Frailty is a biological syndrome characterized by a decreased physiologic reserve, which impairs the ability of patients to recover from acute stressors such as critical illness.1 Several valid measures of clinical frailty exist and can be classified under 1 of 2 main conceptual models2: the frailty phenotype model,3 which defines frailty as a biological syndrome, or the cumulative deficit model,4,5 which defines frailty by enumerating health-related problems with less attention paid to the specific nature of each problem.
The most widely used measure of the phenotype model is the Fried Frailty Phenotype,3 which quantifies deficits in 5 frailty domains: weakness (measured by hand-grip strength), slowness (measured by gait speed over 15 feet), exhaustion (measured by responses to questions about effort and motivation), shrinking (defined as unintentional weight loss of ≥10 pounds in the prior year), and low activity (ascertained from a validated questionnaire). Each frailty domain is assigned 1 point if present or 0 if absent based on established cutoffs (range, 0–5). Participants have been traditionally classified as robust (0 points), prefrail (1–2 points), or frail (≥3 points). These categories were created on the premise that a distinct frailty phenotype emerges when deficits in multiple frailty domains are present. While most frailty phenotype studies in geriatrics and critical care have categorized patients as not-frail versus frail or robust versus prefrail versus frail,3,6–9 some studies with pulmonary and critical care patients have identified independent associations of the Fried Frailty Phenotype score modeled as a continuous predictor variable with exercise limitation and adverse outcomes.10,11
The most widely used measure of the cumulative deficit model is the Clinical Frailty Scale (CFS),4 a 7-point assessment tool wherein a clinician assigns a score on the basis of a patient’s physical activity, social connectedness, burden of comorbidities, and cognition. Traditionally, those with a score ≥5 are considered frail. Although the phenotype and cumulative deficit models are operationally different, both identify individuals at risk for adverse health outcomes both in geriatrics and critical care.12 Additionally, increasing CFS scores are associated with greater risks of disability, worse quality of life, and mortality in critically ill patients and intensive care unit (ICU) survivors.13–16
Frailty research in critical care can be classified broadly into epidemiologic studies that have identified prehospitalization frailty based on the CFS as a risk factor for adverse outcomes,17 the post-ICU frailty phenotype as a risk factor for disability and mortality after hospital discharge,9,11 or mechanistic studies focusing on biological pathways in critical illness that may also drive frailty (eg, systemic inflammation,18 impaired bioenergetics,19–22 and neuroendocrine dysregulation).23
The vast majority of epidemiologic studies in frailty and critical care consist of ICU cohorts from the United States, Canada, and Europe. Taken together, these studies suggest that approximately one-third of all adults and approximately one-fifth of young and middle-aged adult patients admitted to medical and surgical ICUs are prehospital frail based on the CFS assessment.13,16,17 These studies also show that prehospital frailty is independently associated with in-hospital mortality, long-term mortality, and new nursing home admission after an ICU stay.7,13,14,24,25 Collectively, existing epidemiologic data suggest that frailty before hospitalization is a common, and previously underrecognized, risk factor for adverse outcomes. However, a major limitation of these prehospitalization frailty studies is a lack of investigation into the underlying physiologic mechanisms of frailty. Because most critical illness is unpredictable, it is not feasible to enroll patients and make clinical or biological measurements before their ICU admission.
While prehospital frailty may take years to develop in community-dwelling adults, frailty can develop or worsen within days of an ICU admission, likely because common pathways governing age-related frailty are exacerbated by critical illness. The Figure highlights the interconnected inflammatory, myopathy, and neuroendocrinopathy mechanisms which occur in the ICU and potentially drive the development of frailty during and after ICU admissions. Most critical illness is associated with high levels of systemic inflammation,26,27 and subclinical inflammation is associated with accelerated declines in muscle mass, physical function, and frailty in older adults.28–35 Patients with prolonged ICU admissions also have loss of the pulsatile secretion of anterior pituitary hormones,23,36 which results in extremely low levels of anabolic hormones.37,38 Multiple anabolic hormone deficiencies are also associated with frailty in older adults.39 Mechanically ventilated patients lose nearly 20% of their muscle mass during the first ICU week.40 Even in ICUs with early mobilization physical therapy programs, patients with acute respiratory failure (ARF) are often immobile while mechanically ventilated,41 which potentiates muscle atrophy. In mechanically ventilated ICU patients, skeletal muscle mitochondria are reduced and have impaired oxidative phosphorylation (OXPHOS).19,21,42–44 Skeletal muscle mitochondrial number and function decline with aging,45 and worse mitochondrial function is associated with decreased muscle strength, physical function, and frailty in older adults.46–49
In this narrative review, we will discuss how these 3 shared mechanisms of age-related frailty and critical illness—systemic inflammation, mitochondrial myopathy, and neuroendocrinopathy—might reveal potential novel therapeutic targets to improve recovery in critically ill patients and ICU survivors.
Chronic subclinical inflammation associated with aging—known as “inflammaging”—is believed to cause physical frailty in older adults.50 Inflammatory cytokines implicated in inflammaging such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α are extremely elevated in critical illnesses (eg, sepsis, circulatory shock, or ARF).9,11,51 However, systemic inflammation due to critical illness is likely more complex than subclinical inflammation in older adults because it is polyphasic with levels of multiple inflammatory cytokines and other molecules that change over time. These stages are common to both autoimmune inflammatory processes as well as critical illness.18,52–56 During the initiation phase of critical illness inflammation, inflammatory cytokines IL-8, IL-1β, and IL-6 are secreted. In the propagation phase, human neutrophil elastase (HNE) is secreted and promotes neutrophil degranulation and nonapoptotic cell death. Finally, in the resolution phase of critical illness inflammation, proinflammatory cytokines decrease; neutrophil, macrophage and other cellular infiltration abate; and there is enhanced tissue regeneration and debris clearance.57 Resolution is an active process governed by increased serum levels of transforming growth factor (TGF)-β1, a secretory leukocyte protease inhibitor (SLPI); IL-10, an anti-inflammatory cytokine; and specialized proresolving mediators (SPMs) which are derived from polyunsaturated fatty acids.58–60 SPMs inhibit initiation phase cytokines, leukotrienes, and prostaglandins; enhance anti-inflammatory cytokines such as IL-10; and augment the clearance of microbial debris aiding in tissue regeneration.61 Accordingly, critical illness-related inflammation that potentiates frailty may be due to elevated acute phase inflammatory cytokines that also characterize inflammaging, age-related frailty, and dysregulated resolution of acute inflammation.61
Molecular and Cellular Markers of Inflammation in Critical Illness and Frailty
Emerging evidence suggests that the high level of acute inflammation associated with critical illness does not completely resolve in some ICU survivors and that persistent inflammation may drive frailty-related disability and mortality in these patients. In a 2008 multicenter prospective cohort study of 1800 adult pneumonia survivors, elevated IL-6 and IL-10 at hospital discharge were independently associated with 1-year mortality.62 In a subsequent study, higher levels of C-reactive protein (CRP) and soluble programmed death ligand-1 in adult sepsis survivors during and after hospitalization were associated with higher 1-year readmission and mortality rates.63 In survivors of ARF, dysregulation of propagation and resolution phase cytokines are associated with long-term debility. A secondary analysis of the post-ICU rehabilitation trial (Evaluation of a Rehabilitation Complex Intervention for Patients Following Intensive Care Discharge [RECOVER]) identified an association of increased IL-8, increased HNE, and suppressed TGF-β1 with poor physical recovery at 3 months after hospital discharge.18 Although IL-8 was associated with impaired recovery, IL-6 and IL-1β were not, perhaps indicating that initiation phase cytokines are not as strongly associated with frailty in ICU survivors as cytokines and other molecular mediators of the propagation and resolution phases of inflammation.
Nutritional abnormalities may also predispose to ICU frailty. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), form SPMs—which include resolvins, protectins, and maresins.58,64 In addition, lipoxins, which are derived from arachidonic acid (itself a ω-6 PUFA), play a critical role in triggering the resolution of acute inflammation.65 Therefore, it is plausible that nutritional deficits, either preexisting or developed during a prolonged ICU stay, may lead to lower levels of ω-6 PUFAs that, in turn, could result in decreased SPMs and impaired resolution of inflammation.
To date, studies examining associations of serum inflammatory mononuclear cell levels with frailty have been limited to cross-sectional studies in community-dwelling older adults. Compared to nonfrail community-dwelling older adults, their frail counterparts have elevated levels of monocytes, neutrophils,32,66 and proinflammatory T lymphocytes67,68; higher levels of neopterin69 (a monocyte-regulated immune activation marker); and upregulated monocytic expression of CXCL-10, which may potentiate secretion of IL-6.70 These findings suggest that dysregulated peripheral blood mononuclear cell function likely increases subclinical systemic inflammation in community-dwelling older adults. Investigations are still needed to determine whether such dysregulation of peripheral blood mononuclear cells is associated with frailty and its propagation in critically ill patients and ICU survivors.
In animal studies, inflammatory cytokines have direct adverse effects on end-organ and homeostatic pathways that may contribute to frailty, ranging from immune system suppression to skeletal muscle inflammation. For example, in rats, exogenous TNF-α and IL-1 cause prostaglandin-mediated muscle protein breakdown,71 reduce muscle protein content and synthesis,72,73 and impair amino acid transport.74 TNF-α also antagonizes human muscle cell differentiation in vivo by inhibiting genes for molecules such as myosin heavy chain and α-skeletal actin.75 Though these studies suggest mechanisms by which persistent systemic inflammation might perpetuate muscle atrophy and physical frailty, more translational investigation is needed to confirm that critically ill patients and ICU survivors are also susceptible to such effects.
Critical Illness-Related Inflammation as a Frailty Treatment Target
Although administration of monoclonal antibodies to various inflammatory cytokines and mediators improves clinical outcomes in autoimmune and other inflammatory disease,76–79 multiple trials of these compounds for the treatment of inflammation in acute critical illness have found either no benefit or the potential for harm.80–82 However, frailty-related inflammation in ICU survivors likely differs from inflammation in acute critical illness. Therefore, monoclonal antibodies to select cytokines or other inflammatory mediators that remain elevated at a subclinical level in ICU survivors could theoretically treat frailty-related inflammation. For example, Canakinumab (monoclonal antibody to IL-1β) was recently shown to reduce cardiovascular disease (CVD) events in patients with CVD and subclinical elevated CRP levels.83 However, similar to other monoclonal antibodies to inflammatory cytokines, the risk of infection was increased with Canakinumab treatment. Before testing anti-inflammatory monoclonal antibody drugs to prevent or treat frailty in ICU survivors, studies are needed to identify specific cytokines as biomarkers and therapeutic targets for individuals at highest risk for physical frailty and its progression.84 Furthermore, because ICU survivors are at high risk for recurrent infections, any trial of anti-inflammatory therapy with immunosuppressive side effects in ICU survivors should be carefully designed to ensure patient safety.
In a 2018 study of healthy adults, ω-3 PUFA supplementation, after endotoxin administration to cause acute inflammation, triggered an increase in SPMs including unique resolvins and lipoxins.85 These observations suggest that ω-3 PUFA supplementation should be further studied as a potential therapy for persistent inflammation in frail critically ill patients and ICU survivors. The dose–response relationship between ω-3 PUFAs supplementation and increase in the levels of SPMs needs further study61 as does the practicality and safety of direct SPM administration to augment resolution of inflammation.
Cohort studies of older adults and ICU trials have failed to demonstrate that the anti-inflammatory effects of statin therapy can prevent frailty among older adults or improve outcomes in acute respiratory distress syndrome (ARDS) and sepsis patients, respectively. In a cohort study of community-dwelling older adult women, statin use was not associated with preserved functional status.86 In ICU trials with sepsis and ARDS patients, statin therapy did not provide any mortality benefit.87–90 Furthermore, in the 2016 Statins for Acutely Injured Lungs for Sepsis (SAILS) trial, statin administration did not confer any improvement in physical activity or other functional outcomes in ICU survivors.91,92
The hallmark of physical frailty, whether in older adults, critically ill patients, or ICU survivors, is reduced muscle capacity in terms of strength and endurance. Muscle capacity is strongly related to muscle mitochondrial bioenergetic function. With aging, both the total number of mitochondria within cells and the energy production from oxidative phosphorylation in each mitochondrion decline.48,93,94 In mechanically ventilated ICU patients, skeletal muscle mitochondria are reduced and have impaired oxidative phosphorylation (as measured by electron microscopy, lower mitochondrial DNA copy number, reduced respiratory chain activity, and adenosine triphosphate (ATP) synthase measurements).19,21,42–44 Those who survive to hospital discharge show signs of increased mitochondrial biogenesis compared to those who die in the ICU, with upregulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM).19 However, mitochondrial biogenesis may still be inadequate in survivors with ICU-acquired weakness. A study of 15 ARF survivors of prolonged mechanical ventilation found reduced muscle mitochondrial content 7 days after ICU discharge.43 Elevated growth differentiation factor (GDF)-15—a biomarker of inherited mitochondrial myopathy disease95—is associated with weaker diaphragm, limb, and hand-grip strength in older ICU survivors at hospital discharge and is longitudinally associated with lower rates of functional recovery over 6 months.96 Therefore, it is plausible that a substantial proportion of ARF survivors with muscle weakness-related frailty have reduced muscle mitochondrial content due to impaired biogenesis.
Mitochondrial DNA variation may predispose to mitochondrial dysfunction and impaired skeletal muscle capacity and frailty with aging. In the Cardiovascular Health Study of community-dwelling older adults, genotyping of peripheral blood mononuclear cells revealed a single-nucleotide polymorphism in mitochondrial DNA (C allele at mt204) that was associated with frailty.97 Future studies should investigate whether genetic variation in mitochondrial DNA is a risk factor and prognostic biomarker for mitochondrial dysfunction and adverse outcomes in adults with critical illness and ICU survivors.
Critical Illness Myopathy as a Frailty Treatment Target
In older adults, exercise interventions have been shown to improve muscle mitochondrial function.98–100 In ICU patients, early mobilization in ICU patients improves function at hospital discharge,101 but the 3 largest randomized controlled trials (RCTs) of physical and/or occupational therapy interventions delivered on the hospital ward after the ICU and/or during the first months after hospital discharge did not find benefit.102–104 In addition, more sophisticated interventions, such as muscle electrical stimulation, have been proposed to treat ICU-acquired weakness.105,106 However, the most recent and largest trial of in-bed cycle ergometry and electrical stimulation for ICU-acquired weakness did not increase muscle strength at time of ICU discharge.107 These negative trials suggest that physical therapy alone may have limited efficacy in treating critical illness myopathy due to either mitochondrial dysfunction or other neuromuscular pathology.
A recent GDF-15 biomarker study suggests that muscle mitochondrial dysfunction may affect a larger number of older ICU survivors than previously recognized.96 Therefore, future studies in ICU survivors with muscle weakness should examine muscle mitochondrial quantity and oxidative phosphorylation capacity in ICU survivors after hospital discharge to determine whether impaired mitochondrial biogenesis or other mitochondrial dysfunction persists. Such investigations may reveal targets for specific mitochondrial therapies that may aid in improving physical recovery after critical illness.
Ultrasound and muscle biopsy data show that mechanically ventilated patients lose approximately 20% of their muscle mass during the first week of an ICU stay. Since muscle atrophy is a core feature of physical frailty, future studies should also investigate the role of antiatrophy pharmacologic therapy in preserving and restoring muscle mass in critically ill patients and ICU survivors. These therapies may include myostatin agonists and ubiquitin proteasome system mediators.3,40,108,109
Anabolic hormone deficiencies may potentiate several domains of the frailty phenotype, (eg, loss of muscle strength, weight loss, and fatigue) which in turn, may exacerbate slowness and low activity.39,110 In community-dwelling older adults, the frailty phenotype is associated with low levels of insulin-like growth factor 1 (IGF-1) and dehydroepiandrosterone (DHEA),30,111 and the combination of anabolic hormone deficiencies in free testosterone, DHEA, and IGF-1 predicts the frailty phenotype and mortality better than any single hormone deficiency.39,112 This complexity may be why single anabolic hormone replacement trials of testosterone,113,114 growth hormone (GH),115 and DHEA116,117 in community-dwelling older adults have had disappointing results and suggests a need for a multiple, low-dose anabolic hormone replacement approach to prevent frailty and loss of physical function.110,118
Three case series of adults with prolonged mechanical ventilation have shown depression of the neuroendocrine axes during a prolonged ICU stay.119–121 GH and IGF-1 are suppressed,23 and extremely low testosterone levels may all contribute to a state of cachexia that potentiates muscle loss and weakness and results in physical frailty.37,38 However, patients with prolonged mechanical ventilation represent <10% of the ICU population.122 Emerging research suggests that persistent inflammation immunosuppression and catabolism, known as persistent-inflammation immunosuppression and catabolism (PICS), affects many patients with prolonged critical illness.123 Future studies should investigate whether critical illness similarly induces a persistent neuroendocrinopathy that results in suppression of multiple hormones in ICU survivors who have muscle wasting and weakness but have neither acute nor chronic critical illness with prolonged mechanical ventilation.
GH secretion increases sharply during the acute phase of critical illness and quickly becomes suppressed with prolonged ICU admission. These observations provided rationale for a trial of high-dose exogenous GH therapy in adults with severe acute critical illness that resulted in increased mortality in those treated with GH.124 In retrospect, it seems that some anabolic hormone suppression may be an appropriate stress response to critical illness. Future studies of GH replacement therapy in critical illness should consider using GH secretagogues like GH-releasing peptide 2 (GHRP-2) combined with thyrotropin-releasing hormone (TRH), which may promote lower, more physiologic GH levels.125 In addition, if future studies reveal persistent suppression of GH in clinically stable, but debilitated, ICU survivors, then exogenous GH therapy in the postacute phase of critical illness could be considered. The enteroendocrine hormone ghrelin is proanabolic through its appetite-stimulating effects.126 One single-center prospective study demonstrated that mean active, or acylated, plasma ghrelin levels were lower in critically ill patients than in healthy controls.127 Future research into ghrelin administration in frail older adults and ICU survivors populations should be considered.
In community-dwelling older adults, elevated plasma cortisol is associated with the frailty phenotype, dependence on activities of daily living, and 10-year mortality.128 The relationship between cortisol levels and frailty in critically ill patients and ICU survivors is far more complex.120 Similar to GH, cortisol secretion increases during the acute phase of critical illness and becomes suppressed during prolonged critical illness. The initial spike in cortisol levels may be due to decreased cortisol metabolism and reduced cortisol-binding globulin.129 Although adrenocorticotropic hormone (ACTH) levels should rise appropriately when cortisol levels eventually fall, these regulations fail and diurnal variation in ACTH and cortisol is lost in prolonged critical illness.130,131 Furthermore, even though cortisol levels increase during the acute phase of critical illness, patients may still have relative adrenal insufficiency due to glucocorticoid receptor resistance.132 This relative adrenal insufficiency worsens in prolonged critical illness because cortisol levels decline and adrenal glands atrophy from depressed ACTH secretion.
A trial of exogenous corticosteroid therapy for physical frailty in patients with prolonged critical illness is unlikely to occur because corticosteroid therapy is associated with increased mortality when given late in ARDS and may lead to immunosuppression that potentiates nosocomial infections and sepsis.133 However, ACTH or CRH supplementation has been proposed as treatments for patients with prolonged critical illness who may be catabolic and frail because these exogenous hormones have a more favorable safety profile.125 Vitamin D may be an adjunctive therapy that can improve adrenal function in prolonged critical illness because vitamin D is integral to the regulation of cortisol and other hormones.134,135 Vitamin D deficiency is associated with frailty in community-dwelling older adult men,136 and a recent meta-analysis suggests that there is an additive effect of resistance exercise and vitamin D3 supplementation in older adults.137 Severe vitamin D deficiency is observed in many critically ill patients.138 While a 2019 trial of early high-dose vitamin D3 for critically ill vitamin D-deficient patients was negative,139 future studies might consider testing whether vitamin D supplementation for frail ICU survivors with vitamin D deficiency can improve muscle strength.
Circulating estrogen and testosterone decline with age and are associated with muscle wasting in older women and men. Data from prospective and observational trials140–142 suggest that supplementation with testosterone may be protective against frailty, depression, and sexual dysfunction in community-dwelling older adults. During an ICU admission, testosterone declines independent of luteinizing hormone (LH) levels and remains low because LH pulsatility is lost with prolonged critical illness.143 Little is known about changes in estrogen and progesterone in critically ill women, and there are no established cutoffs for testosterone or estrogen deficiency in critical illness or ICU survivors. Future studies should investigate associations between low hormone levels and impaired physical function during the early postacute phase of critical illness to determine whether testosterone supplementation therapy is potentially beneficial for frail ICU survivors. In addition, any trial of testosterone therapy for frailty would need to monitor closely for potential adverse effects, especially cardiovascular events, which are common in sepsis survivors.144–146 In 2 randomized controlled trials, the synthetic anabolic steroid oxandrolone improved hospital length of stay in pediatric burn patients. Oxandrolone is believed to be anabolic in burn patients who suffer from severe catabolism, and exogenous replacement therapy is believed to restore lean mass and wound healing.147,148 Accordingly, future studies should determine whether exogenous oxandrolone therapy in deficient, frail adult ICU survivors is a potential therapeutic target to improve physical recovery.
Approximately one-third of adult ICU patients are already frail at ICU admission and have a significantly increased risk of both short- and long-term disability and mortality. Regardless of whether frailty exists prehospitalization or is ICU acquired, ICU survivors with the frailty phenotype have a high level of disability and an increased risk of death in the year following critical illness. In younger, previously healthy ICU survivors, mechanisms linked to frailty such as systemic inflammation, mitochondrial myopathy, and neuroendocrinopathy are likely all acquired from critical illness. In older adults with comorbidities and frailty before an ICU hospitalization, subclinical inflammation, mitochondrial myopathy, and anabolic hormone suppression following critical illness more likely reflect a combination of what existed before hospitalization and that which is ICU acquired.
Because the level of inflammation and degree of mitochondrial dysfunction in critical illness is exponentially greater than that observed in community-dwelling older adults, most of these frailty deficits in older ICU survivors can likely be attributed to critical illness, especially during the early postacute period. Irrespective of what component of subclinical inflammation, mitochondrial myopathy, or anabolic hormone suppression may be preexisting versus ICU acquired, if ICU survivors are significantly more debilitated and frail at hospital discharge than they were before their hospitalization, then they are at high risk for persistent disability and death. Accordingly, we should study whether treatment of these frailty mechanisms can improve recovery and survival after critical illness. As we strive to identify and test medications and other compounds to treat frailty, we should proceed with caution. Any benefits of frailty treatment in older adults could be potentially offset by deleterious effects of increased polypharmacy. Frailty treatments should also target only those inflammatory, myopathic, and endocrinologic derangements that are harmful and not those which are protective homeostatic responses.
Name: Jonathan A. Paul, DO.
Contribution: This author helped review the literature and co-author the manuscript.
Name: Robert A. Whittington, MD.
Contribution: This author helped review the literature and co-author the manuscript.
Name: Matthew R. Baldwin, MD, MS.
Contribution: This author helped review the literature and co-author the manuscript.
This manuscript was handled by: Avery Tung, MD, FCCM.
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