesis that amplifies expansion of MDSCs. ^{133,135–137} While younger patients are more capable of returning to a balanced state of innate and adaptive immunity after infection, older patients have difficulty returning to homeostasis. ^{124,128,138,139} Our ongoing animal and human studies at the University of Florida Sepsis and Critical Illness Research Center suggest that the long-term, persistent MDSC expansion and infiltration resulting from geriatric post-sepsis dys-homeostasis plays a major role in the simultaneous low-grade inflammation (promoting catabolism and anabolic resistance) and immunosuppression (increasing the risk of secondary infections), which is a major contributor to increased morbidity and mortality. ^{3,124,128,140,141}

Chronic Critical Illness as a Result of Improved ICU Care Management

Improvements in critical care for all ages has led to a decline in inpatient mortality. ^142,143 Improvements in 30-day mortality after critical illness for trauma and sepsis have led to a larger focus on long-term outcomes, including post-discharge mortality. ¹⁹ Among those that survive severe injury or sepsis, there are two clinical trajectories – chronic critical illness (CCI) and rapid recovery (RAP). ^144,145 CCI is defined as prolonged intensive care utilization and/or transfer to inpatient facility post-discharge (≥14 days) and persistent organ dysfunction. ¹⁴⁶ CCI seems to be driven by a persistence in immune dysfunction. ^146–148 Many studies have shown a prolonged elevation of circulating inflammatory cytokines and persistent lymphopenia post-sepsis. ^{133,140,148–150} However, older patients are noted have a longer persistence of this pattern of immune dysfunction with higher levels of soluble programmed death ligand (PDL)-1 and decreased absolute lymphocyte counts out to 28 days, while young patients returned to normal levels by day 14. ¹²⁴

It is estimated that CCI accounts for over $25 billion in health care expenses. ¹⁵¹ Patients over the age of 55 are more likely to have an inpatient disposition (long-term acute care, skilled nursing facilities, inpatient facility, hospice), which is associated with higher one year mortality rates. ^100,124,152 Importantly, CCI disproportionately affects elderly patients. ^151,153,154 In fact, age ≥55-years has been found to be predictive of CCI after severe trauma. ¹⁵⁵

Summary

Although older age is a risk factor for susceptibility to developing critical illness and poor outcomes in the ICU, it is important to recognize that patient’s outcome is still determined primarily by the severity of their critical illness. We have highlighted age-specific changes in physiological systems majorly affected by critical illness (Figure 1), especially as it pertains to sepsis and trauma, which can lead to chronic critical illness. Clinical management decisions should take into account that older adults have lower physiological reserves and impaired immunity and are at high risk of non-recovery from critical illness. Besides customized, life-saving acute clinical management, there is a need for in-hospital and ambulatory interventions to improve the function of the majorly affected systems due to critical illness in older adults, and thus improve in-hospital outcomes, and importantly prevent chronic critical illness.

Synopsis.

Older patients experience a decline in their physiologic reserves as well as chronic low-grade inflammation named ‘inflammaging’. Both of these contribute significantly to aging-related factors that alter the acute, sub-acute and chronic response of these patients to critical illness, such as sepsis. Unfortunately, this altered response to stressors can lead to chronic critical illness followed by dismal outcomes and death. Since the geriatric population is more susceptible to critical illness, it is important to define their unique response to critical illness as well as customize their clinical management. The primary goal of this review is to briefly highlight age-specific changes in physiological systems majorly affected in critical illness, especially as it pertains to sepsis and trauma which can lead to chronic critical illness, and describe implications in clinical management.

Key Points:

• Older adults demonstrate lower physiological reserves of major organs such as brain, cardio-pulmonary, renal, musculoskeletal and intestinal systems and impaired immunity.

• Due to lower physiological reserves, older adults are more susceptible to critical illness and are at high risk of poor short-term and long-term outcomes with failure to recover.

• Intensivists should take into account compromised physiology in the critical care management.

• In-hospital and ambulatory interventions are needed to improve the function of the majorly affected organs due critical illness in older adults to improve in-hospital outcomes, and importantly prevent chronic critical illness.