Jerry H. Gurwitz, MD

Antipsychotic medications are frequently used off label for management of behavioral symptoms associated with delirium and/or dementia. Despite regulations designed to curb inappropriate prescribing of these medications in nursing homes, substantial levels of use and variation in use have been observed in this setting.[1] Although antipsychotic medications are also frequently used in the hospital, the scope and variation in use have not been adequately investigated. Given the lack of oversight for medication prescribing in the hospital setting and the frequency of delirium, occurring in 15% to 26% of hospitalized older adults,[2, 3, 4] off‐label use of antipsychotic medications and variation in use could be substantial.

Because variation in practice is known to increase in the setting of controversy or lack of clarity regarding appropriate management,[5] large degrees of variation can draw attention to priority areas for clinical effectiveness studies, and the need for guidelines, clinical decision support, or regulatory oversight. In the absence of clear guidelines for the use of antipsychotic medication in nonpsychiatric hospitalized patients, we hypothesized that significant variation in use would persist after controlling for patient characteristics. Using a large, nationally representative cohort of admissions to 300 hospitals from July 2009 to June 2010, we sought to investigate prescribing patterns and hospital variation in use of antipsychotic medications in nonpsychiatric admissions to US hospitals.

METHODS

RESULTS

Hospital Variation in Antipsychotic Use

Figure 1 demonstrates the antipsychotic prescribing rate at each hospital in our cohort, and the corresponding quintiles. Patients admitted to hospitals in the highest prescribing quintile were more than twice as likely to be exposed to antipsychotics compared to patients admitted to hospitals in the lowest prescribing quintile, even after adjustment for patient characteristics and comorbidities (Table 4). This relationship was similar across subgroups of admissions with delirium and dementia (see Supporting Information, Appendix, in the online version of this article for the distribution of hospital antipsychotic prescribing rates before and after adjustment for patient characteristics).

Table 4.Relative Risk of Antipsychotic Exposure for Admissions Within Each Hospital Prescribing Quintile, Overall, and Stratified by Delirium and Dementia

	Admissions, No. (% of Total)	Unadjusted RR of Exposure [95% CI]	Adjusted RR of exposure [95% CI]*
NOTE: Abbreviations: CI, confidence interval; Q, quintile; RR, relative risk. *Adjusted for all patient characteristics listed in Table 1 (except discharge disposition), as well as the Elixhauser comorbidities, using a generalized estimating equation with a Poisson error term, a log link, and an exchangeable correlation structure to account for repeated admissions of the same patient during the study. Antipsychotic prescribing rates for hospitals within each quintile were: Q1: <4.6%, Q2: 4.6%5.6%, Q3: 5.7%6.3%, Q4: 6.4%7.4%, Q5: >7.4%.
Overall
Q1	431,017 (16%)	Reference	Reference
Q2	630,486 (23%)	1.67 [1.63, 1.71]	1.59 [1.55, 1.62]
Q3	548,337 (20%)	1.93 [1.88, 1.97]	1.84 [1.80, 1.88]
Q4	639,027 (24%)	2.16 [2.12, 2.21]	2.07 [2.03, 2.12]
Q5	446,214 (17%)	2.83 [2.77, 2.89]	2.56 [2.50, 2.61]
Delirium
Q1	12,878 (15%)	Reference	Reference
Q2	20,588 (24%)	1.58 [1.51, 1.65]	1.58 [1.51, 1.65]
Q3	17,402 (20%)	1.71 [1.64, 1.80]	1.73 [1.65, 1.82]
Q4	20,943 (24%)	2.01 [1.92, 2.10]	1.99 [1.91, 2.08]
Q5	14,883 (17%)	2.15 [2.05, 2.25]	2.16 [2.07, 2.26]
Dementia
Q1	28,290 (15%)	Reference	Reference
Q2	42,018 (22%)	1.43 [1.36, 1.50]	1.40 [1.34, 1.47]
Q3	38,593 (21%)	1.61 [1.53, 1.69]	1.59 [1.51, 1.66]
Q4	44,638 (24%)	1.69 [1.62, 1.77]	1.69 [1.61, 1.77]
Q5	34,442 (18%)	1.92 [1.83, 2.01]	1.90 [1.81, 1.99]

Figure 1

DISCUSSION

In this cohort of nonpsychiatric admissions to 300 US hospitals, antipsychotic medications were used in 6% of admissions, with atypical antipsychotics representing the majority of use. Potentially excessive daily doses based on CMS recommendations for long‐term care facilities occurred in almost half of admissions with any antipsychotic exposure, and in 87% of admissions with haloperidol exposure specifically. We found variation in hospital use of antipsychotics that was not fully accounted for by measured patient characteristics, and which persisted among subgroups of admissions with delirium and/or dementia. Although unmeasured patient characteristics or different billing practices between hospitals are potential explanations, our findings also raise the possibility of different hospital antipsychotic prescribing cultures. These findings provide new information regarding the scope of prescribing in US hospitals, and draw attention to the need for additional studies to better define what constitutes appropriate use of antipsychotics in the hospital setting.

A recent single‐center study at a large academic medical center found an overall antipsychotic exposure rate of 9% of nonpsychiatric admissions.[12] Our finding that 6% of admissions in this multicenter cohort were exposed to antipsychotics is slightly lower, but similar to the previous estimate. Assuming 37 million discharges from US hospitals each year,[13] our study suggests that more than 2 million hospitalized patients receive antipsychotics annually. With around 1.4 million residents in nursing homes on any given day,[14] and an exposure rate of 25% to 30% in that setting,[15, 16, 17] our study suggests that the number of patients exposed in the hospital setting is greater than the number exposed in the nursing home setting, the site of care for which prescribing regulations have been focused thus far.

Because our dataset does not contain preadmission medications, we were unable to specifically investigate new initiation. In the prior single‐center study, approximately 55% of overall use in the hospital setting was new initiation,[12] which would suggest that antipsychotics are newly initiated in around 1 million admissions each year in the hospital. Although we are unable to determine reason for use in our analysis, delirium was a strong predictor of antipsychotic use in our multivariable model, and prior studies have demonstrated delirium to be the most common reason for antipsychotic initiation in hospitalized patients,[12, 18] an indication for which efficacy/effectiveness data are lacking. A recent systematic review of antipsychotics for the treatment of delirium in older adults concluded that because of severe methodological limitations, the small number of existing studies on this topic do not support the use of antipsychotics in the treatment of delirium in older hospitalized adults.[19] Our results further highlight the need for randomized placebo‐controlled trials of antipsychotics in treatment of delirium.

We found variation in antipsychotic use between hospitals that was not fully explained by patient characteristics. Insufficient data to inform clinical decisions surrounding management of agitated delirium/dementia and lack of clear criteria by which to judge appropriateness of antipsychotic use may contribute to this variation. Some variation may relate to resource allocation at different hospitals, and the feasibility of implementing nonpharmacologic management options across settings. Our results collectively highlight the need for studies evaluating the efficacy/effectiveness of antipsychotics in the treatment of delirium and drivers of physician decision‐making in this realm, as well as the need for greater hospital investment in nonpharmacologic delirium‐prevention programs, which have been shown to be effective in prevention of delirium in hospitalized patients.[20]

We observed high levels of potentially excessive daily dosing using cutoffs applied in the long‐term care setting. The majority of the potentially excessive doses were in the setting of typical antipsychotic use, and haloperidol specifically, where doses exceeded 4 mg on at least 1 day in 87% of exposed admissions. Of note, the threshold for haloperidol dosage above which justification is required was decreased from 4 to 2 mg per day in the 2015 update to the CMS guidelines.[21] For the present analysis, we used the guidelines that were contemporaneous to our cohort; we are unable to determine current rates of potentially inappropriate dosages in the present analysis, but given the high prevalence in 2009 to 2010, and the lowering of the dosage threshold since then, it is unlikely that any decrease in use would be enough to substantially reduce the estimate. Whether these high dosages are actually inappropriate in the hospital setting is not established, and we were not able to review medical records to determine whether justification for use of such doses was documented.[22, 23] It is possible that hospitalized patients with altered pharmacodynamics and greater severity of illness could require larger doses of these medications; however, this is an area in need of further investigation, and current critical care guidelines note the lack of sufficient data upon which to justify use of haloperidol in the prevention or treatment of delirium in ICU patients.[24, 25]

The dosages in use are concerning given that the risk of extrapyramidal side effects increases with increasing dose, and prior studies have demonstrated an association between increased dose of antipsychotics and increased risk of other adverse events, including hip fracture and sudden cardiac death.[22, 23] Further, despite these known risks, studies have demonstrated failure to follow recommendations to mitigate risk,[26] such as electrocardiogram monitoring in individuals receiving intravenous haloperidol.[27] Our results suggest that physicians are similarly not following recommendations to use lower doses of haloperidol when treating older patients, given the almost identical incidence of potentially excessive dosing among admissions of patients aged 65 years and older in our cohort.[25] Clinical decision support prompts have been effective at increasing appropriate use of antipsychotic medications in several single‐center analyses,[28, 29, 30] and widespread implementation of such support with a focus on haloperidol dosing should be considered on the basis of our results.

The patient characteristics associated with antipsychotic use in this large, nationally representative analysis are consistent with those identified in prior single‐center analyses.[12, 18] Both prior analyses identified delirium as the most common reason for antipsychotic use, and dementia, intensive care unit stay, and mechanical ventilation were also previously identified as strong predictors of use that we believe hold face validity for the practicing hospitalist. On the other hand, some of the factors associated with antipsychotic use in our model cannot be readily explained, such as insurance status and race, and may be serving as proxies for other variables not included in our analysis. That nonwhite patients are less likely than white patients to receive antipsychotic medications in the hospital has been previously demonstrated,[12] and further investigation to understand this disparity is warranted.

Our study has several additional limitations. First, because our study is observational, the possibility of residual confounding exists, and we cannot rule out that there are other patient factors driving the hospital variation in antipsychotic use that we observed. Second, because guidelines do not exist for antipsychotic dosing in hospitalized patients, we could only comment on potentially excessive dosing, extrapolating from guidelines in the long‐term care setting. Whether such doses are actually excessive in hospitalized patients is not defined. Third, although Premier performs quality checks on charge and ICD‐9‐CM coding data submitted by participating hospitals, the validity of administrative data is uncertain. For example, the use of administrative data to identify delirium diagnoses is likely to have resulted in underestimation of delirium incidence among our different exposure groups. Delirium is likely to be coded more often in the setting of more severe or hyperactive cases, when antipsychotics are more likely to be utilized. This could result in an overestimation of the association between delirium and antipsychotic use. Additionally, differences in coding practices between hospitals for any of the variables in our models could explain some of the variation in antipsychotic prescribing that we observed. Finally, because we were unable to differentiate between new initiation and continuation of a preadmission antipsychotic, some of the variation that we observed is likely to reflect differences in outpatient antipsychotic prescribing practices.

In conclusion, in this large cohort of nonpsychiatric admissions to 300 US hospitals, we found that antipsychotic medication exposure was common, often at high daily doses. Delirium and dementia were the strongest predictors of use among the patient and hospital characteristics examined. The variation in antipsychotic prescribing that we observed was not fully accounted for by measured patient characteristics, and raises the possibility of differing hospital prescribing cultures. Our results draw attention to the need for additional research to better define what constitutes appropriate use of these potentially harmful medications in the hospital setting.

Disclosures: Dr. Herzig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Drs. Herzig, Rothberg, Gurwitz, and Marcantonio. Acquisition of data: Dr. Herzig. Analysis of data: Mr. Guess. Interpretation of data: Drs. Herzig, Rothberg, Gurwitz, Marcantonio, and Mr. Guess. Drafting of the manuscript: Dr. Herzig. Critical revision of the manuscript for important intellectual content: Drs. Rothberg, Gurwitz, Marcantonio, and Mr. Guess. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Marcantonio was funded by grant number K24AG035075 from the National Institute on Aging. The funding organizations had no involvement in any aspect of the study, including design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors report no conflicts of interest.

Antipsychotic medications are frequently used off label for management of behavioral symptoms associated with delirium and/or dementia. Despite regulations designed to curb inappropriate prescribing of these medications in nursing homes, substantial levels of use and variation in use have been observed in this setting.[1] Although antipsychotic medications are also frequently used in the hospital, the scope and variation in use have not been adequately investigated. Given the lack of oversight for medication prescribing in the hospital setting and the frequency of delirium, occurring in 15% to 26% of hospitalized older adults,[2, 3, 4] off‐label use of antipsychotic medications and variation in use could be substantial.

Because variation in practice is known to increase in the setting of controversy or lack of clarity regarding appropriate management,[5] large degrees of variation can draw attention to priority areas for clinical effectiveness studies, and the need for guidelines, clinical decision support, or regulatory oversight. In the absence of clear guidelines for the use of antipsychotic medication in nonpsychiatric hospitalized patients, we hypothesized that significant variation in use would persist after controlling for patient characteristics. Using a large, nationally representative cohort of admissions to 300 hospitals from July 2009 to June 2010, we sought to investigate prescribing patterns and hospital variation in use of antipsychotic medications in nonpsychiatric admissions to US hospitals.

METHODS

RESULTS

Hospital Variation in Antipsychotic Use

Figure 1 demonstrates the antipsychotic prescribing rate at each hospital in our cohort, and the corresponding quintiles. Patients admitted to hospitals in the highest prescribing quintile were more than twice as likely to be exposed to antipsychotics compared to patients admitted to hospitals in the lowest prescribing quintile, even after adjustment for patient characteristics and comorbidities (Table 4). This relationship was similar across subgroups of admissions with delirium and dementia (see Supporting Information, Appendix, in the online version of this article for the distribution of hospital antipsychotic prescribing rates before and after adjustment for patient characteristics).

Table 4.Relative Risk of Antipsychotic Exposure for Admissions Within Each Hospital Prescribing Quintile, Overall, and Stratified by Delirium and Dementia

	Admissions, No. (% of Total)	Unadjusted RR of Exposure [95% CI]	Adjusted RR of exposure [95% CI]*
NOTE: Abbreviations: CI, confidence interval; Q, quintile; RR, relative risk. *Adjusted for all patient characteristics listed in Table 1 (except discharge disposition), as well as the Elixhauser comorbidities, using a generalized estimating equation with a Poisson error term, a log link, and an exchangeable correlation structure to account for repeated admissions of the same patient during the study. Antipsychotic prescribing rates for hospitals within each quintile were: Q1: <4.6%, Q2: 4.6%5.6%, Q3: 5.7%6.3%, Q4: 6.4%7.4%, Q5: >7.4%.
Overall
Q1	431,017 (16%)	Reference	Reference
Q2	630,486 (23%)	1.67 [1.63, 1.71]	1.59 [1.55, 1.62]
Q3	548,337 (20%)	1.93 [1.88, 1.97]	1.84 [1.80, 1.88]
Q4	639,027 (24%)	2.16 [2.12, 2.21]	2.07 [2.03, 2.12]
Q5	446,214 (17%)	2.83 [2.77, 2.89]	2.56 [2.50, 2.61]
Delirium
Q1	12,878 (15%)	Reference	Reference
Q2	20,588 (24%)	1.58 [1.51, 1.65]	1.58 [1.51, 1.65]
Q3	17,402 (20%)	1.71 [1.64, 1.80]	1.73 [1.65, 1.82]
Q4	20,943 (24%)	2.01 [1.92, 2.10]	1.99 [1.91, 2.08]
Q5	14,883 (17%)	2.15 [2.05, 2.25]	2.16 [2.07, 2.26]
Dementia
Q1	28,290 (15%)	Reference	Reference
Q2	42,018 (22%)	1.43 [1.36, 1.50]	1.40 [1.34, 1.47]
Q3	38,593 (21%)	1.61 [1.53, 1.69]	1.59 [1.51, 1.66]
Q4	44,638 (24%)	1.69 [1.62, 1.77]	1.69 [1.61, 1.77]
Q5	34,442 (18%)	1.92 [1.83, 2.01]	1.90 [1.81, 1.99]

Figure 1

DISCUSSION

In this cohort of nonpsychiatric admissions to 300 US hospitals, antipsychotic medications were used in 6% of admissions, with atypical antipsychotics representing the majority of use. Potentially excessive daily doses based on CMS recommendations for long‐term care facilities occurred in almost half of admissions with any antipsychotic exposure, and in 87% of admissions with haloperidol exposure specifically. We found variation in hospital use of antipsychotics that was not fully accounted for by measured patient characteristics, and which persisted among subgroups of admissions with delirium and/or dementia. Although unmeasured patient characteristics or different billing practices between hospitals are potential explanations, our findings also raise the possibility of different hospital antipsychotic prescribing cultures. These findings provide new information regarding the scope of prescribing in US hospitals, and draw attention to the need for additional studies to better define what constitutes appropriate use of antipsychotics in the hospital setting.

A recent single‐center study at a large academic medical center found an overall antipsychotic exposure rate of 9% of nonpsychiatric admissions.[12] Our finding that 6% of admissions in this multicenter cohort were exposed to antipsychotics is slightly lower, but similar to the previous estimate. Assuming 37 million discharges from US hospitals each year,[13] our study suggests that more than 2 million hospitalized patients receive antipsychotics annually. With around 1.4 million residents in nursing homes on any given day,[14] and an exposure rate of 25% to 30% in that setting,[15, 16, 17] our study suggests that the number of patients exposed in the hospital setting is greater than the number exposed in the nursing home setting, the site of care for which prescribing regulations have been focused thus far.

Because our dataset does not contain preadmission medications, we were unable to specifically investigate new initiation. In the prior single‐center study, approximately 55% of overall use in the hospital setting was new initiation,[12] which would suggest that antipsychotics are newly initiated in around 1 million admissions each year in the hospital. Although we are unable to determine reason for use in our analysis, delirium was a strong predictor of antipsychotic use in our multivariable model, and prior studies have demonstrated delirium to be the most common reason for antipsychotic initiation in hospitalized patients,[12, 18] an indication for which efficacy/effectiveness data are lacking. A recent systematic review of antipsychotics for the treatment of delirium in older adults concluded that because of severe methodological limitations, the small number of existing studies on this topic do not support the use of antipsychotics in the treatment of delirium in older hospitalized adults.[19] Our results further highlight the need for randomized placebo‐controlled trials of antipsychotics in treatment of delirium.

We found variation in antipsychotic use between hospitals that was not fully explained by patient characteristics. Insufficient data to inform clinical decisions surrounding management of agitated delirium/dementia and lack of clear criteria by which to judge appropriateness of antipsychotic use may contribute to this variation. Some variation may relate to resource allocation at different hospitals, and the feasibility of implementing nonpharmacologic management options across settings. Our results collectively highlight the need for studies evaluating the efficacy/effectiveness of antipsychotics in the treatment of delirium and drivers of physician decision‐making in this realm, as well as the need for greater hospital investment in nonpharmacologic delirium‐prevention programs, which have been shown to be effective in prevention of delirium in hospitalized patients.[20]

We observed high levels of potentially excessive daily dosing using cutoffs applied in the long‐term care setting. The majority of the potentially excessive doses were in the setting of typical antipsychotic use, and haloperidol specifically, where doses exceeded 4 mg on at least 1 day in 87% of exposed admissions. Of note, the threshold for haloperidol dosage above which justification is required was decreased from 4 to 2 mg per day in the 2015 update to the CMS guidelines.[21] For the present analysis, we used the guidelines that were contemporaneous to our cohort; we are unable to determine current rates of potentially inappropriate dosages in the present analysis, but given the high prevalence in 2009 to 2010, and the lowering of the dosage threshold since then, it is unlikely that any decrease in use would be enough to substantially reduce the estimate. Whether these high dosages are actually inappropriate in the hospital setting is not established, and we were not able to review medical records to determine whether justification for use of such doses was documented.[22, 23] It is possible that hospitalized patients with altered pharmacodynamics and greater severity of illness could require larger doses of these medications; however, this is an area in need of further investigation, and current critical care guidelines note the lack of sufficient data upon which to justify use of haloperidol in the prevention or treatment of delirium in ICU patients.[24, 25]

The dosages in use are concerning given that the risk of extrapyramidal side effects increases with increasing dose, and prior studies have demonstrated an association between increased dose of antipsychotics and increased risk of other adverse events, including hip fracture and sudden cardiac death.[22, 23] Further, despite these known risks, studies have demonstrated failure to follow recommendations to mitigate risk,[26] such as electrocardiogram monitoring in individuals receiving intravenous haloperidol.[27] Our results suggest that physicians are similarly not following recommendations to use lower doses of haloperidol when treating older patients, given the almost identical incidence of potentially excessive dosing among admissions of patients aged 65 years and older in our cohort.[25] Clinical decision support prompts have been effective at increasing appropriate use of antipsychotic medications in several single‐center analyses,[28, 29, 30] and widespread implementation of such support with a focus on haloperidol dosing should be considered on the basis of our results.

The patient characteristics associated with antipsychotic use in this large, nationally representative analysis are consistent with those identified in prior single‐center analyses.[12, 18] Both prior analyses identified delirium as the most common reason for antipsychotic use, and dementia, intensive care unit stay, and mechanical ventilation were also previously identified as strong predictors of use that we believe hold face validity for the practicing hospitalist. On the other hand, some of the factors associated with antipsychotic use in our model cannot be readily explained, such as insurance status and race, and may be serving as proxies for other variables not included in our analysis. That nonwhite patients are less likely than white patients to receive antipsychotic medications in the hospital has been previously demonstrated,[12] and further investigation to understand this disparity is warranted.

Our study has several additional limitations. First, because our study is observational, the possibility of residual confounding exists, and we cannot rule out that there are other patient factors driving the hospital variation in antipsychotic use that we observed. Second, because guidelines do not exist for antipsychotic dosing in hospitalized patients, we could only comment on potentially excessive dosing, extrapolating from guidelines in the long‐term care setting. Whether such doses are actually excessive in hospitalized patients is not defined. Third, although Premier performs quality checks on charge and ICD‐9‐CM coding data submitted by participating hospitals, the validity of administrative data is uncertain. For example, the use of administrative data to identify delirium diagnoses is likely to have resulted in underestimation of delirium incidence among our different exposure groups. Delirium is likely to be coded more often in the setting of more severe or hyperactive cases, when antipsychotics are more likely to be utilized. This could result in an overestimation of the association between delirium and antipsychotic use. Additionally, differences in coding practices between hospitals for any of the variables in our models could explain some of the variation in antipsychotic prescribing that we observed. Finally, because we were unable to differentiate between new initiation and continuation of a preadmission antipsychotic, some of the variation that we observed is likely to reflect differences in outpatient antipsychotic prescribing practices.

In conclusion, in this large cohort of nonpsychiatric admissions to 300 US hospitals, we found that antipsychotic medication exposure was common, often at high daily doses. Delirium and dementia were the strongest predictors of use among the patient and hospital characteristics examined. The variation in antipsychotic prescribing that we observed was not fully accounted for by measured patient characteristics, and raises the possibility of differing hospital prescribing cultures. Our results draw attention to the need for additional research to better define what constitutes appropriate use of these potentially harmful medications in the hospital setting.

Disclosures: Dr. Herzig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Drs. Herzig, Rothberg, Gurwitz, and Marcantonio. Acquisition of data: Dr. Herzig. Analysis of data: Mr. Guess. Interpretation of data: Drs. Herzig, Rothberg, Gurwitz, Marcantonio, and Mr. Guess. Drafting of the manuscript: Dr. Herzig. Critical revision of the manuscript for important intellectual content: Drs. Rothberg, Gurwitz, Marcantonio, and Mr. Guess. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Marcantonio was funded by grant number K24AG035075 from the National Institute on Aging. The funding organizations had no involvement in any aspect of the study, including design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors report no conflicts of interest.

Antipsychotic medications are frequently used off label for management of behavioral symptoms associated with delirium and/or dementia. Despite regulations designed to curb inappropriate prescribing of these medications in nursing homes, substantial levels of use and variation in use have been observed in this setting.[1] Although antipsychotic medications are also frequently used in the hospital, the scope and variation in use have not been adequately investigated. Given the lack of oversight for medication prescribing in the hospital setting and the frequency of delirium, occurring in 15% to 26% of hospitalized older adults,[2, 3, 4] off‐label use of antipsychotic medications and variation in use could be substantial.

Because variation in practice is known to increase in the setting of controversy or lack of clarity regarding appropriate management,[5] large degrees of variation can draw attention to priority areas for clinical effectiveness studies, and the need for guidelines, clinical decision support, or regulatory oversight. In the absence of clear guidelines for the use of antipsychotic medication in nonpsychiatric hospitalized patients, we hypothesized that significant variation in use would persist after controlling for patient characteristics. Using a large, nationally representative cohort of admissions to 300 hospitals from July 2009 to June 2010, we sought to investigate prescribing patterns and hospital variation in use of antipsychotic medications in nonpsychiatric admissions to US hospitals.

METHODS

RESULTS

Hospital Variation in Antipsychotic Use

Figure 1 demonstrates the antipsychotic prescribing rate at each hospital in our cohort, and the corresponding quintiles. Patients admitted to hospitals in the highest prescribing quintile were more than twice as likely to be exposed to antipsychotics compared to patients admitted to hospitals in the lowest prescribing quintile, even after adjustment for patient characteristics and comorbidities (Table 4). This relationship was similar across subgroups of admissions with delirium and dementia (see Supporting Information, Appendix, in the online version of this article for the distribution of hospital antipsychotic prescribing rates before and after adjustment for patient characteristics).

Table 4.Relative Risk of Antipsychotic Exposure for Admissions Within Each Hospital Prescribing Quintile, Overall, and Stratified by Delirium and Dementia

	Admissions, No. (% of Total)	Unadjusted RR of Exposure [95% CI]	Adjusted RR of exposure [95% CI]*
NOTE: Abbreviations: CI, confidence interval; Q, quintile; RR, relative risk. *Adjusted for all patient characteristics listed in Table 1 (except discharge disposition), as well as the Elixhauser comorbidities, using a generalized estimating equation with a Poisson error term, a log link, and an exchangeable correlation structure to account for repeated admissions of the same patient during the study. Antipsychotic prescribing rates for hospitals within each quintile were: Q1: <4.6%, Q2: 4.6%5.6%, Q3: 5.7%6.3%, Q4: 6.4%7.4%, Q5: >7.4%.
Overall
Q1	431,017 (16%)	Reference	Reference
Q2	630,486 (23%)	1.67 [1.63, 1.71]	1.59 [1.55, 1.62]
Q3	548,337 (20%)	1.93 [1.88, 1.97]	1.84 [1.80, 1.88]
Q4	639,027 (24%)	2.16 [2.12, 2.21]	2.07 [2.03, 2.12]
Q5	446,214 (17%)	2.83 [2.77, 2.89]	2.56 [2.50, 2.61]
Delirium
Q1	12,878 (15%)	Reference	Reference
Q2	20,588 (24%)	1.58 [1.51, 1.65]	1.58 [1.51, 1.65]
Q3	17,402 (20%)	1.71 [1.64, 1.80]	1.73 [1.65, 1.82]
Q4	20,943 (24%)	2.01 [1.92, 2.10]	1.99 [1.91, 2.08]
Q5	14,883 (17%)	2.15 [2.05, 2.25]	2.16 [2.07, 2.26]
Dementia
Q1	28,290 (15%)	Reference	Reference
Q2	42,018 (22%)	1.43 [1.36, 1.50]	1.40 [1.34, 1.47]
Q3	38,593 (21%)	1.61 [1.53, 1.69]	1.59 [1.51, 1.66]
Q4	44,638 (24%)	1.69 [1.62, 1.77]	1.69 [1.61, 1.77]
Q5	34,442 (18%)	1.92 [1.83, 2.01]	1.90 [1.81, 1.99]

Figure 1

DISCUSSION

In this cohort of nonpsychiatric admissions to 300 US hospitals, antipsychotic medications were used in 6% of admissions, with atypical antipsychotics representing the majority of use. Potentially excessive daily doses based on CMS recommendations for long‐term care facilities occurred in almost half of admissions with any antipsychotic exposure, and in 87% of admissions with haloperidol exposure specifically. We found variation in hospital use of antipsychotics that was not fully accounted for by measured patient characteristics, and which persisted among subgroups of admissions with delirium and/or dementia. Although unmeasured patient characteristics or different billing practices between hospitals are potential explanations, our findings also raise the possibility of different hospital antipsychotic prescribing cultures. These findings provide new information regarding the scope of prescribing in US hospitals, and draw attention to the need for additional studies to better define what constitutes appropriate use of antipsychotics in the hospital setting.

A recent single‐center study at a large academic medical center found an overall antipsychotic exposure rate of 9% of nonpsychiatric admissions.[12] Our finding that 6% of admissions in this multicenter cohort were exposed to antipsychotics is slightly lower, but similar to the previous estimate. Assuming 37 million discharges from US hospitals each year,[13] our study suggests that more than 2 million hospitalized patients receive antipsychotics annually. With around 1.4 million residents in nursing homes on any given day,[14] and an exposure rate of 25% to 30% in that setting,[15, 16, 17] our study suggests that the number of patients exposed in the hospital setting is greater than the number exposed in the nursing home setting, the site of care for which prescribing regulations have been focused thus far.

Because our dataset does not contain preadmission medications, we were unable to specifically investigate new initiation. In the prior single‐center study, approximately 55% of overall use in the hospital setting was new initiation,[12] which would suggest that antipsychotics are newly initiated in around 1 million admissions each year in the hospital. Although we are unable to determine reason for use in our analysis, delirium was a strong predictor of antipsychotic use in our multivariable model, and prior studies have demonstrated delirium to be the most common reason for antipsychotic initiation in hospitalized patients,[12, 18] an indication for which efficacy/effectiveness data are lacking. A recent systematic review of antipsychotics for the treatment of delirium in older adults concluded that because of severe methodological limitations, the small number of existing studies on this topic do not support the use of antipsychotics in the treatment of delirium in older hospitalized adults.[19] Our results further highlight the need for randomized placebo‐controlled trials of antipsychotics in treatment of delirium.

We found variation in antipsychotic use between hospitals that was not fully explained by patient characteristics. Insufficient data to inform clinical decisions surrounding management of agitated delirium/dementia and lack of clear criteria by which to judge appropriateness of antipsychotic use may contribute to this variation. Some variation may relate to resource allocation at different hospitals, and the feasibility of implementing nonpharmacologic management options across settings. Our results collectively highlight the need for studies evaluating the efficacy/effectiveness of antipsychotics in the treatment of delirium and drivers of physician decision‐making in this realm, as well as the need for greater hospital investment in nonpharmacologic delirium‐prevention programs, which have been shown to be effective in prevention of delirium in hospitalized patients.[20]

We observed high levels of potentially excessive daily dosing using cutoffs applied in the long‐term care setting. The majority of the potentially excessive doses were in the setting of typical antipsychotic use, and haloperidol specifically, where doses exceeded 4 mg on at least 1 day in 87% of exposed admissions. Of note, the threshold for haloperidol dosage above which justification is required was decreased from 4 to 2 mg per day in the 2015 update to the CMS guidelines.[21] For the present analysis, we used the guidelines that were contemporaneous to our cohort; we are unable to determine current rates of potentially inappropriate dosages in the present analysis, but given the high prevalence in 2009 to 2010, and the lowering of the dosage threshold since then, it is unlikely that any decrease in use would be enough to substantially reduce the estimate. Whether these high dosages are actually inappropriate in the hospital setting is not established, and we were not able to review medical records to determine whether justification for use of such doses was documented.[22, 23] It is possible that hospitalized patients with altered pharmacodynamics and greater severity of illness could require larger doses of these medications; however, this is an area in need of further investigation, and current critical care guidelines note the lack of sufficient data upon which to justify use of haloperidol in the prevention or treatment of delirium in ICU patients.[24, 25]

The dosages in use are concerning given that the risk of extrapyramidal side effects increases with increasing dose, and prior studies have demonstrated an association between increased dose of antipsychotics and increased risk of other adverse events, including hip fracture and sudden cardiac death.[22, 23] Further, despite these known risks, studies have demonstrated failure to follow recommendations to mitigate risk,[26] such as electrocardiogram monitoring in individuals receiving intravenous haloperidol.[27] Our results suggest that physicians are similarly not following recommendations to use lower doses of haloperidol when treating older patients, given the almost identical incidence of potentially excessive dosing among admissions of patients aged 65 years and older in our cohort.[25] Clinical decision support prompts have been effective at increasing appropriate use of antipsychotic medications in several single‐center analyses,[28, 29, 30] and widespread implementation of such support with a focus on haloperidol dosing should be considered on the basis of our results.

The patient characteristics associated with antipsychotic use in this large, nationally representative analysis are consistent with those identified in prior single‐center analyses.[12, 18] Both prior analyses identified delirium as the most common reason for antipsychotic use, and dementia, intensive care unit stay, and mechanical ventilation were also previously identified as strong predictors of use that we believe hold face validity for the practicing hospitalist. On the other hand, some of the factors associated with antipsychotic use in our model cannot be readily explained, such as insurance status and race, and may be serving as proxies for other variables not included in our analysis. That nonwhite patients are less likely than white patients to receive antipsychotic medications in the hospital has been previously demonstrated,[12] and further investigation to understand this disparity is warranted.

Our study has several additional limitations. First, because our study is observational, the possibility of residual confounding exists, and we cannot rule out that there are other patient factors driving the hospital variation in antipsychotic use that we observed. Second, because guidelines do not exist for antipsychotic dosing in hospitalized patients, we could only comment on potentially excessive dosing, extrapolating from guidelines in the long‐term care setting. Whether such doses are actually excessive in hospitalized patients is not defined. Third, although Premier performs quality checks on charge and ICD‐9‐CM coding data submitted by participating hospitals, the validity of administrative data is uncertain. For example, the use of administrative data to identify delirium diagnoses is likely to have resulted in underestimation of delirium incidence among our different exposure groups. Delirium is likely to be coded more often in the setting of more severe or hyperactive cases, when antipsychotics are more likely to be utilized. This could result in an overestimation of the association between delirium and antipsychotic use. Additionally, differences in coding practices between hospitals for any of the variables in our models could explain some of the variation in antipsychotic prescribing that we observed. Finally, because we were unable to differentiate between new initiation and continuation of a preadmission antipsychotic, some of the variation that we observed is likely to reflect differences in outpatient antipsychotic prescribing practices.

In conclusion, in this large cohort of nonpsychiatric admissions to 300 US hospitals, we found that antipsychotic medication exposure was common, often at high daily doses. Delirium and dementia were the strongest predictors of use among the patient and hospital characteristics examined. The variation in antipsychotic prescribing that we observed was not fully accounted for by measured patient characteristics, and raises the possibility of differing hospital prescribing cultures. Our results draw attention to the need for additional research to better define what constitutes appropriate use of these potentially harmful medications in the hospital setting.

Disclosures: Dr. Herzig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Drs. Herzig, Rothberg, Gurwitz, and Marcantonio. Acquisition of data: Dr. Herzig. Analysis of data: Mr. Guess. Interpretation of data: Drs. Herzig, Rothberg, Gurwitz, Marcantonio, and Mr. Guess. Drafting of the manuscript: Dr. Herzig. Critical revision of the manuscript for important intellectual content: Drs. Rothberg, Gurwitz, Marcantonio, and Mr. Guess. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Marcantonio was funded by grant number K24AG035075 from the National Institute on Aging. The funding organizations had no involvement in any aspect of the study, including design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors report no conflicts of interest.