Neurocrit Care DOI 10.1007/s12028-014-9985-8
ORIGINAL ARTICLE
Potentially Inappropriate Medication Use is Associated with Clinical Outcomes in Critically Ill Elderly Patients with Neurological Injury Catherine K. Floroff • Patricia W. Slattum • Spencer E. Harpe • Perry Taylor • Gretchen M. Brophy
Ó Springer Science+Business Media New York 2014
Abstract Background Limited data suggest that potentially inappropriate medications (PIMs) impact outcomes in critically ill elderly patients. No data are available on the association between PIM use as well as drug burden index (DBI), which is a measure of PIM use, and clinical outcomes in neurocritical care elderly patients. This study evaluates whether PIM use and a higher DBI are associated with poor clinical outcomes in neurocritical care elderly patients. Methods PIMs were retrospectively identified in critically ill elderly patients admitted to the neuroscience intensive care unit (NSICU) from March to July 2011. DBI was calculated based on PIM doses. Relationships with clinical outcomes were evaluated.
C. K. Floroff P. W. Slattum G. M. Brophy (&) School of Pharmacy, Virginia Commonwealth University, 410 N. 12th Street, Richmond, VA 23298-0533, USA e-mail: [email protected] C. K. Floroff e-mail: [email protected] P. W. Slattum e-mail: [email protected] S. E. Harpe Chicago College of Pharmacy, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA e-mail: [email protected] P. Taylor Virginia Commonwealth University Health System, 401 N. 12th Street, P.O. Box 980042, Richmond, VA 23298, USA e-mail: [email protected]
Results PIMs were prescribed to a majority (81.3 %) of the 112 patients. Opioids were most commonly associated with a decrease in Richmond Agitation Sedation Scale (RASS) scores (56 % of PIM doses). Time to recovery was significantly longer in patients with a higher PIM burden (B2 PIMs: 8 h, >2 PIMs: 29 h; p = 0.02). There was a significantly longer NSICU and hospital length of stay (9 vs 2; 15 vs 5 days; p < 0.0001) as well as a lower Glasgow Coma Scale score upon discharge (14 vs 15, p = 0.02) in patients with a higher DBI after 72 h of hospitalization. There was no difference in mortality. Conclusions PIM use and higher DBI scores were associated with poor clinical outcomes and longer lengths of stay. Further studies are needed to determine the impact of PIMs and DBI on mortality in neurocritical care elderly patients. Keywords Aging Elderly Older adult Critically ill Potentially inappropriate medication(s) Drug burden index Neurological injury
Introduction In the US, patients over 85 years of age represent the fastest growing segment of the older adult population [1]. In addition, older adult patients (aged C 65 years) account for 42– 52 % of all intensive care unit (ICU) admissions and 60 % of all ICU days [2]. Considering these demographic and healthcare utilization patterns, interest in the use of potentially inappropriate medications (PIMs) that can increase cognitive and functional burden in elderly hospitalized patients has also grown. A PIM is a medication having potential risks that outweigh its potential benefits in an elderly patient [3]. Use of PIMs is one risk factor for adverse
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drug reactions and is related to increased health-related expenditures in elderly patients [3, 4]. Originally, the concern with use of PIMs in elderly adults led to the creation of a set of explicit criteria commonly referred to as the Beers Criteria [5]. It was first developed by an expert consensus panel for nursing home patients but has been updated (most recently in 2012) to apply to elderly patients in all clinical settings. Despite updates to the original version of the Beers Criteria, there are still concerns that some medications that may be used inappropriately in older patients are not included in the Beers Criteria. Furthermore, studies evaluating the association between the uses of medications included in the Beers Criteria and patient outcomes often find mixed results [6]. This has led to the development of alternative validated criteria for PIM use in elderly patients including Screening Tool of Older Person’s Prescriptions (STOPP) and Screening Tool to Alert Doctors to Right Treatment (START) [7– 9]. Most of the current literature evaluates PIM use among elderly adults living in the community. Recently, PIM use has been studied in hospitalized non-ICU elderly patients. The prevalence of PIMs was 44 % using the Medication Appropriateness Index [10], 11.56–56.1 % using the Beers Criteria [11–19], 22–36.2 % using STOPP and/or START [20, 21], and 25–49 % using a combination of criteria [22– 24]. Associations between PIMs and outcomes, such as inhospital mortality and length of stay (LOS), are inconsistent [11–13, 15]. Unfortunately, there is limited information regarding PIM use in critically ill elderly patients in the ICU setting, especially in those with neurological injury [26–28]. This is concerning as elderly patients with comorbidities are often taking multiple chronic medications with more medications added to the regimen during the episode of acute illness [25]. Increased medication usage potentially leads to an increased incidence of medication-related problems [29]. However, some PIMs may be reasonably appropriate in elderly ICU patients under certain circumstances. A tailored approach that assesses overall cognitive and functional burden is needed to evaluate PIMs in critically ill elderly patients. The drug burden index (DBI) is another evidence-based tool to measure total exposure to specific PIMs with anticholinergic and/or sedative properties [6]. It considers dose and medications with certain pharmacologic properties. DBI is associated with poor physical and cognitive function as well as functional outcomes, which may be augmented in elderly patients with neurological injury [6]. Reducing the number of PIMs and DBI may improve patient outcomes in the ICU. To our knowledge, no studies have been conducted relating PIMs and DBI to clinical outcomes in ICU patients with neurological injury. The purpose of our study was to
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investigate the use of PIMs and DBI and their associations with clinical outcomes in critically ill elderly patients with neurological injury. Specific aims included: (1) (2)
(3)
Identifying PIMs and determining a DBI for patients during neuroscience ICU (NSICU) admission. Determining if a change in neurological status occurred pre- to post-PIM dosing, using the Glasgow Coma Scale (GCS) and Richmond Agitation and Sedation Scale (RASS) scores as measures of neurological status. Determining if the number of PIMs administered during the ICU stay and DBI, which is calculated based on all PIM doses, is associated with clinical outcomes.
Methods Consecutive adult patients C65 years of age admitted to the NSICU of Virginia Commonwealth University from March 2011 to July 2011 were retrospectively identified through electronic medical records. The VCU Institutional Review Board evaluated the study and approved it as an exempt study. Data collection included demographics, admitting diagnosis, and medications received while in the NSICU. Severity of illness was determined by admission Acute Physiology and Chronic Health Status (APACHE II) score and GCS. The Charlson Comorbidity Index (CCI) was calculated as a measure of the impact of comorbid illness [30]. In patients receiving an antiepileptic agent, EEG results, ICD-9-CM codes, and clinical notes were reviewed to assess whether the patient experienced a seizure during their ICU admission. In-hospital mortality, ICU LOS, hospital LOS, and discharge GCS were also recorded to assess clinical outcomes. Existing data (ICD-9-CM procedure codes and electronic medical records) were reviewed to identify PIMs as well as pre- and post-dose GCS and RASS scores. Outcome measures included (a) reduction of GCS score > 2 points, (b) time to recovery (h) of GCS score to baseline, (c) reduction of RASS score with drug administration, (d) recovery of post-dose RASS score to goal of 0 to -1, and (e) and time to recovery (h) of RASS score to 0 to -1, if applicable. PIMs were identified and used to calculate the DBI. Medications with anticholinergic or sedative properties were defined using the updated Beers and STOPP criteria independent of diagnosis, as well as previously published studies [31–34]. PIMs included opioids, antidepressants, antipsychotics, benzodiazepines, neuromuscular blocking agents (NMBA), and other medications that can affect CNS burden such as H2 receptor antagonists (H2RAs), barbiturates, and GI stimulants. Only medications used during the
Neurocrit Care
ICU stay were included in this study. Chronic and ‘‘as needed’’ doses were identified as well as intermittent doses and continuous infusions. Additional information needed to calculate the DBI included dose, route, frequency, duration, and indication. The DBI for each medication was calculated by dividing the daily dose by the recommended minimum daily dose (Dose/Minimum Daily Dose). Total DBI was determined by summing the daily DBI for each PIM. Minimum daily dose was identified by means of Physician’s Desk Reference and the product information of each PIM. The median number of intermittent PIMs (intPIMs) was determined, and patients were divided into 2 groups for comparisons: those receiving B2 intPIMs and those receiving >2 intPIMs. Age categories were also used to determine if differences existed between the younger old versus the oldest old patients. Demographic and clinical variables were summarized using mean and standard deviation (SD), median with interquartile ranges (IQR) if not normally distributed, or percentages. The number of PIMs prescribed per patient was described and analyzed as continuous variables. The Wilcoxon signed rank test was used to compare continuous variables. Dichotomous variables were evaluated using either Pearson’s Chi-square test or Fisher’s exact test. Logistic regression analysis was conducted to determine the impact of confounding variables, including APACHE II and CCI. Statistical significance was defined as p < 0.05, and all statistical analyses were carried out in Stata SE version 12 (StataCorp LP, College Station, TX).
Results Patient Characteristics There were 112 critically ill elderly NSICU patients included in this study. Of these, 76 patients received B2 intPIMs and 36 received >2 intPIMs during NSICU admission. Baseline characteristics were similar between these groups, with the exception of a greater severity of illness observed in patients with >2 intPIMs (Table 1). The primary neurological injury was acute ischemic stroke (AIS) for those receiving B2 intPIMs (32.9 %) and traumatic brain injury (TBI) for those receiving >2 intPIMs (27.8 %). The median (IQR) NSICU LOS, during which PIMs were prescribed, was 2 intPIMs based on age category. A change in RASS score occurred with 50 PIM doses. RASS scores decreased with 28 (56 %) PIM doses and were most frequently associated with opioid use (Fig. 1). Furthermore, all decreased RASS scores were seen in TBI patients. Median (IQR) recovery time to a goal RASS score of 0 to -1 was 29 (8–102) h (p = 0.022) (Table 2). GCS decreased >2 points with 5 PIM doses and all were in TBI patients. Clinical outcomes based on intPIM use are provided in Table 3. The median NSICU LOS and hospital LOS for patients who received B2 intPIMs, as compared to those with >2 intPIMs, were shortened by 2.16 and 4.5 days, respectively, even after adjusting for baseline APACHE II and CCI scores (p < 0.001). There was no statistically significant difference in mortality between groups. Drug Burden Index There was a statistically significant increase in DBI scores for intPIMs based on age category on days 2 and 3 (Table 4). DBI increased significantly by 1.75 in elderly patients C85 years of age compared to those aged 65– 74 years and by 1.27 compared to those aged 75–84 years on day 2 (p = 0.024). On day 3, DBI increased significantly by 1.56 in elderly patients C85 years of age when compared to those aged 65–74 years and by 1.55 in those aged 75–84 years (p = 0.049). There was no statistically significant increase in DBI scores per group based on cIV PIMs (Table 4). Median cumulative DBI scores were 2.5, 4.5, and 5.5 on days 1, 2, 3 of hospitalization; no statistically significant differences in clinical outcomes were seen for patients with DBI scores equal to or above the median. Hospital and NSICU LOS increased significantly for patients with a DBI C 1 compared to those with a DBI = 0 after 72 h of hospitalization, and NSICU as well as hospital LOS was shortened by 3.54 and 4.87 days, respectively, for those with DBI = 0 (adjusted p value < 0.001) (Fig. 2). There was no difference between patients with a DBI C 1 compared to those with a median DBI = 0 on days 1–3. A total DBI of 0 after 72 h of hospitalization is associated with a higher discharge GCS (by 1 point) even after adjusting for APACHE II and CCI scores (adjusted p value = 0.012) (Table 5). There was no statistically significant difference in mortality between the groups.
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Neurocrit Care Table 1 Baseline characteristics
Characteristic
B2 intPIMs (n = 76)
>2 intPIMs (n = 36)
Age, years old median (IQR)
80.3 (73.9–85.3)
75.8 (70.4–81.2)
Age category, n (%) 25 (32.9)
16 (44.4)
75–84
29 (38.2)
12 (33.3)
C85
22 (29)
8 (22.2)
38 (50)
23 (63.9)
Ethnicity, n (%) 46 (60.1)
21 (58.3)
Black
26 (34.2)
13 (36.1)
Other
4 (5.3)
2 (5.6)
Transfer from another hospital
44 (57.9)
23 (63.9)
Home/work/other
32 (42.1)
13 (36.1)
23 (30.3) 25 (32.9)
10 (27.8) 6 (16.7)
Admitted from, n (%)
0.545
Primary diagnosis, n (%)
IQR interquartile range, TBI traumatic brain injury, AIS acute ischemic stroke, IPH intraparenchymal hemorrhage, SAH subarachnoid hemorrhage, SDH subdural hematoma, SCI spinal cord injury, SE status epilepticus, NSICU neuroscience intensive care unit, LOS length of stay, CCI Charlson Comorbidity Index, GCS glasgow coma scale, APACHE II acute physiology and chronic health evaluation II
0.131
IPH/ICH
8 (10.5)
6 (16.7)
SAH
3 (4)
5 (13.9)
SDH
5 (6.6)
2 (5.6)
Tumor
2 (2.6)
4 (11.1)
SCI
5 (6.6)
1 (2.8)
SE
3 (4)
0 (0)
Other
2 (2.6)
2 (5.6)
52 (68.4)
16 (44.4)
0.015
OR procedure, n (%)
18 (23.7)
13 (36.1)
0.170
Antiepileptic use, n (%)
28 (36.8)
21 (58.3)
0.032
0 (0–1)
1 (0–2)
0.050
1 (3.6)
2 (9.5)
0.390
5 (4–7)
6 (4–9)
0.422
Admit GCS score, median (IQR)
15 (13–15)
14 (12–15)
0.026
APACHE II score, median (IQR)
12 (9–15)
14 (11–17)
0.014
Intubation during NSICU LOS, n (%)
No. of antiepileptic medications, Median (IQR) Confirmed seizure activity, n (%) CCI score, median (IQR) Severity of illness
Discussion This is the first study in which PIMs and DBI scores were used as tools to assess the impact of medication use on clinical outcomes in critically ill elderly patients with neurological injury. Although significant attention has been focused on reducing PIMs in community-dwelling elderly adults, this has not been the case for hospitalized or ICU patients. Most PIMs studied in elderly adults living in the community are used for treatment of chronic disease states and should be taken on a daily basis (i.e., oxybutynin, digoxin, and amiodarone). In comparison, most frequently prescribed PIMs in hospitalized elderly patients include diphenhydramine, benzodiazepines, neuroleptics, and other
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0.168 0.976
White
TBI AIS
0.111 0.482
65–74
Female, n (%)
p value
anticholinergic medications [15, 24, 25]. These medications are usually given on an ‘‘as needed’’ basis and have sedative and anticholinergic properties. The results of this study indicate that PIM use is common and associated with an increased CNS drug burden as identified by the DBI in NSICU patients. In the current study, over 80 % of critically ill elderly patients with neurological injury received at least 1 PIM during ICU admission. The majority of PIMs was given intermittently rather than as continuous infusions. More than 50 % received 2 or more intPIMs. One prospective study identified that the total number of PIMs increased from preadmission to discharge for 120 patients in the medical and surgical ICUs (159 vs 253 PIMs) [26]. The
10
O
th e
r
s
s
BA N M
AP
AC s
D s BZ
tim Is G
H 2R As
O
pi
oi
ds
0
5
Number of doses
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Fig. 1 IntPIM class associated with a decrease in RASS scores H2RAs H2 receptor antagonists, GI stim GI stimulants, BZDs benzodiazepines, ACs anticholinergics, APs antipsychotics, NMBAs neuromuscular blocking agents
three most common PIMs prescribed at hospital discharge following medical, surgical, or cardiovascular ICU admission were opioids, anticholinergics, and antidepressants [28]. The most common PIMs given to our NSICU elderly patients were barbiturates, opioids, and H2RAs; each ICU may have different PIMs that need to be evaluated. Medications considered potentially inappropriate in one patient population may be appropriate in another based on medical necessity or the lack of acceptable alternatives. For example, critically ill patients often experience pain and agitation, therefore the use of evidence-based pharmacotherapy, which may have a higher anticholinergic and sedative burden, may be necessary. In addition, patients with a greater severity of illness were given more intPIMs, which may be warranted. A critical feature of our study was a thorough evaluation of changes in neurological status with each PIM dose and duration of recovery time. RASS score decreased with >50 % of PIM doses in patients receiving >2 PIMs, and median recovery time was significantly longer. Evaluation in ICU patients requires the use of sedation assessment tools, such as RASS, prior to assessing delirium. While this study did not directly assess delirium, a recent study of 304
medical ICU patient found that delirium occurred in 239 (74 %) of patients who received certain benzodiazepines and opioid medications; the median duration of ICU delirium was 3 days [27]. Although there is no evidence that reducing drug burden due to PIMs will lead to improved outcomes in critically ill elderly patients, there is evidence that PIM use increases the likelihood of a serious avoidable adverse drug event in elderly hospitalized patients [22]. The impact of reducing PIMs in critically ill elderly patients on outcomes needs to be investigated. Reduced exposure to PIMs has important outcomes in the elderly critically ill person. Anticholinergic adverse effects have been consistently associated with cognitive impairment [35–38]. Elderly adults given >2 intPIMs stayed in the NISCU over 2 days longer than those given B2 intPIMs. Although GCS was the same in all patients at discharge, older adults who received >2 intPIMs remained hospitalized more than 4 days longer than those given B2 intPIMs. Longer ICU and hospital LOS are associated with occurrence of delirium [39]. Furthermore, patients with longer ICU stays have greater risks for developing nosocomial infections and other ICU-related complications [40]. Total DBI scores were found to be associated with clinical outcomes as well. Median DBI scores increased (i.e., more sedative and anticholinergic burden) from admission to discharge in this elderly NSICU population. A higher total DBI after 72 h in the NSICU was associated with a significantly worse discharge GCS and a longer NSICU and hospital LOS, even after adjusting for baseline severity of illness and comorbid conditions. Elderly patients were stratified according to age category to examine if there was a more profound effect on PIMs and DBI scores in the ‘‘oldest old’’ patients (C85 years). There was a statistically significant lower DBI in the ‘‘youngest old’’ versus the ‘‘oldest old’’ patients on days 2 and 3, even though there tended to be more ‘‘youngest old’’ patients given >2 PIMs. The lack of association between intPIMs and DBI scores in elderly patients on all days might be attributed to the small number of patients evaluated in this study. The evaluation of DBI scores rather than number of PIMs appears to be a better target when selecting optimal
Table 2 Neurological changes
Decrease in RASS score,
No. of doses received by patients with B2 PIMs (n = 10 doses)
No. of doses received by patients with >2 PIMs (n = 40 doses)
p value
3 (30)
25 (63)
0.064
8 (6–14)
29 (8–102)
0.022
n (%) of doses Time to goal RASS score of 0 to -1, median (IQR) hours
RASS Richmond Agitation and Sedation Scale, intPIMs intermittent potentially inappropriate medications, IQR interquartile range PIMs potentially inappropriate medications
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Neurocrit Care Table 3 Clinical outcomes based on intPIMs B2 intPIMs (n = 76)
>2 intPIMs (n = 36)
p value
Discharge GCS, median (IQR)
15 (14–15)
NSICU LOS (days), median (IQR)
1.8 (1.03–2.71)
3.96 (2.65–9.12)
72 h
p value
0 (n = 65)
C1 (n = 30)
0.837
15 (14–15)
14 (8–15)
0.024
0.452
9 (13.84)
4 (13.33)
0.946
DBI drug burden index, GCS glasgow coma scale, IQR interquartile range
Conclusions PIM use and higher DBI scores were associated with poor clinical outcomes in this study. Neurological injury patients with a lower drug burden had a shorter NSICU and hospital LOS, as well as a higher discharge GCS. Larger prospective studies need to be conducted to confirm these findings as well as expand the focus to other types of critically ill elderly patients. Conflict of interest Catherine Floroff, Spencer Harpe, Perry Taylor, Patricia Slattum, and Gretchen Brophy declare that they have no conflict of interest.
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ORIGINAL ARTICLE
Potentially Inappropriate Medication Use is Associated with Clinical Outcomes in Critically Ill Elderly Patients with Neurological Injury Catherine K. Floroff • Patricia W. Slattum • Spencer E. Harpe • Perry Taylor • Gretchen M. Brophy
Ó Springer Science+Business Media New York 2014
Abstract Background Limited data suggest that potentially inappropriate medications (PIMs) impact outcomes in critically ill elderly patients. No data are available on the association between PIM use as well as drug burden index (DBI), which is a measure of PIM use, and clinical outcomes in neurocritical care elderly patients. This study evaluates whether PIM use and a higher DBI are associated with poor clinical outcomes in neurocritical care elderly patients. Methods PIMs were retrospectively identified in critically ill elderly patients admitted to the neuroscience intensive care unit (NSICU) from March to July 2011. DBI was calculated based on PIM doses. Relationships with clinical outcomes were evaluated.
C. K. Floroff P. W. Slattum G. M. Brophy (&) School of Pharmacy, Virginia Commonwealth University, 410 N. 12th Street, Richmond, VA 23298-0533, USA e-mail: [email protected] C. K. Floroff e-mail: [email protected] P. W. Slattum e-mail: [email protected] S. E. Harpe Chicago College of Pharmacy, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA e-mail: [email protected] P. Taylor Virginia Commonwealth University Health System, 401 N. 12th Street, P.O. Box 980042, Richmond, VA 23298, USA e-mail: [email protected]
Results PIMs were prescribed to a majority (81.3 %) of the 112 patients. Opioids were most commonly associated with a decrease in Richmond Agitation Sedation Scale (RASS) scores (56 % of PIM doses). Time to recovery was significantly longer in patients with a higher PIM burden (B2 PIMs: 8 h, >2 PIMs: 29 h; p = 0.02). There was a significantly longer NSICU and hospital length of stay (9 vs 2; 15 vs 5 days; p < 0.0001) as well as a lower Glasgow Coma Scale score upon discharge (14 vs 15, p = 0.02) in patients with a higher DBI after 72 h of hospitalization. There was no difference in mortality. Conclusions PIM use and higher DBI scores were associated with poor clinical outcomes and longer lengths of stay. Further studies are needed to determine the impact of PIMs and DBI on mortality in neurocritical care elderly patients. Keywords Aging Elderly Older adult Critically ill Potentially inappropriate medication(s) Drug burden index Neurological injury
Introduction In the US, patients over 85 years of age represent the fastest growing segment of the older adult population [1]. In addition, older adult patients (aged C 65 years) account for 42– 52 % of all intensive care unit (ICU) admissions and 60 % of all ICU days [2]. Considering these demographic and healthcare utilization patterns, interest in the use of potentially inappropriate medications (PIMs) that can increase cognitive and functional burden in elderly hospitalized patients has also grown. A PIM is a medication having potential risks that outweigh its potential benefits in an elderly patient [3]. Use of PIMs is one risk factor for adverse
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drug reactions and is related to increased health-related expenditures in elderly patients [3, 4]. Originally, the concern with use of PIMs in elderly adults led to the creation of a set of explicit criteria commonly referred to as the Beers Criteria [5]. It was first developed by an expert consensus panel for nursing home patients but has been updated (most recently in 2012) to apply to elderly patients in all clinical settings. Despite updates to the original version of the Beers Criteria, there are still concerns that some medications that may be used inappropriately in older patients are not included in the Beers Criteria. Furthermore, studies evaluating the association between the uses of medications included in the Beers Criteria and patient outcomes often find mixed results [6]. This has led to the development of alternative validated criteria for PIM use in elderly patients including Screening Tool of Older Person’s Prescriptions (STOPP) and Screening Tool to Alert Doctors to Right Treatment (START) [7– 9]. Most of the current literature evaluates PIM use among elderly adults living in the community. Recently, PIM use has been studied in hospitalized non-ICU elderly patients. The prevalence of PIMs was 44 % using the Medication Appropriateness Index [10], 11.56–56.1 % using the Beers Criteria [11–19], 22–36.2 % using STOPP and/or START [20, 21], and 25–49 % using a combination of criteria [22– 24]. Associations between PIMs and outcomes, such as inhospital mortality and length of stay (LOS), are inconsistent [11–13, 15]. Unfortunately, there is limited information regarding PIM use in critically ill elderly patients in the ICU setting, especially in those with neurological injury [26–28]. This is concerning as elderly patients with comorbidities are often taking multiple chronic medications with more medications added to the regimen during the episode of acute illness [25]. Increased medication usage potentially leads to an increased incidence of medication-related problems [29]. However, some PIMs may be reasonably appropriate in elderly ICU patients under certain circumstances. A tailored approach that assesses overall cognitive and functional burden is needed to evaluate PIMs in critically ill elderly patients. The drug burden index (DBI) is another evidence-based tool to measure total exposure to specific PIMs with anticholinergic and/or sedative properties [6]. It considers dose and medications with certain pharmacologic properties. DBI is associated with poor physical and cognitive function as well as functional outcomes, which may be augmented in elderly patients with neurological injury [6]. Reducing the number of PIMs and DBI may improve patient outcomes in the ICU. To our knowledge, no studies have been conducted relating PIMs and DBI to clinical outcomes in ICU patients with neurological injury. The purpose of our study was to
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investigate the use of PIMs and DBI and their associations with clinical outcomes in critically ill elderly patients with neurological injury. Specific aims included: (1) (2)
(3)
Identifying PIMs and determining a DBI for patients during neuroscience ICU (NSICU) admission. Determining if a change in neurological status occurred pre- to post-PIM dosing, using the Glasgow Coma Scale (GCS) and Richmond Agitation and Sedation Scale (RASS) scores as measures of neurological status. Determining if the number of PIMs administered during the ICU stay and DBI, which is calculated based on all PIM doses, is associated with clinical outcomes.
Methods Consecutive adult patients C65 years of age admitted to the NSICU of Virginia Commonwealth University from March 2011 to July 2011 were retrospectively identified through electronic medical records. The VCU Institutional Review Board evaluated the study and approved it as an exempt study. Data collection included demographics, admitting diagnosis, and medications received while in the NSICU. Severity of illness was determined by admission Acute Physiology and Chronic Health Status (APACHE II) score and GCS. The Charlson Comorbidity Index (CCI) was calculated as a measure of the impact of comorbid illness [30]. In patients receiving an antiepileptic agent, EEG results, ICD-9-CM codes, and clinical notes were reviewed to assess whether the patient experienced a seizure during their ICU admission. In-hospital mortality, ICU LOS, hospital LOS, and discharge GCS were also recorded to assess clinical outcomes. Existing data (ICD-9-CM procedure codes and electronic medical records) were reviewed to identify PIMs as well as pre- and post-dose GCS and RASS scores. Outcome measures included (a) reduction of GCS score > 2 points, (b) time to recovery (h) of GCS score to baseline, (c) reduction of RASS score with drug administration, (d) recovery of post-dose RASS score to goal of 0 to -1, and (e) and time to recovery (h) of RASS score to 0 to -1, if applicable. PIMs were identified and used to calculate the DBI. Medications with anticholinergic or sedative properties were defined using the updated Beers and STOPP criteria independent of diagnosis, as well as previously published studies [31–34]. PIMs included opioids, antidepressants, antipsychotics, benzodiazepines, neuromuscular blocking agents (NMBA), and other medications that can affect CNS burden such as H2 receptor antagonists (H2RAs), barbiturates, and GI stimulants. Only medications used during the
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ICU stay were included in this study. Chronic and ‘‘as needed’’ doses were identified as well as intermittent doses and continuous infusions. Additional information needed to calculate the DBI included dose, route, frequency, duration, and indication. The DBI for each medication was calculated by dividing the daily dose by the recommended minimum daily dose (Dose/Minimum Daily Dose). Total DBI was determined by summing the daily DBI for each PIM. Minimum daily dose was identified by means of Physician’s Desk Reference and the product information of each PIM. The median number of intermittent PIMs (intPIMs) was determined, and patients were divided into 2 groups for comparisons: those receiving B2 intPIMs and those receiving >2 intPIMs. Age categories were also used to determine if differences existed between the younger old versus the oldest old patients. Demographic and clinical variables were summarized using mean and standard deviation (SD), median with interquartile ranges (IQR) if not normally distributed, or percentages. The number of PIMs prescribed per patient was described and analyzed as continuous variables. The Wilcoxon signed rank test was used to compare continuous variables. Dichotomous variables were evaluated using either Pearson’s Chi-square test or Fisher’s exact test. Logistic regression analysis was conducted to determine the impact of confounding variables, including APACHE II and CCI. Statistical significance was defined as p < 0.05, and all statistical analyses were carried out in Stata SE version 12 (StataCorp LP, College Station, TX).
Results Patient Characteristics There were 112 critically ill elderly NSICU patients included in this study. Of these, 76 patients received B2 intPIMs and 36 received >2 intPIMs during NSICU admission. Baseline characteristics were similar between these groups, with the exception of a greater severity of illness observed in patients with >2 intPIMs (Table 1). The primary neurological injury was acute ischemic stroke (AIS) for those receiving B2 intPIMs (32.9 %) and traumatic brain injury (TBI) for those receiving >2 intPIMs (27.8 %). The median (IQR) NSICU LOS, during which PIMs were prescribed, was 2 intPIMs based on age category. A change in RASS score occurred with 50 PIM doses. RASS scores decreased with 28 (56 %) PIM doses and were most frequently associated with opioid use (Fig. 1). Furthermore, all decreased RASS scores were seen in TBI patients. Median (IQR) recovery time to a goal RASS score of 0 to -1 was 29 (8–102) h (p = 0.022) (Table 2). GCS decreased >2 points with 5 PIM doses and all were in TBI patients. Clinical outcomes based on intPIM use are provided in Table 3. The median NSICU LOS and hospital LOS for patients who received B2 intPIMs, as compared to those with >2 intPIMs, were shortened by 2.16 and 4.5 days, respectively, even after adjusting for baseline APACHE II and CCI scores (p < 0.001). There was no statistically significant difference in mortality between groups. Drug Burden Index There was a statistically significant increase in DBI scores for intPIMs based on age category on days 2 and 3 (Table 4). DBI increased significantly by 1.75 in elderly patients C85 years of age compared to those aged 65– 74 years and by 1.27 compared to those aged 75–84 years on day 2 (p = 0.024). On day 3, DBI increased significantly by 1.56 in elderly patients C85 years of age when compared to those aged 65–74 years and by 1.55 in those aged 75–84 years (p = 0.049). There was no statistically significant increase in DBI scores per group based on cIV PIMs (Table 4). Median cumulative DBI scores were 2.5, 4.5, and 5.5 on days 1, 2, 3 of hospitalization; no statistically significant differences in clinical outcomes were seen for patients with DBI scores equal to or above the median. Hospital and NSICU LOS increased significantly for patients with a DBI C 1 compared to those with a DBI = 0 after 72 h of hospitalization, and NSICU as well as hospital LOS was shortened by 3.54 and 4.87 days, respectively, for those with DBI = 0 (adjusted p value < 0.001) (Fig. 2). There was no difference between patients with a DBI C 1 compared to those with a median DBI = 0 on days 1–3. A total DBI of 0 after 72 h of hospitalization is associated with a higher discharge GCS (by 1 point) even after adjusting for APACHE II and CCI scores (adjusted p value = 0.012) (Table 5). There was no statistically significant difference in mortality between the groups.
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Neurocrit Care Table 1 Baseline characteristics
Characteristic
B2 intPIMs (n = 76)
>2 intPIMs (n = 36)
Age, years old median (IQR)
80.3 (73.9–85.3)
75.8 (70.4–81.2)
Age category, n (%) 25 (32.9)
16 (44.4)
75–84
29 (38.2)
12 (33.3)
C85
22 (29)
8 (22.2)
38 (50)
23 (63.9)
Ethnicity, n (%) 46 (60.1)
21 (58.3)
Black
26 (34.2)
13 (36.1)
Other
4 (5.3)
2 (5.6)
Transfer from another hospital
44 (57.9)
23 (63.9)
Home/work/other
32 (42.1)
13 (36.1)
23 (30.3) 25 (32.9)
10 (27.8) 6 (16.7)
Admitted from, n (%)
0.545
Primary diagnosis, n (%)
IQR interquartile range, TBI traumatic brain injury, AIS acute ischemic stroke, IPH intraparenchymal hemorrhage, SAH subarachnoid hemorrhage, SDH subdural hematoma, SCI spinal cord injury, SE status epilepticus, NSICU neuroscience intensive care unit, LOS length of stay, CCI Charlson Comorbidity Index, GCS glasgow coma scale, APACHE II acute physiology and chronic health evaluation II
0.131
IPH/ICH
8 (10.5)
6 (16.7)
SAH
3 (4)
5 (13.9)
SDH
5 (6.6)
2 (5.6)
Tumor
2 (2.6)
4 (11.1)
SCI
5 (6.6)
1 (2.8)
SE
3 (4)
0 (0)
Other
2 (2.6)
2 (5.6)
52 (68.4)
16 (44.4)
0.015
OR procedure, n (%)
18 (23.7)
13 (36.1)
0.170
Antiepileptic use, n (%)
28 (36.8)
21 (58.3)
0.032
0 (0–1)
1 (0–2)
0.050
1 (3.6)
2 (9.5)
0.390
5 (4–7)
6 (4–9)
0.422
Admit GCS score, median (IQR)
15 (13–15)
14 (12–15)
0.026
APACHE II score, median (IQR)
12 (9–15)
14 (11–17)
0.014
Intubation during NSICU LOS, n (%)
No. of antiepileptic medications, Median (IQR) Confirmed seizure activity, n (%) CCI score, median (IQR) Severity of illness
Discussion This is the first study in which PIMs and DBI scores were used as tools to assess the impact of medication use on clinical outcomes in critically ill elderly patients with neurological injury. Although significant attention has been focused on reducing PIMs in community-dwelling elderly adults, this has not been the case for hospitalized or ICU patients. Most PIMs studied in elderly adults living in the community are used for treatment of chronic disease states and should be taken on a daily basis (i.e., oxybutynin, digoxin, and amiodarone). In comparison, most frequently prescribed PIMs in hospitalized elderly patients include diphenhydramine, benzodiazepines, neuroleptics, and other
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0.168 0.976
White
TBI AIS
0.111 0.482
65–74
Female, n (%)
p value
anticholinergic medications [15, 24, 25]. These medications are usually given on an ‘‘as needed’’ basis and have sedative and anticholinergic properties. The results of this study indicate that PIM use is common and associated with an increased CNS drug burden as identified by the DBI in NSICU patients. In the current study, over 80 % of critically ill elderly patients with neurological injury received at least 1 PIM during ICU admission. The majority of PIMs was given intermittently rather than as continuous infusions. More than 50 % received 2 or more intPIMs. One prospective study identified that the total number of PIMs increased from preadmission to discharge for 120 patients in the medical and surgical ICUs (159 vs 253 PIMs) [26]. The
10
O
th e
r
s
s
BA N M
AP
AC s
D s BZ
tim Is G
H 2R As
O
pi
oi
ds
0
5
Number of doses
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Fig. 1 IntPIM class associated with a decrease in RASS scores H2RAs H2 receptor antagonists, GI stim GI stimulants, BZDs benzodiazepines, ACs anticholinergics, APs antipsychotics, NMBAs neuromuscular blocking agents
three most common PIMs prescribed at hospital discharge following medical, surgical, or cardiovascular ICU admission were opioids, anticholinergics, and antidepressants [28]. The most common PIMs given to our NSICU elderly patients were barbiturates, opioids, and H2RAs; each ICU may have different PIMs that need to be evaluated. Medications considered potentially inappropriate in one patient population may be appropriate in another based on medical necessity or the lack of acceptable alternatives. For example, critically ill patients often experience pain and agitation, therefore the use of evidence-based pharmacotherapy, which may have a higher anticholinergic and sedative burden, may be necessary. In addition, patients with a greater severity of illness were given more intPIMs, which may be warranted. A critical feature of our study was a thorough evaluation of changes in neurological status with each PIM dose and duration of recovery time. RASS score decreased with >50 % of PIM doses in patients receiving >2 PIMs, and median recovery time was significantly longer. Evaluation in ICU patients requires the use of sedation assessment tools, such as RASS, prior to assessing delirium. While this study did not directly assess delirium, a recent study of 304
medical ICU patient found that delirium occurred in 239 (74 %) of patients who received certain benzodiazepines and opioid medications; the median duration of ICU delirium was 3 days [27]. Although there is no evidence that reducing drug burden due to PIMs will lead to improved outcomes in critically ill elderly patients, there is evidence that PIM use increases the likelihood of a serious avoidable adverse drug event in elderly hospitalized patients [22]. The impact of reducing PIMs in critically ill elderly patients on outcomes needs to be investigated. Reduced exposure to PIMs has important outcomes in the elderly critically ill person. Anticholinergic adverse effects have been consistently associated with cognitive impairment [35–38]. Elderly adults given >2 intPIMs stayed in the NISCU over 2 days longer than those given B2 intPIMs. Although GCS was the same in all patients at discharge, older adults who received >2 intPIMs remained hospitalized more than 4 days longer than those given B2 intPIMs. Longer ICU and hospital LOS are associated with occurrence of delirium [39]. Furthermore, patients with longer ICU stays have greater risks for developing nosocomial infections and other ICU-related complications [40]. Total DBI scores were found to be associated with clinical outcomes as well. Median DBI scores increased (i.e., more sedative and anticholinergic burden) from admission to discharge in this elderly NSICU population. A higher total DBI after 72 h in the NSICU was associated with a significantly worse discharge GCS and a longer NSICU and hospital LOS, even after adjusting for baseline severity of illness and comorbid conditions. Elderly patients were stratified according to age category to examine if there was a more profound effect on PIMs and DBI scores in the ‘‘oldest old’’ patients (C85 years). There was a statistically significant lower DBI in the ‘‘youngest old’’ versus the ‘‘oldest old’’ patients on days 2 and 3, even though there tended to be more ‘‘youngest old’’ patients given >2 PIMs. The lack of association between intPIMs and DBI scores in elderly patients on all days might be attributed to the small number of patients evaluated in this study. The evaluation of DBI scores rather than number of PIMs appears to be a better target when selecting optimal
Table 2 Neurological changes
Decrease in RASS score,
No. of doses received by patients with B2 PIMs (n = 10 doses)
No. of doses received by patients with >2 PIMs (n = 40 doses)
p value
3 (30)
25 (63)
0.064
8 (6–14)
29 (8–102)
0.022
n (%) of doses Time to goal RASS score of 0 to -1, median (IQR) hours
RASS Richmond Agitation and Sedation Scale, intPIMs intermittent potentially inappropriate medications, IQR interquartile range PIMs potentially inappropriate medications
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Neurocrit Care Table 3 Clinical outcomes based on intPIMs B2 intPIMs (n = 76)
>2 intPIMs (n = 36)
p value
Discharge GCS, median (IQR)
15 (14–15)
NSICU LOS (days), median (IQR)
1.8 (1.03–2.71)
3.96 (2.65–9.12)
72 h
p value
0 (n = 65)
C1 (n = 30)
0.837
15 (14–15)
14 (8–15)
0.024
0.452
9 (13.84)
4 (13.33)
0.946
DBI drug burden index, GCS glasgow coma scale, IQR interquartile range
Conclusions PIM use and higher DBI scores were associated with poor clinical outcomes in this study. Neurological injury patients with a lower drug burden had a shorter NSICU and hospital LOS, as well as a higher discharge GCS. Larger prospective studies need to be conducted to confirm these findings as well as expand the focus to other types of critically ill elderly patients. Conflict of interest Catherine Floroff, Spencer Harpe, Perry Taylor, Patricia Slattum, and Gretchen Brophy declare that they have no conflict of interest.
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