Delirium and frailty are both important geriatric syndromes that commonly occur among older adults. Delirium is an acute medical condition characterized by changes in mental and cognitive status and usually occurs among hospitalized older adults,¹⁾ with a prevalence ranging from 15% to 75%, depending on the clinical setting.²⁾ Frailty is a chronic condition characterized by decreased functional status and increased vulnerability to various stressors, with a prevalence ranging from 12% to 24%.^3-5) Although they are different conditions, delirium and frailty also share commonalities and have overlapping features. This study reviewed the definitions and pathophysiologies of these two geriatric conditions, described their similarities and differences, and provided current evidence of delirium management among older adults with frailty.

As both delirium and frailty result from the disintegration of balance and homeostasis across multiple body systems, they are intuitively related and share several commonalities. They occur commonly among older adults, are multifactorial in their etiology, and are associated with poor clinical outcomes, including increased risk of functional loss, institutionalization, and mortality.³²⁾ The exact pathophysiologies of these conditions have not yet been identified, although they share common biologic processes, including inflammation, alterations in vascular systems, genetics, and nutritional deficiency in their development (Fig. 1).³³⁾ As individuals age, their levels of circulating inflammatory cytokines increase, a condition that may be heightened in frailty. With higher baseline cytokine levels, the pro-inflammatory response to stressors becomes more prominent, making individuals more susceptible to stressors and explaining the development of both delirium and frailty.^34,35) Additionally, alterations in the vascular system, particularly small vessel disease, have been associated with geriatric syndromes. As common geriatric syndromes, delirium and frailty are also likely to be associated with small vessel diseases.³⁶⁾ Moreover, frailty is a subclinical marker of cardiovascular disease, and delirium occurs twice as often among individuals undergoing cardiovascular surgery compared with that among patients undergoing orthopedic or abdominal surgeries.^37-39) Malnutrition, reduction in caloric intake, and subsequent weight loss are prevalent in older adults and may lead to sarcopenia and thus frailty.⁴⁰⁾ According to the phenotype frailty model, weight loss is a prominent characteristic of frailty.²⁶⁾ Furthermore, malnutrition is considered an important predisposing risk factor for delirium.⁴¹⁾

Although frailty and delirium share common features, as described above, there are also differences between the two conditions (Fig. 1). Frailty results from a long-term decline in functions across an individual’s multiple systems, and its process is considered chronic and progressive. In contrast, delirium is an acute process or reaction to a newly introduced stressor. Delirium may progress and resolve rapidly compared to frailty, although full recovery could take weeks or even months.²³⁾ Delirium is mainly characterized by alterations in mental and cognitive functions, while frailty is more often characterized by changes in physical function and the accumulation of physical deficits. When multiple insults affect an already susceptible individual, the brain may not compensate, leading to delirium.

Therefore, despite their differences, from a practical perspective, frailty and delirium show important overlapping pictures: individuals already vulnerable to various stressors, e.g., older adults with pre-existing frailty, are at a greater risk for delirium. Several studies on the association between delirium and frailty in older adults showed that frailty was associated with an increased risk of delirium compared to those who do not have frailty. In 2018, a systematic review and meta-analysis of 999 patients by Presico et al.⁴²⁾ showed a 2.19-fold increased risk of delirium among frail patients (risk ratio [RR]=2.19; 95% CI, 1.65–2.91). Although limited to surgical patients, a meta-analysis of the cohort study by Fu et al.⁴³⁾ reported that frailty patients had an increased risk for delirium, with an odds ratio (OR) of 3.23 (95% CI, 2.56–4.07). More recently, in 2021, Zhang et al.⁴⁴⁾ reported a meta-analysis study including 217,623 patients and showed that frailty was associated with an increased risk for delirium compared to the risk in patients without frailty (OR=2.96; 95% CI. 2.36–3.71). They also conducted further analyses to assess the association in different patient groups. Frailty was associated with a 2.43-fold increased risk of delirium (95% CI, 1.88–3.14) in selective surgical patients, a 3.61-fold increased risk (95% CI, 1.65–7.89) in medical patients, a 3.76-fold increased risk (95% CI, 2.88–4.92) in surgical patients, and a 6.66-fold increased risk (95% CI, 1.41–31.47) in emergency or critical patients (Table 1).⁴⁴⁾

However, the studies also found significant heterogeneity in the instruments used to identify delirium and frailty. These instruments include at least 10 different frailty index or scales (including but not limited to the frailty phenotype, FRAIL Scale, Frailty Index, Clinical Frailty Scale, Edmonton Frail Scale, Erasmus frailty score, Emergency General Surgery Frailty Index, Japanese version of the Cardiovascular Health Study criteria, Groningen Frailty Indicator, mobility impairment, Clinical judgment frailty, Kihon Checklist score, and Comprehensive Geriatric Assessment) and more than five measurement tools for identifying delirium (the Confusion Assessment Method for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; the intensive care delirium screening checklist; the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; the Confusion Assessment Method for the intensive care unit, the Delirium Rating Scale Revised-98; and the interRAI-Acute Care for Comprehensive Geriatric Assessment).^42,44) Although more studies have examined the interplay between frailty and delirium, historically, studies on this topic have not been sufficient. In their 2017 systematic review, Presico et al.⁴²⁾ identified only 20 studies eligible for systematic review and eight studies for the meta-analysis. Fortunately, more studies have been published since that time; in 2020, Zhang et al.⁴⁴⁾ identified 30 studies for their meta-analysis. It is promising that the association between frailty and delirium is receiving more attention because the number of patients who may experience these two geriatric conditions is likely to increase along with the rapidly growing number of older adults worldwide.

Although it is reassuring that more studies on these two important geriatric syndromes are being conducted, exactly how their interplay results in adverse clinical outcomes and to what extent it affects outcomes remain unknown. As both frailty and delirium are independently associated with adverse clinical outcomes, patients with frailty who develop delirium during hospitalization may experience worse clinical outcomes. However, the existing literature is scarce and is mainly limited to outcomes of mortality or surgical patients as the populations. Furthermore, given the overlapping characteristics between frailty and delirium, frailty may act as a confounder in the association between delirium and clinical outcomes. The inconsistent results from various studies support this hypothesis. Eeles et al.⁴⁵⁾ assessed the impact of frailty on mortality among older inpatients who had delirium in a single-center study and reported that frail patients had greater long-term mortality among those with delirium compared with that among those without frailty—median survival of 88 days (95% CI, 5–171) for frail patients vs. 359 days (95% CI, 118–600) for fit patients. However, Mazzola et al.⁴⁶⁾ reported that delirium alone was not associated with mortality after adjusting for frailty, supporting the role of frailty as a confounder, increasing the vulnerability to stressors that lead to death. Dani et al.⁴⁷⁾ conducted a survival analysis to identify the impact of delirium on frailty in hospitalized older adults; interestingly, they reported an inverse gradient of association, with a stronger association observed in the fitter group and a higher hazard ratio for delirium in patients with a lower frailty index.

In addition to mortality as a clinical outcome, Ogawa et al.⁴⁸⁾ assessed the impact of postoperative frailty on major adverse cardiac events after cardiac surgery in a single-center study. They reported that delirium increased the risk of postoperative frailty (HR=2.98; 95% CI, 1.46–6.20). Moreover, postoperative frailty increased the risk of a major cardiac adverse event after cardiac surgery (HR=2.21; 95% CI, 1.01–4.82). However, after adjusting for delirium, preoperative frailty was not significantly associated with major adverse cardiac events after discharge.

Given the high prevalence and complex interactions between the two conditions, managing older adults with both frailty and delirium also becomes challenging. One of the most important challenges in clinical practice is that these two conditions are usually under-recognized, despite their strong associations with adverse clinical outcomes. Hospitalized older adults may experience different types of delirium, including hyperactive, hypoactive, mixed, and without motor symptoms.⁴⁹⁾ However, while hyperactive delirium, mixed-type delirium, or delirium without motor symptoms is easily recognized because of their distinguishing behaviors, hypoactive delirium is less likely to be discovered or reported.⁴⁹⁾ However, hypoactive delirium may occur more commonly than hyperactive delirium.^49-51) Moreover, several studies reported a worse prognosis among patients with hypoactive delirium compared with that among patients with hyperactive delirium.^52,53) The under-recognition of delirium may increase its adverse impact on various clinical outcomes. Frailty is also easily missed in clinical practice because there is no standardized systematic screening tool, and some measures are not practical to perform in routine clinical settings.⁵⁴⁾ For example, Beckert et al.⁵⁵⁾ reported frailty in a high proportion of patients (68.8%) deemed to be surgical candidates and referred for surgeries. They speculated that physicians did not recognize a patient’s frailty at the time of referral for surgery. As frailty is a risk factor for delirium, under-recognized frailty among hospitalized older adults can result in a higher incidence of delirium and associated adverse clinical outcomes. Similarly, since delirium may increase the risk of postoperative frailty, the early recognition, prevention, and proper management of delirium is also important for providing optimal care for older adults in hospitals.

Another challenge is that as much as they are ignored in routine clinical settings, studies assessing the prevalence of the coexistence of the two conditions or their combined impact on patient outcomes are also scarce. Most studies have focused on the association between these two conditions. Individual estimates for each study with relevant information in the most recent systematic review study by Zhang et al.⁴⁴⁾ showed a prevalence of the coexistence of the two conditions ranging from 2% to 26%. Studies with a high prevalence (>20%) had cohorts with an older age group (mean age, 82.3 or 82.1 years) or included only critically ill patients. Studies with older age groups included patients in either acute general medicine wards⁴⁵⁾ or an acute geriatric unit.³²⁾ However, some studies also showed relatively high prevalence, approximately 15%, in a relatively younger population (mean age, 71 years) and in patients undergoing selective surgery.⁵⁶⁾ Nevertheless, accurate determination of the association between the prevalence and age or type of admission will require more investigations and systematic reviews. Moreover, very few studies have assessed the impact of the coexistence of the two conditions on patient outcomes. Eeles et al.⁴⁵⁾ reported that the combination of delirium and frailty was associated with poor survival among patients admitted to general medicine wards. A single-center study by Gandossi et al.⁵⁷⁾ revealed that the combination of frailty and postoperative delirium was associated with poor functional status upon discharge among hospitalized patients with hip fracture (RR=1.47; 95% CI, 1.28–1.69). Kwak et al.⁵⁸⁾ estimated the economic outcomes of various combinations of three geriatric syndromes—delirium, frailty, and dementia—among patients who underwent transcatheter aortic valve replacement procedure and reported that delirium with frailty but without dementia showed the strongest association with higher hospital cost (a 45.1% increase in hospital cost; 95% CI, 26.45–66.45).

Delirium and frailty are highly prevalent geriatric syndromes among older adults and are associated with adverse clinical outcomes. While the exact pathophysiology of these two conditions remains unclear, the etiology is multifactorial. Although they are distinct conditions, delirium and frailty share similarities and are significantly associated. Hospitalized older adults with frailty are more likely to develop delirium. Thus, the identification of high-risk patients with frailty is critical for the proper management of delirium. Given the multifactorial etiology of delirium and frailty, the prevention and management of delirium must incorporate a multicomponent patient-centered approach to improve the quality of care among hospitalized older adults.