John F. Schnelle, PhD

METHODS

RESULTS

DISCUSSION

CONCLUSIONS

METHODS

RESULTS

DISCUSSION

CONCLUSIONS

METHODS

RESULTS

DISCUSSION

CONCLUSIONS

Geriatric syndromes are common clinical conditions in older adults that do not fall into specific disease categories. Unlike the traditional definition of a syndrome, geriatric syndrome refers to a condition that is mediated by multiple shared underlying risk factors.[1, 2] Conditions commonly referred to as geriatric syndromes include delirium, cognitive impairment, falls, unintentional weight loss, depressive symptoms, and incontinence. Even though many perceive it as medical misnomer,[3] geriatric syndromes have been shown to negatively impact quality of life and activities of daily living in older adults.[2] They are also associated with adverse outcomes such as increased healthcare utilization, functional decline, and mortality, even after adjusting for age and disease severity.[4, 5, 6] Hospitalized older adults, including those discharged to skilled nursing facilities (SNFs)[7, 8] are particularly at high risk for new‐onset or exacerbation of geriatric syndromes and poor outcomes.[7, 9, 10] However, hospital providers seldom assess, manage, or document geriatric syndromes because they are often overshadowed by disease conditions that lead to an acute episode requiring hospitalization (e.g., heart disease).[11]

Pharmacotherapy is the cornerstone of hospital treatment, and it is well‐known that it affects multiple physiologic systems causing side effects apart from the condition they are approved to treat. Given that geriatric syndromes are a result of impairments in multiple organ systems, it is plausible that pharmacotherapy may initiate or worsen these syndromes.[12] Medication‐related problems in older adults are well known. Polypharmacy and adverse drug events (as a result of drug‐drug/disease interactions and changes in pharmacokinetics and pharmacodynamics) are prevalent in multimorbid elderly patients.[13, 14, 15, 16] The prescribing cascade[17] increases the medication burden and may be a contributing factor for geriatric syndromes in hospitalized patients.[18] For instance, laxatives may be prescribed to counteract constipation caused by anticholinergic drugs.

The American Geriatric Society (AGS) Beers list[19, 20] and similar criteria[21] provide excellent resources to identify medications with potentially harmful interactions or adverse effects in older adults. Although these lists include medicines associated with a specific geriatric syndrome, they were not developed to explicitly link medicines across multiple geriatric syndromes, regardless of indication or appropriateness. For example, medications that effect important geriatric syndromes like unintentional weight/appetite loss, depression, and urinary incontinence are not extensively covered. In addition, disease‐appropriate medications (eg, ‐blockers for systolic heart failure), that may be associated with a geriatric syndrome (eg, falls) are not included; however, they may be important to consider for a patient and clinician who are weighing the disease benefits compared to the geriatric syndrome‐related risks. Finally, the AGS 2015 Beers criteria panel mentions the limitation that many medication associations may be excluded because older adults are less represented in clinical trials.[20] Clinicians are currently limited in identifying medications potentially contributing to a broad set of geriatric syndromes in their patients without a specific list of medications associated with geriatric syndromes (MAGS).[20]

In response to this gap, identifying these medications is important and should be a starting point in efforts toward prevention and treatment of geriatric syndromes. The 2 main objectives of this study were to first identify medications that may meaningfully contribute to 6 geriatric syndromes and subsequently describe the frequency of these medications in a population transitioning from acute care to postacute care to highlight the need and potential impact of such a list.

METHODS

This study included 2 phases that aligned with our 2 primary objectives. Phase 1 involved identifying medications associated with 6 geriatric syndromes, and phase 2 included a cross‐sectional analysis of the prevalence of these medications in a sample of patients discharged to SNFs.

Phase 1: Development of the MAGS List

Figure 1 depicts the underlying conceptual model and approach that was used in phase 1. The interaction between the patient factors and medication leads to polypharmacy that contributes to geriatric syndromes and additional adverse outcomes. As a starting point for mitigating geriatric syndromes, we used an iterative analytical process to identify a list of medications associated with the following geriatric syndromes that were documented to be highly prevalent in patients discharged to SNFs: cognitive impairment, delirium, falls, unintentional weight and/or appetite loss, urinary incontinence, and depression.[8] To be inclusive and sensitive, our approach differed from traditional systematic reviews, and in fact was meant to bring together much of the established systematic literature about disparate geriatric syndromes in 1 place, because patients often do not experience a geriatric syndrome in isolation, but rather experience multiple geriatric syndromes.[8] The MAGS list had 3 main inclusion criteria (Figure 1): (1) evidence in the published literature (systematic reviews, cohort studies, randomized clinical trials) that the medication is related to the syndrome, (2) expert panel opinion, and (3) drug databases (Lexicomp Online database[22] and/or US Food and Drug Administration [FDA]approved package inserts).[23] We generated an initial list of medications based on these 3 main criteria to identify medications with significant associations to each geriatric syndrome. The list was further expanded and vetted using an iterative review of each medication list as it related to each geriatric syndrome through a series of group meetings focused around each geriatric syndrome. Following further discussion, we obtained agreement among all team members for medications included in the final list. For each geriatric syndrome, we excluded medications from consideration if they were used to treat the same geriatric syndrome (eg, ‐adrenergic blockers used to treat incontinence in men were listed as associated with incontinence only in women). We classified medications according to the Established Pharmacologic Class available at the FDA website. We also compared our final MAGS list with the 2015 AGS Beer's list[20] by identifying medications that were related to the 6 geriatric syndromes. This included Beers[20]‐cited rationale of anticholinergic, extrapyramidal symptoms, orthostatic hypotension (eg, falls), high‐risk adverse central nervous system effects, sedating, cognitive decline (eg, antipsychotics), delirium, falls, fractures, incontinence, and gastrointestinal (eg, nausea, vomiting). Specifically, we assessed whether the medications were included as inappropriate by the AGS Beers 2015[20] list and also whether they documented the syndrome association for that medication.

Figure 1

RESULTS

DISCUSSION

An iterative process of evidence review by a multidisciplinary panel resulted in a list of 513 medications associated with 6 common geriatric syndromes. This analysis demonstrated that hospitalized, older patients discharged to SNFs were frequently prescribed MAGS. The rate of prescribing ranged from 100% of patients with a medication associated with falls to 36% for unintentional weight loss. Moreover, an alarming 43% of all medications at hospital discharge were MAGS. For this vulnerable population, the combination of high prevalence of MAGS and high risk of geriatric syndromes emphasize a need to critically review the risks and benefits of MAGS throughout hospitalization and at the time of discharge.

A body of evidence demonstrates that many drugs in a typical older adult regimen have no specific clinical indication, are considered inappropriate, or have uncertain efficacy in the geriatric population.[24, 25, 26] This study builds on the foundational work described in landmark reviews such as the AGS Beers[20] and STOPP/START[21] (Screening Tool of Older Persons' Potentially Inappropriate Prescriptions/Screening Tool to Alert doctors to Right, i.e. appropriate indicated Treatment) criteria. Both of these tools, however, were specifically designed as screening tools to identify medications considered unsafe for older adults under most circumstances and within specific illness states.[19, 20, 21] They are most often utilized when starting a medication to avoid acute adverse events. In contrast, the MAGS list was developed to be inclusive of medications that are often appropriate for many medical diagnoses but may also contribute to underlying geriatric syndromes that are more chronic in nature. In addition, inclusion of such medicines increases the sensitivity of screening for medications that can be targeted through patient‐centered deprescribing efforts when clinically appropriate.

A major strength of this study is that we bring together evidence across a spectrum of geriatric syndromes commonly experienced by hospitalized elders. In addition to evaluating multiple syndromes, we applied multiple modalities; particularly the use of an iterative review process by a multidisciplinary team of experts and using Lexicomp and FDA insert packages for linking medications to specific geriatric conditions. The inclusion criteria were broadened beyond single sources of evidence in an effort to capture a comprehensive list of medications. As a result, the MAGS list can be implemented as a screening tool for deprescribing interventions and assessing medication appropriateness to address individual or clusters of geriatric syndromes within a patient.

In addition to expanding this knowledge base, clinical relevance of the MAGS list is highlighted by its application to a sample of hospitalized older adults discharged to SNFs, a cohort known to experience geriatric syndromes. In fact, 43% of patients' medications at hospital discharge were MAGS. Importantly, due to the cross‐sectional nature of this study, we cannot be certain if the medication caused or potentiated each of the geriatric syndromes. However, hospitals and SNFs are devoting major resources toward reduction of falls, avoidance of urinary catheter use, and reduction of preventable readmissions. These efforts can be complemented by considering the number of medications associated with falls, urinary incontinence, and overall MAGS burden. The striking prevalence of MAGS demonstrates a rigorous need to weigh the risks and benefits of these medications. Above all, the intent of this study is not to propose that any MAGS be reflexively stopped, but rather that the MAGS list should facilitate a holistic approach to care for the complex older adult. For example, standard therapies such as gabapentin may be appropriate for treating neuralgic pain but may also contribute to falls and urinary incontinence. Thus, alternative pain treatments could be selected in place of gabapentin for a 75‐year old patient who is experiencing recurrent falls and increasing incontinence. Therefore, the MAGS list enables a patient‐provider discussion wherein medications' therapeutic benefits can be weighed against risks posed by specific clusters of geriatric syndromes, potential impact on quality of life, and consistency with goals of care.

This study has some limitations. First, although we examined a broad number of geriatric syndromes, several other geriatric syndromes experienced by hospitalized older adults were not addressed including: fecal incontinence, insomnia, and functional impairment. These syndromes were intentionally excluded from the study a priori due to reasons of feasibility and scope. Second, unlike the Beer's 2015 criteria, the MAGS list does not sub‐classify associations of medications with geriatric syndromes for patients with specific diseases (eg, heart failure). In fact, our MAGS list included medications often indicated in treating these diagnoses. A clinician must work with the patient to weigh the disease‐specific benefits of some medications with the potential effect on geriatric syndrome symptoms and outcomes. Third, the instrument has a very high sensitivity, which was intended to generate an inclusive list of medications that enables providers to weigh risks of geriatric syndromes with the intended indication benefit. The objective is not to use this list as a reflexive tool but rather help clinicians identify a starting point to address geriatric syndromes in their patients to make patient‐centered medication decisions. Although the MAGS list is intentionally large (sensitive), the advent of advanced bioinformatics can enable MAGS to be assessed in the future for both clinical and research purposes. Fourth, FDA insert packages and Lexicomp databases report anything experienced by the patient while on the particular medication, but it might not necessarily imply a causative link. The high use of MAGS and the specific geriatric syndrome may coexist due to the high prevalence and interplay of multimorbidity, polypharmacy, and geriatric syndromes in this population. Last, the list was developed by expert panel members predominantly from a single institution, which may introduce bias. Despite these limitations, the prevalence of these medications in a sample of patients transitioning from acute to postacute care highlights the utility of the MAGS list in future clinical research and quality improvement endeavors.

In conclusion, the MAGS list provides a comprehensive and sensitive indicator of medications associated with any of 6 geriatric syndromes regardless of medication indication and appropriateness. The MAGS list provides an overall degree of medication burden with respect to geriatric syndromes and a foundation for future research to assess the relationship between the presence of geriatric syndromes and syndrome‐associated medications. The MAGS list is an important first step in summarizing the data that link medications to geriatric syndromes. Future studies are needed to broaden the analysis of MAGS for other common geriatric syndromes and to identify new and emerging medications not present during the time of this analysis. The MAGS list has the potential to facilitate deprescribing efforts needed to combat the epidemic of overprescribing that may be contributing to the burden of geriatric syndromes among older patients.

Geriatric syndromes are common clinical conditions in older adults that do not fall into specific disease categories. Unlike the traditional definition of a syndrome, geriatric syndrome refers to a condition that is mediated by multiple shared underlying risk factors.[1, 2] Conditions commonly referred to as geriatric syndromes include delirium, cognitive impairment, falls, unintentional weight loss, depressive symptoms, and incontinence. Even though many perceive it as medical misnomer,[3] geriatric syndromes have been shown to negatively impact quality of life and activities of daily living in older adults.[2] They are also associated with adverse outcomes such as increased healthcare utilization, functional decline, and mortality, even after adjusting for age and disease severity.[4, 5, 6] Hospitalized older adults, including those discharged to skilled nursing facilities (SNFs)[7, 8] are particularly at high risk for new‐onset or exacerbation of geriatric syndromes and poor outcomes.[7, 9, 10] However, hospital providers seldom assess, manage, or document geriatric syndromes because they are often overshadowed by disease conditions that lead to an acute episode requiring hospitalization (e.g., heart disease).[11]

Pharmacotherapy is the cornerstone of hospital treatment, and it is well‐known that it affects multiple physiologic systems causing side effects apart from the condition they are approved to treat. Given that geriatric syndromes are a result of impairments in multiple organ systems, it is plausible that pharmacotherapy may initiate or worsen these syndromes.[12] Medication‐related problems in older adults are well known. Polypharmacy and adverse drug events (as a result of drug‐drug/disease interactions and changes in pharmacokinetics and pharmacodynamics) are prevalent in multimorbid elderly patients.[13, 14, 15, 16] The prescribing cascade[17] increases the medication burden and may be a contributing factor for geriatric syndromes in hospitalized patients.[18] For instance, laxatives may be prescribed to counteract constipation caused by anticholinergic drugs.

The American Geriatric Society (AGS) Beers list[19, 20] and similar criteria[21] provide excellent resources to identify medications with potentially harmful interactions or adverse effects in older adults. Although these lists include medicines associated with a specific geriatric syndrome, they were not developed to explicitly link medicines across multiple geriatric syndromes, regardless of indication or appropriateness. For example, medications that effect important geriatric syndromes like unintentional weight/appetite loss, depression, and urinary incontinence are not extensively covered. In addition, disease‐appropriate medications (eg, ‐blockers for systolic heart failure), that may be associated with a geriatric syndrome (eg, falls) are not included; however, they may be important to consider for a patient and clinician who are weighing the disease benefits compared to the geriatric syndrome‐related risks. Finally, the AGS 2015 Beers criteria panel mentions the limitation that many medication associations may be excluded because older adults are less represented in clinical trials.[20] Clinicians are currently limited in identifying medications potentially contributing to a broad set of geriatric syndromes in their patients without a specific list of medications associated with geriatric syndromes (MAGS).[20]

In response to this gap, identifying these medications is important and should be a starting point in efforts toward prevention and treatment of geriatric syndromes. The 2 main objectives of this study were to first identify medications that may meaningfully contribute to 6 geriatric syndromes and subsequently describe the frequency of these medications in a population transitioning from acute care to postacute care to highlight the need and potential impact of such a list.

METHODS

This study included 2 phases that aligned with our 2 primary objectives. Phase 1 involved identifying medications associated with 6 geriatric syndromes, and phase 2 included a cross‐sectional analysis of the prevalence of these medications in a sample of patients discharged to SNFs.

Phase 1: Development of the MAGS List

Figure 1 depicts the underlying conceptual model and approach that was used in phase 1. The interaction between the patient factors and medication leads to polypharmacy that contributes to geriatric syndromes and additional adverse outcomes. As a starting point for mitigating geriatric syndromes, we used an iterative analytical process to identify a list of medications associated with the following geriatric syndromes that were documented to be highly prevalent in patients discharged to SNFs: cognitive impairment, delirium, falls, unintentional weight and/or appetite loss, urinary incontinence, and depression.[8] To be inclusive and sensitive, our approach differed from traditional systematic reviews, and in fact was meant to bring together much of the established systematic literature about disparate geriatric syndromes in 1 place, because patients often do not experience a geriatric syndrome in isolation, but rather experience multiple geriatric syndromes.[8] The MAGS list had 3 main inclusion criteria (Figure 1): (1) evidence in the published literature (systematic reviews, cohort studies, randomized clinical trials) that the medication is related to the syndrome, (2) expert panel opinion, and (3) drug databases (Lexicomp Online database[22] and/or US Food and Drug Administration [FDA]approved package inserts).[23] We generated an initial list of medications based on these 3 main criteria to identify medications with significant associations to each geriatric syndrome. The list was further expanded and vetted using an iterative review of each medication list as it related to each geriatric syndrome through a series of group meetings focused around each geriatric syndrome. Following further discussion, we obtained agreement among all team members for medications included in the final list. For each geriatric syndrome, we excluded medications from consideration if they were used to treat the same geriatric syndrome (eg, ‐adrenergic blockers used to treat incontinence in men were listed as associated with incontinence only in women). We classified medications according to the Established Pharmacologic Class available at the FDA website. We also compared our final MAGS list with the 2015 AGS Beer's list[20] by identifying medications that were related to the 6 geriatric syndromes. This included Beers[20]‐cited rationale of anticholinergic, extrapyramidal symptoms, orthostatic hypotension (eg, falls), high‐risk adverse central nervous system effects, sedating, cognitive decline (eg, antipsychotics), delirium, falls, fractures, incontinence, and gastrointestinal (eg, nausea, vomiting). Specifically, we assessed whether the medications were included as inappropriate by the AGS Beers 2015[20] list and also whether they documented the syndrome association for that medication.

Figure 1

RESULTS

DISCUSSION

An iterative process of evidence review by a multidisciplinary panel resulted in a list of 513 medications associated with 6 common geriatric syndromes. This analysis demonstrated that hospitalized, older patients discharged to SNFs were frequently prescribed MAGS. The rate of prescribing ranged from 100% of patients with a medication associated with falls to 36% for unintentional weight loss. Moreover, an alarming 43% of all medications at hospital discharge were MAGS. For this vulnerable population, the combination of high prevalence of MAGS and high risk of geriatric syndromes emphasize a need to critically review the risks and benefits of MAGS throughout hospitalization and at the time of discharge.

A body of evidence demonstrates that many drugs in a typical older adult regimen have no specific clinical indication, are considered inappropriate, or have uncertain efficacy in the geriatric population.[24, 25, 26] This study builds on the foundational work described in landmark reviews such as the AGS Beers[20] and STOPP/START[21] (Screening Tool of Older Persons' Potentially Inappropriate Prescriptions/Screening Tool to Alert doctors to Right, i.e. appropriate indicated Treatment) criteria. Both of these tools, however, were specifically designed as screening tools to identify medications considered unsafe for older adults under most circumstances and within specific illness states.[19, 20, 21] They are most often utilized when starting a medication to avoid acute adverse events. In contrast, the MAGS list was developed to be inclusive of medications that are often appropriate for many medical diagnoses but may also contribute to underlying geriatric syndromes that are more chronic in nature. In addition, inclusion of such medicines increases the sensitivity of screening for medications that can be targeted through patient‐centered deprescribing efforts when clinically appropriate.

A major strength of this study is that we bring together evidence across a spectrum of geriatric syndromes commonly experienced by hospitalized elders. In addition to evaluating multiple syndromes, we applied multiple modalities; particularly the use of an iterative review process by a multidisciplinary team of experts and using Lexicomp and FDA insert packages for linking medications to specific geriatric conditions. The inclusion criteria were broadened beyond single sources of evidence in an effort to capture a comprehensive list of medications. As a result, the MAGS list can be implemented as a screening tool for deprescribing interventions and assessing medication appropriateness to address individual or clusters of geriatric syndromes within a patient.

In addition to expanding this knowledge base, clinical relevance of the MAGS list is highlighted by its application to a sample of hospitalized older adults discharged to SNFs, a cohort known to experience geriatric syndromes. In fact, 43% of patients' medications at hospital discharge were MAGS. Importantly, due to the cross‐sectional nature of this study, we cannot be certain if the medication caused or potentiated each of the geriatric syndromes. However, hospitals and SNFs are devoting major resources toward reduction of falls, avoidance of urinary catheter use, and reduction of preventable readmissions. These efforts can be complemented by considering the number of medications associated with falls, urinary incontinence, and overall MAGS burden. The striking prevalence of MAGS demonstrates a rigorous need to weigh the risks and benefits of these medications. Above all, the intent of this study is not to propose that any MAGS be reflexively stopped, but rather that the MAGS list should facilitate a holistic approach to care for the complex older adult. For example, standard therapies such as gabapentin may be appropriate for treating neuralgic pain but may also contribute to falls and urinary incontinence. Thus, alternative pain treatments could be selected in place of gabapentin for a 75‐year old patient who is experiencing recurrent falls and increasing incontinence. Therefore, the MAGS list enables a patient‐provider discussion wherein medications' therapeutic benefits can be weighed against risks posed by specific clusters of geriatric syndromes, potential impact on quality of life, and consistency with goals of care.

This study has some limitations. First, although we examined a broad number of geriatric syndromes, several other geriatric syndromes experienced by hospitalized older adults were not addressed including: fecal incontinence, insomnia, and functional impairment. These syndromes were intentionally excluded from the study a priori due to reasons of feasibility and scope. Second, unlike the Beer's 2015 criteria, the MAGS list does not sub‐classify associations of medications with geriatric syndromes for patients with specific diseases (eg, heart failure). In fact, our MAGS list included medications often indicated in treating these diagnoses. A clinician must work with the patient to weigh the disease‐specific benefits of some medications with the potential effect on geriatric syndrome symptoms and outcomes. Third, the instrument has a very high sensitivity, which was intended to generate an inclusive list of medications that enables providers to weigh risks of geriatric syndromes with the intended indication benefit. The objective is not to use this list as a reflexive tool but rather help clinicians identify a starting point to address geriatric syndromes in their patients to make patient‐centered medication decisions. Although the MAGS list is intentionally large (sensitive), the advent of advanced bioinformatics can enable MAGS to be assessed in the future for both clinical and research purposes. Fourth, FDA insert packages and Lexicomp databases report anything experienced by the patient while on the particular medication, but it might not necessarily imply a causative link. The high use of MAGS and the specific geriatric syndrome may coexist due to the high prevalence and interplay of multimorbidity, polypharmacy, and geriatric syndromes in this population. Last, the list was developed by expert panel members predominantly from a single institution, which may introduce bias. Despite these limitations, the prevalence of these medications in a sample of patients transitioning from acute to postacute care highlights the utility of the MAGS list in future clinical research and quality improvement endeavors.

In conclusion, the MAGS list provides a comprehensive and sensitive indicator of medications associated with any of 6 geriatric syndromes regardless of medication indication and appropriateness. The MAGS list provides an overall degree of medication burden with respect to geriatric syndromes and a foundation for future research to assess the relationship between the presence of geriatric syndromes and syndrome‐associated medications. The MAGS list is an important first step in summarizing the data that link medications to geriatric syndromes. Future studies are needed to broaden the analysis of MAGS for other common geriatric syndromes and to identify new and emerging medications not present during the time of this analysis. The MAGS list has the potential to facilitate deprescribing efforts needed to combat the epidemic of overprescribing that may be contributing to the burden of geriatric syndromes among older patients.

Geriatric syndromes are common clinical conditions in older adults that do not fall into specific disease categories. Unlike the traditional definition of a syndrome, geriatric syndrome refers to a condition that is mediated by multiple shared underlying risk factors.[1, 2] Conditions commonly referred to as geriatric syndromes include delirium, cognitive impairment, falls, unintentional weight loss, depressive symptoms, and incontinence. Even though many perceive it as medical misnomer,[3] geriatric syndromes have been shown to negatively impact quality of life and activities of daily living in older adults.[2] They are also associated with adverse outcomes such as increased healthcare utilization, functional decline, and mortality, even after adjusting for age and disease severity.[4, 5, 6] Hospitalized older adults, including those discharged to skilled nursing facilities (SNFs)[7, 8] are particularly at high risk for new‐onset or exacerbation of geriatric syndromes and poor outcomes.[7, 9, 10] However, hospital providers seldom assess, manage, or document geriatric syndromes because they are often overshadowed by disease conditions that lead to an acute episode requiring hospitalization (e.g., heart disease).[11]

Pharmacotherapy is the cornerstone of hospital treatment, and it is well‐known that it affects multiple physiologic systems causing side effects apart from the condition they are approved to treat. Given that geriatric syndromes are a result of impairments in multiple organ systems, it is plausible that pharmacotherapy may initiate or worsen these syndromes.[12] Medication‐related problems in older adults are well known. Polypharmacy and adverse drug events (as a result of drug‐drug/disease interactions and changes in pharmacokinetics and pharmacodynamics) are prevalent in multimorbid elderly patients.[13, 14, 15, 16] The prescribing cascade[17] increases the medication burden and may be a contributing factor for geriatric syndromes in hospitalized patients.[18] For instance, laxatives may be prescribed to counteract constipation caused by anticholinergic drugs.

The American Geriatric Society (AGS) Beers list[19, 20] and similar criteria[21] provide excellent resources to identify medications with potentially harmful interactions or adverse effects in older adults. Although these lists include medicines associated with a specific geriatric syndrome, they were not developed to explicitly link medicines across multiple geriatric syndromes, regardless of indication or appropriateness. For example, medications that effect important geriatric syndromes like unintentional weight/appetite loss, depression, and urinary incontinence are not extensively covered. In addition, disease‐appropriate medications (eg, ‐blockers for systolic heart failure), that may be associated with a geriatric syndrome (eg, falls) are not included; however, they may be important to consider for a patient and clinician who are weighing the disease benefits compared to the geriatric syndrome‐related risks. Finally, the AGS 2015 Beers criteria panel mentions the limitation that many medication associations may be excluded because older adults are less represented in clinical trials.[20] Clinicians are currently limited in identifying medications potentially contributing to a broad set of geriatric syndromes in their patients without a specific list of medications associated with geriatric syndromes (MAGS).[20]

In response to this gap, identifying these medications is important and should be a starting point in efforts toward prevention and treatment of geriatric syndromes. The 2 main objectives of this study were to first identify medications that may meaningfully contribute to 6 geriatric syndromes and subsequently describe the frequency of these medications in a population transitioning from acute care to postacute care to highlight the need and potential impact of such a list.

METHODS

This study included 2 phases that aligned with our 2 primary objectives. Phase 1 involved identifying medications associated with 6 geriatric syndromes, and phase 2 included a cross‐sectional analysis of the prevalence of these medications in a sample of patients discharged to SNFs.

Phase 1: Development of the MAGS List

Figure 1 depicts the underlying conceptual model and approach that was used in phase 1. The interaction between the patient factors and medication leads to polypharmacy that contributes to geriatric syndromes and additional adverse outcomes. As a starting point for mitigating geriatric syndromes, we used an iterative analytical process to identify a list of medications associated with the following geriatric syndromes that were documented to be highly prevalent in patients discharged to SNFs: cognitive impairment, delirium, falls, unintentional weight and/or appetite loss, urinary incontinence, and depression.[8] To be inclusive and sensitive, our approach differed from traditional systematic reviews, and in fact was meant to bring together much of the established systematic literature about disparate geriatric syndromes in 1 place, because patients often do not experience a geriatric syndrome in isolation, but rather experience multiple geriatric syndromes.[8] The MAGS list had 3 main inclusion criteria (Figure 1): (1) evidence in the published literature (systematic reviews, cohort studies, randomized clinical trials) that the medication is related to the syndrome, (2) expert panel opinion, and (3) drug databases (Lexicomp Online database[22] and/or US Food and Drug Administration [FDA]approved package inserts).[23] We generated an initial list of medications based on these 3 main criteria to identify medications with significant associations to each geriatric syndrome. The list was further expanded and vetted using an iterative review of each medication list as it related to each geriatric syndrome through a series of group meetings focused around each geriatric syndrome. Following further discussion, we obtained agreement among all team members for medications included in the final list. For each geriatric syndrome, we excluded medications from consideration if they were used to treat the same geriatric syndrome (eg, ‐adrenergic blockers used to treat incontinence in men were listed as associated with incontinence only in women). We classified medications according to the Established Pharmacologic Class available at the FDA website. We also compared our final MAGS list with the 2015 AGS Beer's list[20] by identifying medications that were related to the 6 geriatric syndromes. This included Beers[20]‐cited rationale of anticholinergic, extrapyramidal symptoms, orthostatic hypotension (eg, falls), high‐risk adverse central nervous system effects, sedating, cognitive decline (eg, antipsychotics), delirium, falls, fractures, incontinence, and gastrointestinal (eg, nausea, vomiting). Specifically, we assessed whether the medications were included as inappropriate by the AGS Beers 2015[20] list and also whether they documented the syndrome association for that medication.

Figure 1

RESULTS

DISCUSSION

An iterative process of evidence review by a multidisciplinary panel resulted in a list of 513 medications associated with 6 common geriatric syndromes. This analysis demonstrated that hospitalized, older patients discharged to SNFs were frequently prescribed MAGS. The rate of prescribing ranged from 100% of patients with a medication associated with falls to 36% for unintentional weight loss. Moreover, an alarming 43% of all medications at hospital discharge were MAGS. For this vulnerable population, the combination of high prevalence of MAGS and high risk of geriatric syndromes emphasize a need to critically review the risks and benefits of MAGS throughout hospitalization and at the time of discharge.

A body of evidence demonstrates that many drugs in a typical older adult regimen have no specific clinical indication, are considered inappropriate, or have uncertain efficacy in the geriatric population.[24, 25, 26] This study builds on the foundational work described in landmark reviews such as the AGS Beers[20] and STOPP/START[21] (Screening Tool of Older Persons' Potentially Inappropriate Prescriptions/Screening Tool to Alert doctors to Right, i.e. appropriate indicated Treatment) criteria. Both of these tools, however, were specifically designed as screening tools to identify medications considered unsafe for older adults under most circumstances and within specific illness states.[19, 20, 21] They are most often utilized when starting a medication to avoid acute adverse events. In contrast, the MAGS list was developed to be inclusive of medications that are often appropriate for many medical diagnoses but may also contribute to underlying geriatric syndromes that are more chronic in nature. In addition, inclusion of such medicines increases the sensitivity of screening for medications that can be targeted through patient‐centered deprescribing efforts when clinically appropriate.

A major strength of this study is that we bring together evidence across a spectrum of geriatric syndromes commonly experienced by hospitalized elders. In addition to evaluating multiple syndromes, we applied multiple modalities; particularly the use of an iterative review process by a multidisciplinary team of experts and using Lexicomp and FDA insert packages for linking medications to specific geriatric conditions. The inclusion criteria were broadened beyond single sources of evidence in an effort to capture a comprehensive list of medications. As a result, the MAGS list can be implemented as a screening tool for deprescribing interventions and assessing medication appropriateness to address individual or clusters of geriatric syndromes within a patient.

In addition to expanding this knowledge base, clinical relevance of the MAGS list is highlighted by its application to a sample of hospitalized older adults discharged to SNFs, a cohort known to experience geriatric syndromes. In fact, 43% of patients' medications at hospital discharge were MAGS. Importantly, due to the cross‐sectional nature of this study, we cannot be certain if the medication caused or potentiated each of the geriatric syndromes. However, hospitals and SNFs are devoting major resources toward reduction of falls, avoidance of urinary catheter use, and reduction of preventable readmissions. These efforts can be complemented by considering the number of medications associated with falls, urinary incontinence, and overall MAGS burden. The striking prevalence of MAGS demonstrates a rigorous need to weigh the risks and benefits of these medications. Above all, the intent of this study is not to propose that any MAGS be reflexively stopped, but rather that the MAGS list should facilitate a holistic approach to care for the complex older adult. For example, standard therapies such as gabapentin may be appropriate for treating neuralgic pain but may also contribute to falls and urinary incontinence. Thus, alternative pain treatments could be selected in place of gabapentin for a 75‐year old patient who is experiencing recurrent falls and increasing incontinence. Therefore, the MAGS list enables a patient‐provider discussion wherein medications' therapeutic benefits can be weighed against risks posed by specific clusters of geriatric syndromes, potential impact on quality of life, and consistency with goals of care.

This study has some limitations. First, although we examined a broad number of geriatric syndromes, several other geriatric syndromes experienced by hospitalized older adults were not addressed including: fecal incontinence, insomnia, and functional impairment. These syndromes were intentionally excluded from the study a priori due to reasons of feasibility and scope. Second, unlike the Beer's 2015 criteria, the MAGS list does not sub‐classify associations of medications with geriatric syndromes for patients with specific diseases (eg, heart failure). In fact, our MAGS list included medications often indicated in treating these diagnoses. A clinician must work with the patient to weigh the disease‐specific benefits of some medications with the potential effect on geriatric syndrome symptoms and outcomes. Third, the instrument has a very high sensitivity, which was intended to generate an inclusive list of medications that enables providers to weigh risks of geriatric syndromes with the intended indication benefit. The objective is not to use this list as a reflexive tool but rather help clinicians identify a starting point to address geriatric syndromes in their patients to make patient‐centered medication decisions. Although the MAGS list is intentionally large (sensitive), the advent of advanced bioinformatics can enable MAGS to be assessed in the future for both clinical and research purposes. Fourth, FDA insert packages and Lexicomp databases report anything experienced by the patient while on the particular medication, but it might not necessarily imply a causative link. The high use of MAGS and the specific geriatric syndrome may coexist due to the high prevalence and interplay of multimorbidity, polypharmacy, and geriatric syndromes in this population. Last, the list was developed by expert panel members predominantly from a single institution, which may introduce bias. Despite these limitations, the prevalence of these medications in a sample of patients transitioning from acute to postacute care highlights the utility of the MAGS list in future clinical research and quality improvement endeavors.

In conclusion, the MAGS list provides a comprehensive and sensitive indicator of medications associated with any of 6 geriatric syndromes regardless of medication indication and appropriateness. The MAGS list provides an overall degree of medication burden with respect to geriatric syndromes and a foundation for future research to assess the relationship between the presence of geriatric syndromes and syndrome‐associated medications. The MAGS list is an important first step in summarizing the data that link medications to geriatric syndromes. Future studies are needed to broaden the analysis of MAGS for other common geriatric syndromes and to identify new and emerging medications not present during the time of this analysis. The MAGS list has the potential to facilitate deprescribing efforts needed to combat the epidemic of overprescribing that may be contributing to the burden of geriatric syndromes among older patients.

Arousal is defined as the patient's overall level of responsiveness to the environment. Its assessment is standard of care in most intensive care units (ICUs) to monitor depth of sedation and underlying brain dysfunction. There has been recent interest in expanding the role of arousal assessment beyond the ICU. Specifically, the Veterans Affairs Delirium Working Group proposed that simple arousal assessment be a vital sign to quantify underlying brain dysfunction.[1] The rationale is that impaired arousal is closely linked with delirium,[2] and is an integral component of multiple delirium assessments.[3, 4, 5] Chester et al. observed that the presence of impaired arousal was 64% sensitive and 93% specific for delirium diagnosed by a psychiatrist.[2] Delirium is an under‐recognized public health problem that affects up to 25% of older hospitalized patients,[6, 7] is associated with a multitude of adverse outcomes such as death and accelerated cognitive decline,[8] and costs the US healthcare system an excess of $152 billion dollars.[9]

Most delirium assessments require the patient to undergo additional cognitive testing. The assessment of arousal, however, requires the rater to merely observe the patient during routine clinical care and can be easily integrated into the clinical workflow.[10] Because of its simplicity and brevity, assessing arousal alone using validated scales such as the Richmond Agitation‐Sedation Scale (RASS) may be a more appealing alternative to traditional, more complex delirium screening in the acute care setting. Its clinical utility would be further strengthened if impaired arousal was also associated with mortality, and conferred risk even in the absence of delirium. As a result, we sought to determine if impaired arousal at initial presentation in older acutely ill patients predicted 6‐month mortality and whether this relationship was present in the absence of delirium.

METHODS

RESULTS

A total of 1903 patients were screened, and 1084 patients met enrollment criteria (Figure 1). Of these, 1051 (97.0%) were non‐ICU patients. Patient characteristics of this cohort can be seen in Table 2. Enrolled patients and potentially eligible patients who presented to the emergency department during the enrollment window were similar in age, gender, and severity of illness, but enrolled patients were slightly more likely to have a chief complaint of chest pain and syncope (unpublished data).

Figure 1

Of those enrolled, 249 (23.0%) had an abnormal RASS at initial presentation, and their distribution can be seen in Figure 2. Within 6 months, patients with an abnormal RASS were more likely to die compared with patients with a RASS of 0 (23.7% vs 9.7%, P<0.001). The Kaplan‐Meier survival curves for all enrolled patients with impaired and normal RASS can be seen in Figure 3; the survival curve declined more slowly in patients with a normal RASS compared with those with an abnormal RASS.

Figure 2

Figure 3

Using Cox proportional hazards regression, the relationship between an abnormal RASS at initial presentation and 6‐month mortality persisted (HR: 1.73, 95% CI: 1.21‐2.49) after adjusting for age, sex, nonwhite race, comorbidity burden, severity of illness, dementia, functional dependence, nursing home residence, psychoactive medications given, and admission status. The interaction between an abnormal RASS and APS (severity of illness) had a P value of 0.52. The interaction between an abnormal RASS and benzodiazepine or opioid medication administration had a P value of 0.38. The interaction between an abnormal RASS and admission status had a P value of 0.57. This indicated that severity of illness, psychoactive medication administration, and admission status did not modify the relationship between an abnormal RASS and 6‐month mortality.

We analyzed a subset of 406 patients who received a psychiatrist's assessment to determine if an abnormal RASS was associated with 6‐month mortality regardless of delirium status using Cox proportional hazard regression weighted by the inverse of the propensity score. Patients with an abnormal RASS and no delirium were significantly associated with higher mortality compared to those with a normal RASS (HR: 2.20, 95% CI: 1.10‐4.41). Patients with an abnormal RASS with delirium also had an increased risk for 6‐month mortality (HR: 2.86, 95% CI: 1.29‐6.34).

All regression models were internally validated. There was no evidence of substantial overfitting or collinearity. The Schoenfeld residuals for each model were examined graphically and there was good model fit overall, and no significant outliers were observed.

DISCUSSION

Vital sign measurements are a fundamental component of patient care, and abnormalities can serve as an early warning signal of the patient's clinical deterioration. However, traditional vital signs do not include an assessment of the patient's brain function. Our chief finding is that impaired arousal at initial presentation, as determined by the nonphysician research staff, increased the risk of 6‐month mortality by 73% after adjusting for confounders in a diverse group of acutely ill older patients. This relationship existed regardless of severity of illness, administration of psychoactive medications, and admission status. Though impaired arousal is closely linked with delirium,[2, 24] which is another well‐known predictor of mortality,[11, 25, 26] the prognostic significance of impaired arousal appeared to extend beyond delirium. We observed that the relationship between 6‐month mortality and impaired arousal in the absence of delirium was remarkably similar to that observed with impaired arousal with delirium. Arousal can be assessed for by simply observing the patient during routine clinical care and can be performed by nonphysician and physician healthcare providers. Its assessment should be performed and communicated in conjunction with traditional vital sign measurements in the emergency department and inpatient settings.[1]

Most of the data linking impaired arousal to death have been collected in the ICU. Coma, which represents the most severe form of depressed arousal, has been shown to increase the likelihood of death regardless of underlying etiology.[27, 28, 29, 30, 31] This includes patients who have impaired arousal because they received sedative medications during mechanical ventilation.[32] Few studies have investigated the effect of impaired arousal in a non‐ICU patient population. Zuliani et al. observed that impaired arousal was associated with 30‐day mortality, but their study was conducted in 469 older stroke patients, limiting the study's external validity to a more general patient population.[33] Our data advance the current stage of knowledge; we observed a similar relationship between impaired arousal and 6‐month mortality in a much broader clinical population who were predominantly not critically ill regardless of delirium status. Additionally, most of our impaired arousal cohort had a RASS of 1, indicating that even subtle abnormalities portended adverse outcomes.

In addition to long‐term prognosis, the presence of impaired arousal has immediate clinical implications. Using arousal scales like the RASS can serve as a way for healthcare providers to succinctly communicate the patient's mental status in a standardized manner during transitions of care (eg, emergency physician to inpatient team). Regardless of which clinical setting they are in, older acutely ill patients with an impaired arousal may also require close monitoring, especially if the impairment is acute. Because of its close relationship with delirium, these patients likely have an underlying acute medical illness that precipitated their impaired arousal.

Understanding the true clinical significance of impaired arousal in the absence of delirium requires further study. Because of the fluctuating nature of delirium, it is possible that these patients may have initially been delirious and then became nondelirious during the psychiatrist's evaluation. Conversely, it is also possible that these patients may have eventually transitioned into delirium at later point in time; the presence of impaired arousal alone may be a precursor to delirium. Last, these patients may have had subsyndromal delirium, which is defined as having 1 or more delirium symptoms without ever meeting full DSM‐IV‐TR criteria for delirium.[34] Patients with subsyndromal delirium have poorer outcomes, such as prolonged hospitalizations, and higher mortality than patients without delirium symptoms.[34]

Additional studies are also needed to further clarify the impact of impaired arousal on nonmortality outcomes such as functional and cognitive decline. The prognostic significance of serial arousal measurements also requires further study. It is possible that patients whose impaired arousal rapidly resolves after an intervention may have better prognoses than those who have persistent impairment. The measurement of arousal may have additional clinical applications in disease prognosis models. The presence of altered mental status is incorporated in various disease‐specific risk scores such as the CURB‐65 or Pneumonia Severity Index for pneumonia,[35, 36] and the Pulmonary Embolism Severity Index for pulmonary embolism.[37] However, the definition of altered mental status is highly variable; it ranges from subjective impressions that can be unreliable to formal cognitive testing, which can be time consuming. Arousal scales such as the RASS may allow for more feasible, reliable, and standardized assessment of mental status. Future studies should investigate if incorporating the RASS would improve the discrimination of these disease‐severity indices.

This study has several notable limitations. We excluded patients with a RASS of 4 and 5, which represented comatose patients. This exclusion, however, likely biased our findings toward the null. We enrolled a convenience sample that may have introduced selection bias. However, our enrolled cohort was similar to all potentially eligible patients who presented to the emergency department during the study period. We also attempted to mitigate this selection bias by using multivariable regression and adjusting for factors that may have confounded the relationship between RASS and 6‐month mortality. This study was performed at a single, urban, academic hospital and enrolled patients who were aged 65 years and older. Our findings may not be generalizable to other settings and to those who are under 65 years of age. Because 406 patients received a psychiatric evaluation, this limited the number of covariates that could be incorporated into the multivariable model to evaluate if impaired arousal in the absence of delirium is associated with 6‐month mortality. To minimize residual confounding, we used the inverse weighted propensity score, but we acknowledge that this bias may still exist. Larger studies are needed to clarify the relationships between arousal, delirium, and mortality.

CONCLUSION

In conclusion, impaired arousal at initial presentation is an independent predictor for 6‐month mortality in a diverse group of acutely ill older patients, and this risk appears to be present even in the absence of delirium. Because of its ease of use and prognostic significance, it may be a useful vital sign for underlying brain dysfunction. Routine standardized assessment and communication of arousal during routine clinical care may be warranted.

Disclosures: Research reported in this publication was supported by the Vanderbilt Physician Scientist Development Award, Emergency Medicine Foundation, and National Institute on Aging of the National Institutes of Health under award number K23AG032355. This study was also supported by the National Center for Research Resources, grant UL1 RR024975‐01, and is now at the National Center for Advancing Translational Sciences, grant 2 UL1 TR000445‐06. Dr. Vasilevskis was supported in part by the National Institute on Aging of the National Institutes of Health under award number K23AG040157. Dr. Powers was supported by Health Resources and Services Administration Geriatric Education Centers, grant 1D31HP08823‐01‐00. Dr. Storrow was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number K12HL1090 and the National Center for Advancing Translational Sciences under award number UL1TR000445. Dr. Ely was supported in part by the National Institute on Aging of the National Institutes of Health under award numbers R01AG027472 and R01AG035117, and a Veteran Affairs MERIT award. Drs. Vasilevskis, Schnelle, Dittus, Powers, and Ely were supported by the Veteran Affairs Geriatric Research, Education, and Clinical Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of Vanderbilt University, Emergency Medicine Foundation, National Institutes of Health, and Veterans Affairs. The funding agencies did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

J.H.H., E.W.E., J.F.S., A.B.S., and R.D.S. conceived the trial. J.H.H., E.W.E., A.B.S., J.F.S., R.D.S., A.S., and A.W. participated in the study design. J.H.H. and A.W. recruited patients and collected the data. J.H.H., A.J.G., and A.S. analyzed the data. All authors participated in the interpretation of results. J.H.H. drafted the manuscript, and all authors contributed to the critical review and revision of the manuscript.

The authors report no conflicts of interest.

Arousal is defined as the patient's overall level of responsiveness to the environment. Its assessment is standard of care in most intensive care units (ICUs) to monitor depth of sedation and underlying brain dysfunction. There has been recent interest in expanding the role of arousal assessment beyond the ICU. Specifically, the Veterans Affairs Delirium Working Group proposed that simple arousal assessment be a vital sign to quantify underlying brain dysfunction.[1] The rationale is that impaired arousal is closely linked with delirium,[2] and is an integral component of multiple delirium assessments.[3, 4, 5] Chester et al. observed that the presence of impaired arousal was 64% sensitive and 93% specific for delirium diagnosed by a psychiatrist.[2] Delirium is an under‐recognized public health problem that affects up to 25% of older hospitalized patients,[6, 7] is associated with a multitude of adverse outcomes such as death and accelerated cognitive decline,[8] and costs the US healthcare system an excess of $152 billion dollars.[9]

Most delirium assessments require the patient to undergo additional cognitive testing. The assessment of arousal, however, requires the rater to merely observe the patient during routine clinical care and can be easily integrated into the clinical workflow.[10] Because of its simplicity and brevity, assessing arousal alone using validated scales such as the Richmond Agitation‐Sedation Scale (RASS) may be a more appealing alternative to traditional, more complex delirium screening in the acute care setting. Its clinical utility would be further strengthened if impaired arousal was also associated with mortality, and conferred risk even in the absence of delirium. As a result, we sought to determine if impaired arousal at initial presentation in older acutely ill patients predicted 6‐month mortality and whether this relationship was present in the absence of delirium.

METHODS

RESULTS

A total of 1903 patients were screened, and 1084 patients met enrollment criteria (Figure 1). Of these, 1051 (97.0%) were non‐ICU patients. Patient characteristics of this cohort can be seen in Table 2. Enrolled patients and potentially eligible patients who presented to the emergency department during the enrollment window were similar in age, gender, and severity of illness, but enrolled patients were slightly more likely to have a chief complaint of chest pain and syncope (unpublished data).

Figure 1

Of those enrolled, 249 (23.0%) had an abnormal RASS at initial presentation, and their distribution can be seen in Figure 2. Within 6 months, patients with an abnormal RASS were more likely to die compared with patients with a RASS of 0 (23.7% vs 9.7%, P<0.001). The Kaplan‐Meier survival curves for all enrolled patients with impaired and normal RASS can be seen in Figure 3; the survival curve declined more slowly in patients with a normal RASS compared with those with an abnormal RASS.

Figure 2

Figure 3

Using Cox proportional hazards regression, the relationship between an abnormal RASS at initial presentation and 6‐month mortality persisted (HR: 1.73, 95% CI: 1.21‐2.49) after adjusting for age, sex, nonwhite race, comorbidity burden, severity of illness, dementia, functional dependence, nursing home residence, psychoactive medications given, and admission status. The interaction between an abnormal RASS and APS (severity of illness) had a P value of 0.52. The interaction between an abnormal RASS and benzodiazepine or opioid medication administration had a P value of 0.38. The interaction between an abnormal RASS and admission status had a P value of 0.57. This indicated that severity of illness, psychoactive medication administration, and admission status did not modify the relationship between an abnormal RASS and 6‐month mortality.

We analyzed a subset of 406 patients who received a psychiatrist's assessment to determine if an abnormal RASS was associated with 6‐month mortality regardless of delirium status using Cox proportional hazard regression weighted by the inverse of the propensity score. Patients with an abnormal RASS and no delirium were significantly associated with higher mortality compared to those with a normal RASS (HR: 2.20, 95% CI: 1.10‐4.41). Patients with an abnormal RASS with delirium also had an increased risk for 6‐month mortality (HR: 2.86, 95% CI: 1.29‐6.34).

All regression models were internally validated. There was no evidence of substantial overfitting or collinearity. The Schoenfeld residuals for each model were examined graphically and there was good model fit overall, and no significant outliers were observed.

DISCUSSION

Vital sign measurements are a fundamental component of patient care, and abnormalities can serve as an early warning signal of the patient's clinical deterioration. However, traditional vital signs do not include an assessment of the patient's brain function. Our chief finding is that impaired arousal at initial presentation, as determined by the nonphysician research staff, increased the risk of 6‐month mortality by 73% after adjusting for confounders in a diverse group of acutely ill older patients. This relationship existed regardless of severity of illness, administration of psychoactive medications, and admission status. Though impaired arousal is closely linked with delirium,[2, 24] which is another well‐known predictor of mortality,[11, 25, 26] the prognostic significance of impaired arousal appeared to extend beyond delirium. We observed that the relationship between 6‐month mortality and impaired arousal in the absence of delirium was remarkably similar to that observed with impaired arousal with delirium. Arousal can be assessed for by simply observing the patient during routine clinical care and can be performed by nonphysician and physician healthcare providers. Its assessment should be performed and communicated in conjunction with traditional vital sign measurements in the emergency department and inpatient settings.[1]

Most of the data linking impaired arousal to death have been collected in the ICU. Coma, which represents the most severe form of depressed arousal, has been shown to increase the likelihood of death regardless of underlying etiology.[27, 28, 29, 30, 31] This includes patients who have impaired arousal because they received sedative medications during mechanical ventilation.[32] Few studies have investigated the effect of impaired arousal in a non‐ICU patient population. Zuliani et al. observed that impaired arousal was associated with 30‐day mortality, but their study was conducted in 469 older stroke patients, limiting the study's external validity to a more general patient population.[33] Our data advance the current stage of knowledge; we observed a similar relationship between impaired arousal and 6‐month mortality in a much broader clinical population who were predominantly not critically ill regardless of delirium status. Additionally, most of our impaired arousal cohort had a RASS of 1, indicating that even subtle abnormalities portended adverse outcomes.

In addition to long‐term prognosis, the presence of impaired arousal has immediate clinical implications. Using arousal scales like the RASS can serve as a way for healthcare providers to succinctly communicate the patient's mental status in a standardized manner during transitions of care (eg, emergency physician to inpatient team). Regardless of which clinical setting they are in, older acutely ill patients with an impaired arousal may also require close monitoring, especially if the impairment is acute. Because of its close relationship with delirium, these patients likely have an underlying acute medical illness that precipitated their impaired arousal.

Understanding the true clinical significance of impaired arousal in the absence of delirium requires further study. Because of the fluctuating nature of delirium, it is possible that these patients may have initially been delirious and then became nondelirious during the psychiatrist's evaluation. Conversely, it is also possible that these patients may have eventually transitioned into delirium at later point in time; the presence of impaired arousal alone may be a precursor to delirium. Last, these patients may have had subsyndromal delirium, which is defined as having 1 or more delirium symptoms without ever meeting full DSM‐IV‐TR criteria for delirium.[34] Patients with subsyndromal delirium have poorer outcomes, such as prolonged hospitalizations, and higher mortality than patients without delirium symptoms.[34]

Additional studies are also needed to further clarify the impact of impaired arousal on nonmortality outcomes such as functional and cognitive decline. The prognostic significance of serial arousal measurements also requires further study. It is possible that patients whose impaired arousal rapidly resolves after an intervention may have better prognoses than those who have persistent impairment. The measurement of arousal may have additional clinical applications in disease prognosis models. The presence of altered mental status is incorporated in various disease‐specific risk scores such as the CURB‐65 or Pneumonia Severity Index for pneumonia,[35, 36] and the Pulmonary Embolism Severity Index for pulmonary embolism.[37] However, the definition of altered mental status is highly variable; it ranges from subjective impressions that can be unreliable to formal cognitive testing, which can be time consuming. Arousal scales such as the RASS may allow for more feasible, reliable, and standardized assessment of mental status. Future studies should investigate if incorporating the RASS would improve the discrimination of these disease‐severity indices.

This study has several notable limitations. We excluded patients with a RASS of 4 and 5, which represented comatose patients. This exclusion, however, likely biased our findings toward the null. We enrolled a convenience sample that may have introduced selection bias. However, our enrolled cohort was similar to all potentially eligible patients who presented to the emergency department during the study period. We also attempted to mitigate this selection bias by using multivariable regression and adjusting for factors that may have confounded the relationship between RASS and 6‐month mortality. This study was performed at a single, urban, academic hospital and enrolled patients who were aged 65 years and older. Our findings may not be generalizable to other settings and to those who are under 65 years of age. Because 406 patients received a psychiatric evaluation, this limited the number of covariates that could be incorporated into the multivariable model to evaluate if impaired arousal in the absence of delirium is associated with 6‐month mortality. To minimize residual confounding, we used the inverse weighted propensity score, but we acknowledge that this bias may still exist. Larger studies are needed to clarify the relationships between arousal, delirium, and mortality.

CONCLUSION

In conclusion, impaired arousal at initial presentation is an independent predictor for 6‐month mortality in a diverse group of acutely ill older patients, and this risk appears to be present even in the absence of delirium. Because of its ease of use and prognostic significance, it may be a useful vital sign for underlying brain dysfunction. Routine standardized assessment and communication of arousal during routine clinical care may be warranted.

Disclosures: Research reported in this publication was supported by the Vanderbilt Physician Scientist Development Award, Emergency Medicine Foundation, and National Institute on Aging of the National Institutes of Health under award number K23AG032355. This study was also supported by the National Center for Research Resources, grant UL1 RR024975‐01, and is now at the National Center for Advancing Translational Sciences, grant 2 UL1 TR000445‐06. Dr. Vasilevskis was supported in part by the National Institute on Aging of the National Institutes of Health under award number K23AG040157. Dr. Powers was supported by Health Resources and Services Administration Geriatric Education Centers, grant 1D31HP08823‐01‐00. Dr. Storrow was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number K12HL1090 and the National Center for Advancing Translational Sciences under award number UL1TR000445. Dr. Ely was supported in part by the National Institute on Aging of the National Institutes of Health under award numbers R01AG027472 and R01AG035117, and a Veteran Affairs MERIT award. Drs. Vasilevskis, Schnelle, Dittus, Powers, and Ely were supported by the Veteran Affairs Geriatric Research, Education, and Clinical Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of Vanderbilt University, Emergency Medicine Foundation, National Institutes of Health, and Veterans Affairs. The funding agencies did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

J.H.H., E.W.E., J.F.S., A.B.S., and R.D.S. conceived the trial. J.H.H., E.W.E., A.B.S., J.F.S., R.D.S., A.S., and A.W. participated in the study design. J.H.H. and A.W. recruited patients and collected the data. J.H.H., A.J.G., and A.S. analyzed the data. All authors participated in the interpretation of results. J.H.H. drafted the manuscript, and all authors contributed to the critical review and revision of the manuscript.

The authors report no conflicts of interest.

Arousal is defined as the patient's overall level of responsiveness to the environment. Its assessment is standard of care in most intensive care units (ICUs) to monitor depth of sedation and underlying brain dysfunction. There has been recent interest in expanding the role of arousal assessment beyond the ICU. Specifically, the Veterans Affairs Delirium Working Group proposed that simple arousal assessment be a vital sign to quantify underlying brain dysfunction.[1] The rationale is that impaired arousal is closely linked with delirium,[2] and is an integral component of multiple delirium assessments.[3, 4, 5] Chester et al. observed that the presence of impaired arousal was 64% sensitive and 93% specific for delirium diagnosed by a psychiatrist.[2] Delirium is an under‐recognized public health problem that affects up to 25% of older hospitalized patients,[6, 7] is associated with a multitude of adverse outcomes such as death and accelerated cognitive decline,[8] and costs the US healthcare system an excess of $152 billion dollars.[9]

Most delirium assessments require the patient to undergo additional cognitive testing. The assessment of arousal, however, requires the rater to merely observe the patient during routine clinical care and can be easily integrated into the clinical workflow.[10] Because of its simplicity and brevity, assessing arousal alone using validated scales such as the Richmond Agitation‐Sedation Scale (RASS) may be a more appealing alternative to traditional, more complex delirium screening in the acute care setting. Its clinical utility would be further strengthened if impaired arousal was also associated with mortality, and conferred risk even in the absence of delirium. As a result, we sought to determine if impaired arousal at initial presentation in older acutely ill patients predicted 6‐month mortality and whether this relationship was present in the absence of delirium.

METHODS

RESULTS

A total of 1903 patients were screened, and 1084 patients met enrollment criteria (Figure 1). Of these, 1051 (97.0%) were non‐ICU patients. Patient characteristics of this cohort can be seen in Table 2. Enrolled patients and potentially eligible patients who presented to the emergency department during the enrollment window were similar in age, gender, and severity of illness, but enrolled patients were slightly more likely to have a chief complaint of chest pain and syncope (unpublished data).

Figure 1

Of those enrolled, 249 (23.0%) had an abnormal RASS at initial presentation, and their distribution can be seen in Figure 2. Within 6 months, patients with an abnormal RASS were more likely to die compared with patients with a RASS of 0 (23.7% vs 9.7%, P<0.001). The Kaplan‐Meier survival curves for all enrolled patients with impaired and normal RASS can be seen in Figure 3; the survival curve declined more slowly in patients with a normal RASS compared with those with an abnormal RASS.

Figure 2

Figure 3

Using Cox proportional hazards regression, the relationship between an abnormal RASS at initial presentation and 6‐month mortality persisted (HR: 1.73, 95% CI: 1.21‐2.49) after adjusting for age, sex, nonwhite race, comorbidity burden, severity of illness, dementia, functional dependence, nursing home residence, psychoactive medications given, and admission status. The interaction between an abnormal RASS and APS (severity of illness) had a P value of 0.52. The interaction between an abnormal RASS and benzodiazepine or opioid medication administration had a P value of 0.38. The interaction between an abnormal RASS and admission status had a P value of 0.57. This indicated that severity of illness, psychoactive medication administration, and admission status did not modify the relationship between an abnormal RASS and 6‐month mortality.

We analyzed a subset of 406 patients who received a psychiatrist's assessment to determine if an abnormal RASS was associated with 6‐month mortality regardless of delirium status using Cox proportional hazard regression weighted by the inverse of the propensity score. Patients with an abnormal RASS and no delirium were significantly associated with higher mortality compared to those with a normal RASS (HR: 2.20, 95% CI: 1.10‐4.41). Patients with an abnormal RASS with delirium also had an increased risk for 6‐month mortality (HR: 2.86, 95% CI: 1.29‐6.34).

All regression models were internally validated. There was no evidence of substantial overfitting or collinearity. The Schoenfeld residuals for each model were examined graphically and there was good model fit overall, and no significant outliers were observed.

DISCUSSION

Vital sign measurements are a fundamental component of patient care, and abnormalities can serve as an early warning signal of the patient's clinical deterioration. However, traditional vital signs do not include an assessment of the patient's brain function. Our chief finding is that impaired arousal at initial presentation, as determined by the nonphysician research staff, increased the risk of 6‐month mortality by 73% after adjusting for confounders in a diverse group of acutely ill older patients. This relationship existed regardless of severity of illness, administration of psychoactive medications, and admission status. Though impaired arousal is closely linked with delirium,[2, 24] which is another well‐known predictor of mortality,[11, 25, 26] the prognostic significance of impaired arousal appeared to extend beyond delirium. We observed that the relationship between 6‐month mortality and impaired arousal in the absence of delirium was remarkably similar to that observed with impaired arousal with delirium. Arousal can be assessed for by simply observing the patient during routine clinical care and can be performed by nonphysician and physician healthcare providers. Its assessment should be performed and communicated in conjunction with traditional vital sign measurements in the emergency department and inpatient settings.[1]

Most of the data linking impaired arousal to death have been collected in the ICU. Coma, which represents the most severe form of depressed arousal, has been shown to increase the likelihood of death regardless of underlying etiology.[27, 28, 29, 30, 31] This includes patients who have impaired arousal because they received sedative medications during mechanical ventilation.[32] Few studies have investigated the effect of impaired arousal in a non‐ICU patient population. Zuliani et al. observed that impaired arousal was associated with 30‐day mortality, but their study was conducted in 469 older stroke patients, limiting the study's external validity to a more general patient population.[33] Our data advance the current stage of knowledge; we observed a similar relationship between impaired arousal and 6‐month mortality in a much broader clinical population who were predominantly not critically ill regardless of delirium status. Additionally, most of our impaired arousal cohort had a RASS of 1, indicating that even subtle abnormalities portended adverse outcomes.

In addition to long‐term prognosis, the presence of impaired arousal has immediate clinical implications. Using arousal scales like the RASS can serve as a way for healthcare providers to succinctly communicate the patient's mental status in a standardized manner during transitions of care (eg, emergency physician to inpatient team). Regardless of which clinical setting they are in, older acutely ill patients with an impaired arousal may also require close monitoring, especially if the impairment is acute. Because of its close relationship with delirium, these patients likely have an underlying acute medical illness that precipitated their impaired arousal.

Understanding the true clinical significance of impaired arousal in the absence of delirium requires further study. Because of the fluctuating nature of delirium, it is possible that these patients may have initially been delirious and then became nondelirious during the psychiatrist's evaluation. Conversely, it is also possible that these patients may have eventually transitioned into delirium at later point in time; the presence of impaired arousal alone may be a precursor to delirium. Last, these patients may have had subsyndromal delirium, which is defined as having 1 or more delirium symptoms without ever meeting full DSM‐IV‐TR criteria for delirium.[34] Patients with subsyndromal delirium have poorer outcomes, such as prolonged hospitalizations, and higher mortality than patients without delirium symptoms.[34]

Additional studies are also needed to further clarify the impact of impaired arousal on nonmortality outcomes such as functional and cognitive decline. The prognostic significance of serial arousal measurements also requires further study. It is possible that patients whose impaired arousal rapidly resolves after an intervention may have better prognoses than those who have persistent impairment. The measurement of arousal may have additional clinical applications in disease prognosis models. The presence of altered mental status is incorporated in various disease‐specific risk scores such as the CURB‐65 or Pneumonia Severity Index for pneumonia,[35, 36] and the Pulmonary Embolism Severity Index for pulmonary embolism.[37] However, the definition of altered mental status is highly variable; it ranges from subjective impressions that can be unreliable to formal cognitive testing, which can be time consuming. Arousal scales such as the RASS may allow for more feasible, reliable, and standardized assessment of mental status. Future studies should investigate if incorporating the RASS would improve the discrimination of these disease‐severity indices.

This study has several notable limitations. We excluded patients with a RASS of 4 and 5, which represented comatose patients. This exclusion, however, likely biased our findings toward the null. We enrolled a convenience sample that may have introduced selection bias. However, our enrolled cohort was similar to all potentially eligible patients who presented to the emergency department during the study period. We also attempted to mitigate this selection bias by using multivariable regression and adjusting for factors that may have confounded the relationship between RASS and 6‐month mortality. This study was performed at a single, urban, academic hospital and enrolled patients who were aged 65 years and older. Our findings may not be generalizable to other settings and to those who are under 65 years of age. Because 406 patients received a psychiatric evaluation, this limited the number of covariates that could be incorporated into the multivariable model to evaluate if impaired arousal in the absence of delirium is associated with 6‐month mortality. To minimize residual confounding, we used the inverse weighted propensity score, but we acknowledge that this bias may still exist. Larger studies are needed to clarify the relationships between arousal, delirium, and mortality.

CONCLUSION

In conclusion, impaired arousal at initial presentation is an independent predictor for 6‐month mortality in a diverse group of acutely ill older patients, and this risk appears to be present even in the absence of delirium. Because of its ease of use and prognostic significance, it may be a useful vital sign for underlying brain dysfunction. Routine standardized assessment and communication of arousal during routine clinical care may be warranted.

Disclosures: Research reported in this publication was supported by the Vanderbilt Physician Scientist Development Award, Emergency Medicine Foundation, and National Institute on Aging of the National Institutes of Health under award number K23AG032355. This study was also supported by the National Center for Research Resources, grant UL1 RR024975‐01, and is now at the National Center for Advancing Translational Sciences, grant 2 UL1 TR000445‐06. Dr. Vasilevskis was supported in part by the National Institute on Aging of the National Institutes of Health under award number K23AG040157. Dr. Powers was supported by Health Resources and Services Administration Geriatric Education Centers, grant 1D31HP08823‐01‐00. Dr. Storrow was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number K12HL1090 and the National Center for Advancing Translational Sciences under award number UL1TR000445. Dr. Ely was supported in part by the National Institute on Aging of the National Institutes of Health under award numbers R01AG027472 and R01AG035117, and a Veteran Affairs MERIT award. Drs. Vasilevskis, Schnelle, Dittus, Powers, and Ely were supported by the Veteran Affairs Geriatric Research, Education, and Clinical Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of Vanderbilt University, Emergency Medicine Foundation, National Institutes of Health, and Veterans Affairs. The funding agencies did not have any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

J.H.H., E.W.E., J.F.S., A.B.S., and R.D.S. conceived the trial. J.H.H., E.W.E., A.B.S., J.F.S., R.D.S., A.S., and A.W. participated in the study design. J.H.H. and A.W. recruited patients and collected the data. J.H.H., A.J.G., and A.S. analyzed the data. All authors participated in the interpretation of results. J.H.H. drafted the manuscript, and all authors contributed to the critical review and revision of the manuscript.

The authors report no conflicts of interest.