Folate deficiency has been associated with a number of medical conditions. It is well established that folate deficiency leads to macrocytic anemia,[1, 2] and that supplementation of folic acid during pregnancy leads to decreased rates of neural tube defects.[3] Folate deficiency has also been hypothesized to affect other conditions including dementia, delirium, peripheral neuropathy, depression, cancer, and cardiovascular disease.[4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18] Most of these latter assertions are based on case reports or observational studies, with randomized controlled trials failing to demonstrate benefit of folic acid supplementation.[19, 20, 21]

Prior to mandatory folic acid fortification in the United States, the prevalence of folate deficiency was estimated to be between 3% and 16%.[16, 22, 23] In a study conducted prior to fortification, serum folate levels were evaluated in patients presenting with macrocytosis and anemia.[24] The study found that 2.3% of patients were serum folate deficient, with a change in management occurring in 24% of the deficient patients. The study also found that patients were charged $9979 per result that changed physician management.

In 1998, mandatory folic acid fortification began in the United States, and the prevalence of folate deficiency in the general population decreased to an estimated 0.5%.[23, 25] In a postfortification study, serum folate levels were evaluated in patients with anemia, dementia, or altered mental status.[26] The overall rate of serum folate deficiency was 0.4%, with the authors concluding that there was a lack of utility in serum folate testing. Despite this, algorithms addressing the evaluation of anemia continue to include serum folate levels.[2, 27, 28]

To our knowledge, the use of serum folate testing in the inpatient and emergency department population has never been independently evaluated. In our study, we aimed to characterize the indications, rate of deficiency, charge and cost per deficient result, and change in management per deficient result in inpatient and emergency department serum folate testing. We hypothesized that serum folate testing in these populations would have poor utility and would not be cost‐effective for any indication.

METHODS

We conducted a retrospective review of all serum folate tests ordered in inpatient units and the emergency department at a large academic medical center in Boston, Massachusetts from January 1, 2011 through December 31, 2011. The test was considered to be an inpatient or emergency department test based on the location of the blood draw on which the test was performed. Serum folate values were determined using a chemiluminescent competitive binding protein assay on an E170 analyzer as prescribed by the manufacturer (Roche Diagnostics, Indianapolis, IN). We defined serum folate levels as deficient (3.0 ng/mL), low‐normal (3.0 ng/mL3.9 ng/mL),[26] normal (4.0 ng/mL20.0 ng/mL), and high (>20.0 ng/mL). Erythrocyte folate levels are not routinely ordered at our institution and were not measured in our study.[29] Macrocytosis was defined as mean corpuscular volume of >99 fL. Vitamin B12 deficiency was defined as vitamin B12 level of under 200 pg/mL or vitamin B12 level of 200 to 300 pg/mL, with a methylmalonic acid >270 nmol/L and a normal homocysteine level (514 mol/L).[30, 31]

We evaluated 250 randomly selected serum folate levels and all deficient or low‐normal serum folate levels and recorded indication, comorbidities, age, sex, race or ethnicity, hemoglobin, hematocrit, mean corpuscular volume, vitamin B12 level, folic acid supplement on presentation, and folic acid supplement on discharge. Indications were determined by chart review. If serum folate was checked at the same time as iron studies, it was assumed that the indication was anemia without macrocytosis or anemia with macrocytosis unless otherwise documented. Comorbidities were selected based on historical risk factors and included depression, peripheral neuropathy, intestinal surgery, gastric bypass, cirrhosis, inflammatory bowel disease, celiac disease, delirium, dementia, alcohol abuse, malnutrition, anemia, end‐stage renal disease, vitamin B12 deficiency, or current use of phenytoin, valproic acid, or methotrexate.[32]

A charge analysis was performed using the same methodology as Robinson and Mladenovic.[24] We defined the charge of serum folate testing as our institution's charge to the patient or payer, which was $151.00 per test. Because hospital charges are variable, we also made a second calculation based on the charge per patient or payer from the Robinson and Mladenovic study,[24] which was $71.00. The analytical cost to our hospital of performing each serum folate test was <$2.00. We determined the total charge and cost for all serum folate tests and the charge and cost per deficient result.

The study was reviewed by the institutional review board and determined to be exempt.

RESULTS

In 2011, a total of 2093 serum folate levels were obtained on 1944 inpatients and emergency department patients. Of the total patients, 79.9% were inpatients and 20.1% were emergency department patients. Of the patients with tests performed in the emergency department, 98.1% were admitted to an inpatient unit.

Of the 250 random chart reviews, all had normal or high serum folate levels. The demographics, indications, and comorbidities are listed in Table 1. The most common indications were anemia without macrocytosis (43.2%), anemia with macrocytosis (13.2%; mean corpuscular volume [MCV], 106.8 fL), delirium (12.0%), malnutrition (6.4%), and peripheral neuropathy (6.0%). The other indications included thrombocytopenia, macrocytosis (without anemia), methotrexate use, alcohol abuse, frequent falls, syncope, headache, lethargy, optic nerve neuropathy, paranoia, psychosis, leukopenia, anxiety, and suicidal ideation. All of these individual indications were 2% of total reviewed indications. There were 16 cases (6.4%) without a documented indication.

Of the 2093 serum folate levels, there were 2 deficient (0.1%), 7 low‐normal (0.3%), 1487 normal (71.1%), and 597 high (28.5%) levels (Table 2). There were 128 patients (6.6%) who had more than 1 serum folate level checked within the prior 12 months, with 1 patient having 5 levels obtained during that time period. All of the deficient and low‐normal serum folate results are listed in Table 3. Of the 9 deficient or low‐normal serum folate levels, 8 had comorbid risk factors for folate deficiency. One of the deficient cases was on folic acid and multivitamin supplementation on presentation, although nonadherence with these supplements was documented in the medical record. The other deficient case was not on folic acid supplementation and did not receive folic acid supplementation for the deficient result. Vitamin B12 levels were checked simultaneously to serum folate levels in 85.2% of cases and within 6 months in 99.2% of cases. Of these patients, 2.0% were found to have vitamin B12 deficiency.

Based on our institution's charge for serum folate, a total of $316,043 was charged for the 2093 serum folate tests. The amount charged per deficient result was $158,022. Substituting the charge from the Robinson and Mladenovic study,[24] we calculated the corresponding total charge and charge per deficient result as $149,545 and $74,772, respectively. The actual total cost to our hospital was <$4186, with a cost per deficient test of <$2093.

DISCUSSION

Serum folate levels are often obtained when evaluating anemia without macrocytosis and anemia with macrocytosis.[2] They are also frequently obtained in the evaluation of delirium and dementia. A prior study evaluated both inpatient and outpatient serum folate levels in anemia, dementia, and altered mental status and found only 0.4% of serum folate results to be deficient.[26] In their study, the indications for serum folate tests were anemia or macrocytic anemia (60%) and dementia or altered mental status (30%).

We found the indications for serum folate testing in inpatients and emergency department patients to be different than prior studies. The majority of tests were done to evaluate anemia without macrocytosis (43.2%) or anemia with macrocytosis (13.2%). Lower percentages were done for the evaluation of delirium (12.0%) or dementia (3.2%). In addition, there were multiple indications that have not been noted in previous studies, including depression, peripheral neuropathy, malnutrition, pancytopenia, and others. These accounted for 28.0% of all indications. The reason for the difference in indications compared to prior studies is unknown but may be related to our cohort of exclusively inpatients and emergency department patients. Also, we observed a high concurrence of serum folate and vitamin B12 testing, with 85.2% of serum folate levels ordered at the same time as vitamin B12 levels. It appears that the tests are often ordered together even when the indication suggests that vitamin B12 alone may be more appropriate, such as peripheral neuropathy.

We found that serum folate deficiency was rare, occurring in only 2 of 2093 results. Furthermore, the deficient serum folate results may have been checked for inappropriate indications. The first deficient result was noted as part of a stroke workup in a patient not taking folic acid supplementation. Current guidelines do not recommend serum folate testing in patients with new stroke.[33] In the second deficient case, serum folate testing was performed for evaluation of macrocytic anemia with an MCV of 119 fL. Although reasonable, this was an alcoholic patient presenting with acute gastrointestinal bleeding already on folic acid and multivitamin supplementation and known nonadherence with these supplements. In neither case was there a change in management based on the deficient result.

Given the low rate of serum folate deficiency and the lack of change in management based on deficient results, we conclude that there is a low utility of serum folate testing for any indication in inpatients and emergency department patients in folic acid‐fortified countries. Based on prior studies, and supported by our results, there is no evidence for checking serum folate levels in delirium, dementia, peripheral neuropathy, malnutrition, or any of the other indications. In addition, our results demonstrate a low utility even in patients with anemia or macrocytic anemia.

The rate of serum folate deficiency in our study was significantly lower than prior studies.[24, 26] There may have been geographical factors that led to a lower prevalence of folate deficiency in our study population. Our cohort included inpatients and emergency department patients, whereas previous studies had a majority of outpatients. It is known that serum folate levels can rapidly fluctuate with proper nutrition.[34] It may be that our patients received nutrition in the hospital that corrected serum folate levels prior to laboratory testing.

In addition to the low utility of serum folate testing, the charge per deficient result in our study ($158,022) was more than 100‐fold higher than that in the Robinson and Mladenovic study ($1321).[24] Even when correcting for variability in hospital charges by using the charge from the latter study, the charge per deficient serum folate test remained 50‐fold higher ($74,772). This implies that the increase in charge per deficient result was driven in part by a decreased rate of deficient tests. Folic acid fortification is likely responsible for some of the decrease. However, we believe another source is the excessive ordering of serum folate tests in patients without previously accepted indications. Because no change in management was made for the deficient patients in our study, the charge per serum folate deficient result that changed management approached infinity. This compares to $9979 in the Robinson and Mladenovic analysis.[24]

The cost to the hospital of a serum folate test was much lower than the charge, and estimated to be <$2093 per deficient result. Because serum folate tests are performed on a highly automated, random access analyzer that performs thousands of other measurements daily, the capital and labor costs for each test was well below $0.50 combined. With the addition of reagent costs, our total cost for each serum folate measurement was <$2.00. It is somewhat difficult to extrapolate these values to other hospitals, as exact costs and charges are variable. Nonetheless, the exceptionally low utility of serum folate testing makes the costs associated with these tests excessive.

Our study has several limitations. We conducted our study at a single institution in a country with mandatory folic acid fortification. Our results may not be generalizable to other institutions or patient populations, such as those in countries without mandatory folic acid fortification. Only 259 (12.4%) charts were reviewed, and indications were determined in 93.6% of charts, which may have caused our frequency to vary from the true frequency. Additionally, the low rate of deficient serum folate results limited our ability to identify associations with deficiency. Further evaluation for geographic variations of serum folate deficiency may reveal variable rates.

We conclude that in folic acid fortified countries, the rate of serum folate deficiency is increasingly rare, and the charge to patients and payers per deficient result is exceptionally high. In addition, testing in our study did not change clinical management, which makes the costs associated with these test wasteful. Further evaluation of serum folate testing of inpatients and emergency department patients in folic acid fortified countries is warranted; however, based on our results the utility appears poor for all indications.

Folate deficiency has been associated with a number of medical conditions. It is well established that folate deficiency leads to macrocytic anemia,[1, 2] and that supplementation of folic acid during pregnancy leads to decreased rates of neural tube defects.[3] Folate deficiency has also been hypothesized to affect other conditions including dementia, delirium, peripheral neuropathy, depression, cancer, and cardiovascular disease.[4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18] Most of these latter assertions are based on case reports or observational studies, with randomized controlled trials failing to demonstrate benefit of folic acid supplementation.[19, 20, 21]

Prior to mandatory folic acid fortification in the United States, the prevalence of folate deficiency was estimated to be between 3% and 16%.[16, 22, 23] In a study conducted prior to fortification, serum folate levels were evaluated in patients presenting with macrocytosis and anemia.[24] The study found that 2.3% of patients were serum folate deficient, with a change in management occurring in 24% of the deficient patients. The study also found that patients were charged $9979 per result that changed physician management.

In 1998, mandatory folic acid fortification began in the United States, and the prevalence of folate deficiency in the general population decreased to an estimated 0.5%.[23, 25] In a postfortification study, serum folate levels were evaluated in patients with anemia, dementia, or altered mental status.[26] The overall rate of serum folate deficiency was 0.4%, with the authors concluding that there was a lack of utility in serum folate testing. Despite this, algorithms addressing the evaluation of anemia continue to include serum folate levels.[2, 27, 28]

To our knowledge, the use of serum folate testing in the inpatient and emergency department population has never been independently evaluated. In our study, we aimed to characterize the indications, rate of deficiency, charge and cost per deficient result, and change in management per deficient result in inpatient and emergency department serum folate testing. We hypothesized that serum folate testing in these populations would have poor utility and would not be cost‐effective for any indication.

METHODS

We conducted a retrospective review of all serum folate tests ordered in inpatient units and the emergency department at a large academic medical center in Boston, Massachusetts from January 1, 2011 through December 31, 2011. The test was considered to be an inpatient or emergency department test based on the location of the blood draw on which the test was performed. Serum folate values were determined using a chemiluminescent competitive binding protein assay on an E170 analyzer as prescribed by the manufacturer (Roche Diagnostics, Indianapolis, IN). We defined serum folate levels as deficient (3.0 ng/mL), low‐normal (3.0 ng/mL3.9 ng/mL),[26] normal (4.0 ng/mL20.0 ng/mL), and high (>20.0 ng/mL). Erythrocyte folate levels are not routinely ordered at our institution and were not measured in our study.[29] Macrocytosis was defined as mean corpuscular volume of >99 fL. Vitamin B12 deficiency was defined as vitamin B12 level of under 200 pg/mL or vitamin B12 level of 200 to 300 pg/mL, with a methylmalonic acid >270 nmol/L and a normal homocysteine level (514 mol/L).[30, 31]

We evaluated 250 randomly selected serum folate levels and all deficient or low‐normal serum folate levels and recorded indication, comorbidities, age, sex, race or ethnicity, hemoglobin, hematocrit, mean corpuscular volume, vitamin B12 level, folic acid supplement on presentation, and folic acid supplement on discharge. Indications were determined by chart review. If serum folate was checked at the same time as iron studies, it was assumed that the indication was anemia without macrocytosis or anemia with macrocytosis unless otherwise documented. Comorbidities were selected based on historical risk factors and included depression, peripheral neuropathy, intestinal surgery, gastric bypass, cirrhosis, inflammatory bowel disease, celiac disease, delirium, dementia, alcohol abuse, malnutrition, anemia, end‐stage renal disease, vitamin B12 deficiency, or current use of phenytoin, valproic acid, or methotrexate.[32]

A charge analysis was performed using the same methodology as Robinson and Mladenovic.[24] We defined the charge of serum folate testing as our institution's charge to the patient or payer, which was $151.00 per test. Because hospital charges are variable, we also made a second calculation based on the charge per patient or payer from the Robinson and Mladenovic study,[24] which was $71.00. The analytical cost to our hospital of performing each serum folate test was <$2.00. We determined the total charge and cost for all serum folate tests and the charge and cost per deficient result.

The study was reviewed by the institutional review board and determined to be exempt.

RESULTS

In 2011, a total of 2093 serum folate levels were obtained on 1944 inpatients and emergency department patients. Of the total patients, 79.9% were inpatients and 20.1% were emergency department patients. Of the patients with tests performed in the emergency department, 98.1% were admitted to an inpatient unit.

Of the 250 random chart reviews, all had normal or high serum folate levels. The demographics, indications, and comorbidities are listed in Table 1. The most common indications were anemia without macrocytosis (43.2%), anemia with macrocytosis (13.2%; mean corpuscular volume [MCV], 106.8 fL), delirium (12.0%), malnutrition (6.4%), and peripheral neuropathy (6.0%). The other indications included thrombocytopenia, macrocytosis (without anemia), methotrexate use, alcohol abuse, frequent falls, syncope, headache, lethargy, optic nerve neuropathy, paranoia, psychosis, leukopenia, anxiety, and suicidal ideation. All of these individual indications were 2% of total reviewed indications. There were 16 cases (6.4%) without a documented indication.

Of the 2093 serum folate levels, there were 2 deficient (0.1%), 7 low‐normal (0.3%), 1487 normal (71.1%), and 597 high (28.5%) levels (Table 2). There were 128 patients (6.6%) who had more than 1 serum folate level checked within the prior 12 months, with 1 patient having 5 levels obtained during that time period. All of the deficient and low‐normal serum folate results are listed in Table 3. Of the 9 deficient or low‐normal serum folate levels, 8 had comorbid risk factors for folate deficiency. One of the deficient cases was on folic acid and multivitamin supplementation on presentation, although nonadherence with these supplements was documented in the medical record. The other deficient case was not on folic acid supplementation and did not receive folic acid supplementation for the deficient result. Vitamin B12 levels were checked simultaneously to serum folate levels in 85.2% of cases and within 6 months in 99.2% of cases. Of these patients, 2.0% were found to have vitamin B12 deficiency.

Based on our institution's charge for serum folate, a total of $316,043 was charged for the 2093 serum folate tests. The amount charged per deficient result was $158,022. Substituting the charge from the Robinson and Mladenovic study,[24] we calculated the corresponding total charge and charge per deficient result as $149,545 and $74,772, respectively. The actual total cost to our hospital was <$4186, with a cost per deficient test of <$2093.

DISCUSSION

Serum folate levels are often obtained when evaluating anemia without macrocytosis and anemia with macrocytosis.[2] They are also frequently obtained in the evaluation of delirium and dementia. A prior study evaluated both inpatient and outpatient serum folate levels in anemia, dementia, and altered mental status and found only 0.4% of serum folate results to be deficient.[26] In their study, the indications for serum folate tests were anemia or macrocytic anemia (60%) and dementia or altered mental status (30%).

We found the indications for serum folate testing in inpatients and emergency department patients to be different than prior studies. The majority of tests were done to evaluate anemia without macrocytosis (43.2%) or anemia with macrocytosis (13.2%). Lower percentages were done for the evaluation of delirium (12.0%) or dementia (3.2%). In addition, there were multiple indications that have not been noted in previous studies, including depression, peripheral neuropathy, malnutrition, pancytopenia, and others. These accounted for 28.0% of all indications. The reason for the difference in indications compared to prior studies is unknown but may be related to our cohort of exclusively inpatients and emergency department patients. Also, we observed a high concurrence of serum folate and vitamin B12 testing, with 85.2% of serum folate levels ordered at the same time as vitamin B12 levels. It appears that the tests are often ordered together even when the indication suggests that vitamin B12 alone may be more appropriate, such as peripheral neuropathy.

We found that serum folate deficiency was rare, occurring in only 2 of 2093 results. Furthermore, the deficient serum folate results may have been checked for inappropriate indications. The first deficient result was noted as part of a stroke workup in a patient not taking folic acid supplementation. Current guidelines do not recommend serum folate testing in patients with new stroke.[33] In the second deficient case, serum folate testing was performed for evaluation of macrocytic anemia with an MCV of 119 fL. Although reasonable, this was an alcoholic patient presenting with acute gastrointestinal bleeding already on folic acid and multivitamin supplementation and known nonadherence with these supplements. In neither case was there a change in management based on the deficient result.

Given the low rate of serum folate deficiency and the lack of change in management based on deficient results, we conclude that there is a low utility of serum folate testing for any indication in inpatients and emergency department patients in folic acid‐fortified countries. Based on prior studies, and supported by our results, there is no evidence for checking serum folate levels in delirium, dementia, peripheral neuropathy, malnutrition, or any of the other indications. In addition, our results demonstrate a low utility even in patients with anemia or macrocytic anemia.

The rate of serum folate deficiency in our study was significantly lower than prior studies.[24, 26] There may have been geographical factors that led to a lower prevalence of folate deficiency in our study population. Our cohort included inpatients and emergency department patients, whereas previous studies had a majority of outpatients. It is known that serum folate levels can rapidly fluctuate with proper nutrition.[34] It may be that our patients received nutrition in the hospital that corrected serum folate levels prior to laboratory testing.

In addition to the low utility of serum folate testing, the charge per deficient result in our study ($158,022) was more than 100‐fold higher than that in the Robinson and Mladenovic study ($1321).[24] Even when correcting for variability in hospital charges by using the charge from the latter study, the charge per deficient serum folate test remained 50‐fold higher ($74,772). This implies that the increase in charge per deficient result was driven in part by a decreased rate of deficient tests. Folic acid fortification is likely responsible for some of the decrease. However, we believe another source is the excessive ordering of serum folate tests in patients without previously accepted indications. Because no change in management was made for the deficient patients in our study, the charge per serum folate deficient result that changed management approached infinity. This compares to $9979 in the Robinson and Mladenovic analysis.[24]

The cost to the hospital of a serum folate test was much lower than the charge, and estimated to be <$2093 per deficient result. Because serum folate tests are performed on a highly automated, random access analyzer that performs thousands of other measurements daily, the capital and labor costs for each test was well below $0.50 combined. With the addition of reagent costs, our total cost for each serum folate measurement was <$2.00. It is somewhat difficult to extrapolate these values to other hospitals, as exact costs and charges are variable. Nonetheless, the exceptionally low utility of serum folate testing makes the costs associated with these tests excessive.

Our study has several limitations. We conducted our study at a single institution in a country with mandatory folic acid fortification. Our results may not be generalizable to other institutions or patient populations, such as those in countries without mandatory folic acid fortification. Only 259 (12.4%) charts were reviewed, and indications were determined in 93.6% of charts, which may have caused our frequency to vary from the true frequency. Additionally, the low rate of deficient serum folate results limited our ability to identify associations with deficiency. Further evaluation for geographic variations of serum folate deficiency may reveal variable rates.

We conclude that in folic acid fortified countries, the rate of serum folate deficiency is increasingly rare, and the charge to patients and payers per deficient result is exceptionally high. In addition, testing in our study did not change clinical management, which makes the costs associated with these test wasteful. Further evaluation of serum folate testing of inpatients and emergency department patients in folic acid fortified countries is warranted; however, based on our results the utility appears poor for all indications.

Folate deficiency has been associated with a number of medical conditions. It is well established that folate deficiency leads to macrocytic anemia,[1, 2] and that supplementation of folic acid during pregnancy leads to decreased rates of neural tube defects.[3] Folate deficiency has also been hypothesized to affect other conditions including dementia, delirium, peripheral neuropathy, depression, cancer, and cardiovascular disease.[4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18] Most of these latter assertions are based on case reports or observational studies, with randomized controlled trials failing to demonstrate benefit of folic acid supplementation.[19, 20, 21]

Prior to mandatory folic acid fortification in the United States, the prevalence of folate deficiency was estimated to be between 3% and 16%.[16, 22, 23] In a study conducted prior to fortification, serum folate levels were evaluated in patients presenting with macrocytosis and anemia.[24] The study found that 2.3% of patients were serum folate deficient, with a change in management occurring in 24% of the deficient patients. The study also found that patients were charged $9979 per result that changed physician management.

In 1998, mandatory folic acid fortification began in the United States, and the prevalence of folate deficiency in the general population decreased to an estimated 0.5%.[23, 25] In a postfortification study, serum folate levels were evaluated in patients with anemia, dementia, or altered mental status.[26] The overall rate of serum folate deficiency was 0.4%, with the authors concluding that there was a lack of utility in serum folate testing. Despite this, algorithms addressing the evaluation of anemia continue to include serum folate levels.[2, 27, 28]

To our knowledge, the use of serum folate testing in the inpatient and emergency department population has never been independently evaluated. In our study, we aimed to characterize the indications, rate of deficiency, charge and cost per deficient result, and change in management per deficient result in inpatient and emergency department serum folate testing. We hypothesized that serum folate testing in these populations would have poor utility and would not be cost‐effective for any indication.

METHODS

We conducted a retrospective review of all serum folate tests ordered in inpatient units and the emergency department at a large academic medical center in Boston, Massachusetts from January 1, 2011 through December 31, 2011. The test was considered to be an inpatient or emergency department test based on the location of the blood draw on which the test was performed. Serum folate values were determined using a chemiluminescent competitive binding protein assay on an E170 analyzer as prescribed by the manufacturer (Roche Diagnostics, Indianapolis, IN). We defined serum folate levels as deficient (3.0 ng/mL), low‐normal (3.0 ng/mL3.9 ng/mL),[26] normal (4.0 ng/mL20.0 ng/mL), and high (>20.0 ng/mL). Erythrocyte folate levels are not routinely ordered at our institution and were not measured in our study.[29] Macrocytosis was defined as mean corpuscular volume of >99 fL. Vitamin B12 deficiency was defined as vitamin B12 level of under 200 pg/mL or vitamin B12 level of 200 to 300 pg/mL, with a methylmalonic acid >270 nmol/L and a normal homocysteine level (514 mol/L).[30, 31]

We evaluated 250 randomly selected serum folate levels and all deficient or low‐normal serum folate levels and recorded indication, comorbidities, age, sex, race or ethnicity, hemoglobin, hematocrit, mean corpuscular volume, vitamin B12 level, folic acid supplement on presentation, and folic acid supplement on discharge. Indications were determined by chart review. If serum folate was checked at the same time as iron studies, it was assumed that the indication was anemia without macrocytosis or anemia with macrocytosis unless otherwise documented. Comorbidities were selected based on historical risk factors and included depression, peripheral neuropathy, intestinal surgery, gastric bypass, cirrhosis, inflammatory bowel disease, celiac disease, delirium, dementia, alcohol abuse, malnutrition, anemia, end‐stage renal disease, vitamin B12 deficiency, or current use of phenytoin, valproic acid, or methotrexate.[32]

A charge analysis was performed using the same methodology as Robinson and Mladenovic.[24] We defined the charge of serum folate testing as our institution's charge to the patient or payer, which was $151.00 per test. Because hospital charges are variable, we also made a second calculation based on the charge per patient or payer from the Robinson and Mladenovic study,[24] which was $71.00. The analytical cost to our hospital of performing each serum folate test was <$2.00. We determined the total charge and cost for all serum folate tests and the charge and cost per deficient result.

The study was reviewed by the institutional review board and determined to be exempt.

RESULTS

In 2011, a total of 2093 serum folate levels were obtained on 1944 inpatients and emergency department patients. Of the total patients, 79.9% were inpatients and 20.1% were emergency department patients. Of the patients with tests performed in the emergency department, 98.1% were admitted to an inpatient unit.

Of the 250 random chart reviews, all had normal or high serum folate levels. The demographics, indications, and comorbidities are listed in Table 1. The most common indications were anemia without macrocytosis (43.2%), anemia with macrocytosis (13.2%; mean corpuscular volume [MCV], 106.8 fL), delirium (12.0%), malnutrition (6.4%), and peripheral neuropathy (6.0%). The other indications included thrombocytopenia, macrocytosis (without anemia), methotrexate use, alcohol abuse, frequent falls, syncope, headache, lethargy, optic nerve neuropathy, paranoia, psychosis, leukopenia, anxiety, and suicidal ideation. All of these individual indications were 2% of total reviewed indications. There were 16 cases (6.4%) without a documented indication.

Of the 2093 serum folate levels, there were 2 deficient (0.1%), 7 low‐normal (0.3%), 1487 normal (71.1%), and 597 high (28.5%) levels (Table 2). There were 128 patients (6.6%) who had more than 1 serum folate level checked within the prior 12 months, with 1 patient having 5 levels obtained during that time period. All of the deficient and low‐normal serum folate results are listed in Table 3. Of the 9 deficient or low‐normal serum folate levels, 8 had comorbid risk factors for folate deficiency. One of the deficient cases was on folic acid and multivitamin supplementation on presentation, although nonadherence with these supplements was documented in the medical record. The other deficient case was not on folic acid supplementation and did not receive folic acid supplementation for the deficient result. Vitamin B12 levels were checked simultaneously to serum folate levels in 85.2% of cases and within 6 months in 99.2% of cases. Of these patients, 2.0% were found to have vitamin B12 deficiency.

Based on our institution's charge for serum folate, a total of $316,043 was charged for the 2093 serum folate tests. The amount charged per deficient result was $158,022. Substituting the charge from the Robinson and Mladenovic study,[24] we calculated the corresponding total charge and charge per deficient result as $149,545 and $74,772, respectively. The actual total cost to our hospital was <$4186, with a cost per deficient test of <$2093.

DISCUSSION

Serum folate levels are often obtained when evaluating anemia without macrocytosis and anemia with macrocytosis.[2] They are also frequently obtained in the evaluation of delirium and dementia. A prior study evaluated both inpatient and outpatient serum folate levels in anemia, dementia, and altered mental status and found only 0.4% of serum folate results to be deficient.[26] In their study, the indications for serum folate tests were anemia or macrocytic anemia (60%) and dementia or altered mental status (30%).

We found the indications for serum folate testing in inpatients and emergency department patients to be different than prior studies. The majority of tests were done to evaluate anemia without macrocytosis (43.2%) or anemia with macrocytosis (13.2%). Lower percentages were done for the evaluation of delirium (12.0%) or dementia (3.2%). In addition, there were multiple indications that have not been noted in previous studies, including depression, peripheral neuropathy, malnutrition, pancytopenia, and others. These accounted for 28.0% of all indications. The reason for the difference in indications compared to prior studies is unknown but may be related to our cohort of exclusively inpatients and emergency department patients. Also, we observed a high concurrence of serum folate and vitamin B12 testing, with 85.2% of serum folate levels ordered at the same time as vitamin B12 levels. It appears that the tests are often ordered together even when the indication suggests that vitamin B12 alone may be more appropriate, such as peripheral neuropathy.

We found that serum folate deficiency was rare, occurring in only 2 of 2093 results. Furthermore, the deficient serum folate results may have been checked for inappropriate indications. The first deficient result was noted as part of a stroke workup in a patient not taking folic acid supplementation. Current guidelines do not recommend serum folate testing in patients with new stroke.[33] In the second deficient case, serum folate testing was performed for evaluation of macrocytic anemia with an MCV of 119 fL. Although reasonable, this was an alcoholic patient presenting with acute gastrointestinal bleeding already on folic acid and multivitamin supplementation and known nonadherence with these supplements. In neither case was there a change in management based on the deficient result.

Given the low rate of serum folate deficiency and the lack of change in management based on deficient results, we conclude that there is a low utility of serum folate testing for any indication in inpatients and emergency department patients in folic acid‐fortified countries. Based on prior studies, and supported by our results, there is no evidence for checking serum folate levels in delirium, dementia, peripheral neuropathy, malnutrition, or any of the other indications. In addition, our results demonstrate a low utility even in patients with anemia or macrocytic anemia.

The rate of serum folate deficiency in our study was significantly lower than prior studies.[24, 26] There may have been geographical factors that led to a lower prevalence of folate deficiency in our study population. Our cohort included inpatients and emergency department patients, whereas previous studies had a majority of outpatients. It is known that serum folate levels can rapidly fluctuate with proper nutrition.[34] It may be that our patients received nutrition in the hospital that corrected serum folate levels prior to laboratory testing.

In addition to the low utility of serum folate testing, the charge per deficient result in our study ($158,022) was more than 100‐fold higher than that in the Robinson and Mladenovic study ($1321).[24] Even when correcting for variability in hospital charges by using the charge from the latter study, the charge per deficient serum folate test remained 50‐fold higher ($74,772). This implies that the increase in charge per deficient result was driven in part by a decreased rate of deficient tests. Folic acid fortification is likely responsible for some of the decrease. However, we believe another source is the excessive ordering of serum folate tests in patients without previously accepted indications. Because no change in management was made for the deficient patients in our study, the charge per serum folate deficient result that changed management approached infinity. This compares to $9979 in the Robinson and Mladenovic analysis.[24]

The cost to the hospital of a serum folate test was much lower than the charge, and estimated to be <$2093 per deficient result. Because serum folate tests are performed on a highly automated, random access analyzer that performs thousands of other measurements daily, the capital and labor costs for each test was well below $0.50 combined. With the addition of reagent costs, our total cost for each serum folate measurement was <$2.00. It is somewhat difficult to extrapolate these values to other hospitals, as exact costs and charges are variable. Nonetheless, the exceptionally low utility of serum folate testing makes the costs associated with these tests excessive.

Our study has several limitations. We conducted our study at a single institution in a country with mandatory folic acid fortification. Our results may not be generalizable to other institutions or patient populations, such as those in countries without mandatory folic acid fortification. Only 259 (12.4%) charts were reviewed, and indications were determined in 93.6% of charts, which may have caused our frequency to vary from the true frequency. Additionally, the low rate of deficient serum folate results limited our ability to identify associations with deficiency. Further evaluation for geographic variations of serum folate deficiency may reveal variable rates.

We conclude that in folic acid fortified countries, the rate of serum folate deficiency is increasingly rare, and the charge to patients and payers per deficient result is exceptionally high. In addition, testing in our study did not change clinical management, which makes the costs associated with these test wasteful. Further evaluation of serum folate testing of inpatients and emergency department patients in folic acid fortified countries is warranted; however, based on our results the utility appears poor for all indications.

Sickle cell disease (SCD) accounts for approximately 113,000 hospital admissions annually in the United States, at a cost of approximately $500 million.1 The majority of these hospital admissions are due to painful episodes, vaso‐occlusive crises, often triggered by a psychological or physical stressor.2 Most individuals manage these crises at home,3 with sporadic admissions occurring, on average, 1.5 times per year.4 However, a minority of patients are admitted as often as several times per month, persistent over successive years,5, 6 a phenomenon we call extremely high hospital use (EHHU). These patients account for a disproportionate share of total costs, and may suffer worse health outcomes. Three or more hospital admissions per year has been correlated with a lower 5‐year survival rate,7 and high emergency room utilization was found to be associated with more reported pain, and more opioid use at home.8

To improve patient quality of life and to decrease healthcare costs in the management of SCD, there has been increased focus on predicting high utilization9 and identifying strategies to decrease hospitalization rates, especially among patients with EHHU.10 Although SCD patients with EHHU have been identified as a small group of outliers,5 the psychosocial factors associated with EHHU in adults with SCD have not been investigated. The objective of this qualitative study is to characterize the subjective experience of patients with sickle cell disease and EHHU, and generate hypotheses about its antecedents and consequences.

METHODS

The institutional review board (IRB) of Yale University School of Medicine, New Haven, CT, approved the research protocol.

Narrative Analysis

The analysis team consisted of 2 psychiatrists (1 with additional training in internal medicine), 1 medical student, and 1 internist with additional training in addiction medicine. Analysts read each transcript, became thoroughly familiar with its content, and met to discuss preliminary findings. Then, we created patient experts among the group, assigning each analyst 2 interviews with which s/he prepared a detailed summary in the first person, using the participant's own words, according to an established process in phenomenological research13 (Figure 1). These narrative summaries allowed for the development of a holistic view of the participant, the creation of a narrative structure, and the fostering of an empathic bridge,13 a connection between the experiences of the participant and those of the reviewer. The summaries were read aloud at research meetings allowing for discussion, and the content of the summaries were modified based on the consensus of the group.

Figure 1

Next, we randomly rotated the narrative summaries so that each of the 4 analysts became an expert for 2 additional participants in order to critically evaluate the compiled narratives, and develop a structural summary14a summary of the prevalent themes. We extracted content from the narrative summaries based on these common themes, and returned to the transcripts as needed for relevant quotations. This inductive process allowed unique participant narratives to come through unconstrained by a predetermined coding structure.

The team reached consensus on organizing themes following the chronology of childhood to adulthood. This model was utilized to preserve the narrative basis of the methodology, and to ultimately elucidate the antecedents, subjective experience, and consequences of EHHU. An audit trail was maintained throughout the data analysis process.

RESULTS

Table 1 displays demographic, clinical, and hospitalization data for the 8 participants. These patients represented approximately 8% of the population with sickle cell disease at the study institution, but accounted for 57% of hospital days among sickle cell disease patients over a 3‐year period, with cumulative hospital days near or above 100 days per patient each year. Greater than 90% of admissions were for vaso‐occlusive crises without other SCD‐related complications. However, many participants had complicated medical histories, including avascular necrosis, acute chest syndrome, and leg ulcers.

Participant interviews presented a common narrative of the evolution of EHHU from a young age, culminating in a universally negative description of hospitalization: It's like jail. (participant 2); It's like a massacre, coming in the hospital; I get tortured. (participant 1). Saturation was reached on major themes, which fit into 3 general categories: pain and opioid medication use, interpersonal relationships, and personal development.

DISCUSSION

Our study population represents a unique and understudied group among patients with SCD. While several themes from prior research on individuals with SCD were presentreciprocal mistrust between patients and providers surrounding opioid analgesics and pain reporting,15, 16 racial and disease‐related bias,17 patient dissatisfaction with clinical services,18the common narrative of thwarted personal development in the setting of a long history of hospitalization and opioid use was striking.

The developmental perspective posits that age‐appropriate tasks govern basic capacities and skills (academic, interpersonal, affective, and cognitive) honed through institutional interactions (family, school, and community), which allow individuals to develop autonomy that guides them into effective participation in social groups and civil society, and eventually to becoming guarantors for the next generation. Our participants described problems such as social isolation, depression, and dependence on medications, all linked to their description of recurrent stays in the hospital during childhood and adolescence, where missed vocational and social opportunities left their indelible mark. Participants expressed an awareness of their inability to lead productive lives, and the perception that they were burdensome to their caregivers and the hospital.

While previous research has correlated high hospital utilization in SCD with factors like poor coping strategies,1921 high levels of stress,22 and inadequate support,17 our interviews suggest that such psychosocial difficulties may be consequences as well as causes of hospitalization, creating an accelerating downward spiral of dysfunction. At the center of this spiral is participants' ongoing experience of pain, which may be related to SCD, medications, or neither.23 Additionally, chronic anemia, opioid exposure, airway disease, and cerebrovascular disease are all implicated in impaired neuropsychological functioning in children and adolescents with sickle cell disease.24, 25

Clinical features of SCD remain relevant to hospitalization in adulthood. Chart review revealed that the vast majority of inpatient admissions were due to vaso‐occlusive crises uncomplicated by SCD‐related pathology, such as aseptic necrosis of bone or acute chest syndrome. This finding is consistent with previous work,9 which correlated new onset of high hospital use with SCD‐related complications, but not reliably with persistent EHHU, our study population.

The double‐edged sword of opioid use26 was starkly evident in participants' narratives. Crippling vaso‐occlusive crises were competently treated with opioids starting in childhood, but then a cycle of increasing outpatient doses of opioids and more frequent and longer courses of inpatient intravenous opioids followed. Participants felt judged and stigmatized for seeking one of the few treatment options they had been offered, resulting in confusion and bitterness at times. Other potential complications of long‐term opioid therapy less well known to patients and providers such as hypogonadism and hyperalgesia27may have played a role in the patient experience and should be examined in future research. In addition, undertreatment of pain may lead to pseudoaddiction,28 underscoring the complexity of delineating the pathologies of dependence, addiction, withdrawal, acute pain, and chronic pain.

Our study is limited primarily by the fact that it was conducted with a small number of participants. It is also possible that institutional variation, especially with regard to pain management, makes it difficult to generalize our hypotheses. Similarly, our participants grew up in similar environments outside the hospital, which may differ significantly from environments of other individuals with EHHU. Lastly, participants were all interviewed as inpatients, and the acuteness of their illness may have influenced responses. Despite these limitations, we achieved saturation on the major themes, and there was substantial agreement in their experiences of their illness.

Breaking the cycle of alienation from the external world and dependence on the hospital necessitates an acknowledgement of the role of the hospital, pain, and opioid use in the long‐term development of individuals with EHHU. Further research should test this developmental hypothesis, and focus on early interventions and the critical transition from pediatric to adult care.25 Longitudinal quantitative analysis could include psychosocial variables in SCD in the attempt to predict EHHU as has been accomplished in the chronic pain literature.29 Additionally, a comprehensive qualitative approach including the perspectives of caregivers, family members, and comparison to low hospital utilizers will better inform interventions aimed at ameliorating EHHU. It is particularly important to understand the similarities and differences in the long‐term development of patients with SCD who demonstrate EHHU versus low hospital use. The optimal strategy for opioid use in the long‐term management of pain in patients with SCD remains to be determined. Alternatives to opioids should be investigated in a controlled trial, and institutional differences should be examined as they relate to EHHU and pain‐management strategies. Lastly, our results suggest that psychosocial and skill rehabilitation may mitigate EHHU, and that multidisciplinary resources proactively directed towards this population will reduce hospitalization.30

Sickle cell disease (SCD) accounts for approximately 113,000 hospital admissions annually in the United States, at a cost of approximately $500 million.1 The majority of these hospital admissions are due to painful episodes, vaso‐occlusive crises, often triggered by a psychological or physical stressor.2 Most individuals manage these crises at home,3 with sporadic admissions occurring, on average, 1.5 times per year.4 However, a minority of patients are admitted as often as several times per month, persistent over successive years,5, 6 a phenomenon we call extremely high hospital use (EHHU). These patients account for a disproportionate share of total costs, and may suffer worse health outcomes. Three or more hospital admissions per year has been correlated with a lower 5‐year survival rate,7 and high emergency room utilization was found to be associated with more reported pain, and more opioid use at home.8

To improve patient quality of life and to decrease healthcare costs in the management of SCD, there has been increased focus on predicting high utilization9 and identifying strategies to decrease hospitalization rates, especially among patients with EHHU.10 Although SCD patients with EHHU have been identified as a small group of outliers,5 the psychosocial factors associated with EHHU in adults with SCD have not been investigated. The objective of this qualitative study is to characterize the subjective experience of patients with sickle cell disease and EHHU, and generate hypotheses about its antecedents and consequences.

METHODS

The institutional review board (IRB) of Yale University School of Medicine, New Haven, CT, approved the research protocol.

Narrative Analysis

The analysis team consisted of 2 psychiatrists (1 with additional training in internal medicine), 1 medical student, and 1 internist with additional training in addiction medicine. Analysts read each transcript, became thoroughly familiar with its content, and met to discuss preliminary findings. Then, we created patient experts among the group, assigning each analyst 2 interviews with which s/he prepared a detailed summary in the first person, using the participant's own words, according to an established process in phenomenological research13 (Figure 1). These narrative summaries allowed for the development of a holistic view of the participant, the creation of a narrative structure, and the fostering of an empathic bridge,13 a connection between the experiences of the participant and those of the reviewer. The summaries were read aloud at research meetings allowing for discussion, and the content of the summaries were modified based on the consensus of the group.

Figure 1

Next, we randomly rotated the narrative summaries so that each of the 4 analysts became an expert for 2 additional participants in order to critically evaluate the compiled narratives, and develop a structural summary14a summary of the prevalent themes. We extracted content from the narrative summaries based on these common themes, and returned to the transcripts as needed for relevant quotations. This inductive process allowed unique participant narratives to come through unconstrained by a predetermined coding structure.

The team reached consensus on organizing themes following the chronology of childhood to adulthood. This model was utilized to preserve the narrative basis of the methodology, and to ultimately elucidate the antecedents, subjective experience, and consequences of EHHU. An audit trail was maintained throughout the data analysis process.

RESULTS

Table 1 displays demographic, clinical, and hospitalization data for the 8 participants. These patients represented approximately 8% of the population with sickle cell disease at the study institution, but accounted for 57% of hospital days among sickle cell disease patients over a 3‐year period, with cumulative hospital days near or above 100 days per patient each year. Greater than 90% of admissions were for vaso‐occlusive crises without other SCD‐related complications. However, many participants had complicated medical histories, including avascular necrosis, acute chest syndrome, and leg ulcers.

Participant interviews presented a common narrative of the evolution of EHHU from a young age, culminating in a universally negative description of hospitalization: It's like jail. (participant 2); It's like a massacre, coming in the hospital; I get tortured. (participant 1). Saturation was reached on major themes, which fit into 3 general categories: pain and opioid medication use, interpersonal relationships, and personal development.

DISCUSSION

Our study population represents a unique and understudied group among patients with SCD. While several themes from prior research on individuals with SCD were presentreciprocal mistrust between patients and providers surrounding opioid analgesics and pain reporting,15, 16 racial and disease‐related bias,17 patient dissatisfaction with clinical services,18the common narrative of thwarted personal development in the setting of a long history of hospitalization and opioid use was striking.

The developmental perspective posits that age‐appropriate tasks govern basic capacities and skills (academic, interpersonal, affective, and cognitive) honed through institutional interactions (family, school, and community), which allow individuals to develop autonomy that guides them into effective participation in social groups and civil society, and eventually to becoming guarantors for the next generation. Our participants described problems such as social isolation, depression, and dependence on medications, all linked to their description of recurrent stays in the hospital during childhood and adolescence, where missed vocational and social opportunities left their indelible mark. Participants expressed an awareness of their inability to lead productive lives, and the perception that they were burdensome to their caregivers and the hospital.

While previous research has correlated high hospital utilization in SCD with factors like poor coping strategies,1921 high levels of stress,22 and inadequate support,17 our interviews suggest that such psychosocial difficulties may be consequences as well as causes of hospitalization, creating an accelerating downward spiral of dysfunction. At the center of this spiral is participants' ongoing experience of pain, which may be related to SCD, medications, or neither.23 Additionally, chronic anemia, opioid exposure, airway disease, and cerebrovascular disease are all implicated in impaired neuropsychological functioning in children and adolescents with sickle cell disease.24, 25

Clinical features of SCD remain relevant to hospitalization in adulthood. Chart review revealed that the vast majority of inpatient admissions were due to vaso‐occlusive crises uncomplicated by SCD‐related pathology, such as aseptic necrosis of bone or acute chest syndrome. This finding is consistent with previous work,9 which correlated new onset of high hospital use with SCD‐related complications, but not reliably with persistent EHHU, our study population.

The double‐edged sword of opioid use26 was starkly evident in participants' narratives. Crippling vaso‐occlusive crises were competently treated with opioids starting in childhood, but then a cycle of increasing outpatient doses of opioids and more frequent and longer courses of inpatient intravenous opioids followed. Participants felt judged and stigmatized for seeking one of the few treatment options they had been offered, resulting in confusion and bitterness at times. Other potential complications of long‐term opioid therapy less well known to patients and providers such as hypogonadism and hyperalgesia27may have played a role in the patient experience and should be examined in future research. In addition, undertreatment of pain may lead to pseudoaddiction,28 underscoring the complexity of delineating the pathologies of dependence, addiction, withdrawal, acute pain, and chronic pain.

Our study is limited primarily by the fact that it was conducted with a small number of participants. It is also possible that institutional variation, especially with regard to pain management, makes it difficult to generalize our hypotheses. Similarly, our participants grew up in similar environments outside the hospital, which may differ significantly from environments of other individuals with EHHU. Lastly, participants were all interviewed as inpatients, and the acuteness of their illness may have influenced responses. Despite these limitations, we achieved saturation on the major themes, and there was substantial agreement in their experiences of their illness.

Breaking the cycle of alienation from the external world and dependence on the hospital necessitates an acknowledgement of the role of the hospital, pain, and opioid use in the long‐term development of individuals with EHHU. Further research should test this developmental hypothesis, and focus on early interventions and the critical transition from pediatric to adult care.25 Longitudinal quantitative analysis could include psychosocial variables in SCD in the attempt to predict EHHU as has been accomplished in the chronic pain literature.29 Additionally, a comprehensive qualitative approach including the perspectives of caregivers, family members, and comparison to low hospital utilizers will better inform interventions aimed at ameliorating EHHU. It is particularly important to understand the similarities and differences in the long‐term development of patients with SCD who demonstrate EHHU versus low hospital use. The optimal strategy for opioid use in the long‐term management of pain in patients with SCD remains to be determined. Alternatives to opioids should be investigated in a controlled trial, and institutional differences should be examined as they relate to EHHU and pain‐management strategies. Lastly, our results suggest that psychosocial and skill rehabilitation may mitigate EHHU, and that multidisciplinary resources proactively directed towards this population will reduce hospitalization.30

Sickle cell disease (SCD) accounts for approximately 113,000 hospital admissions annually in the United States, at a cost of approximately $500 million.1 The majority of these hospital admissions are due to painful episodes, vaso‐occlusive crises, often triggered by a psychological or physical stressor.2 Most individuals manage these crises at home,3 with sporadic admissions occurring, on average, 1.5 times per year.4 However, a minority of patients are admitted as often as several times per month, persistent over successive years,5, 6 a phenomenon we call extremely high hospital use (EHHU). These patients account for a disproportionate share of total costs, and may suffer worse health outcomes. Three or more hospital admissions per year has been correlated with a lower 5‐year survival rate,7 and high emergency room utilization was found to be associated with more reported pain, and more opioid use at home.8

To improve patient quality of life and to decrease healthcare costs in the management of SCD, there has been increased focus on predicting high utilization9 and identifying strategies to decrease hospitalization rates, especially among patients with EHHU.10 Although SCD patients with EHHU have been identified as a small group of outliers,5 the psychosocial factors associated with EHHU in adults with SCD have not been investigated. The objective of this qualitative study is to characterize the subjective experience of patients with sickle cell disease and EHHU, and generate hypotheses about its antecedents and consequences.

METHODS

The institutional review board (IRB) of Yale University School of Medicine, New Haven, CT, approved the research protocol.

Narrative Analysis

The analysis team consisted of 2 psychiatrists (1 with additional training in internal medicine), 1 medical student, and 1 internist with additional training in addiction medicine. Analysts read each transcript, became thoroughly familiar with its content, and met to discuss preliminary findings. Then, we created patient experts among the group, assigning each analyst 2 interviews with which s/he prepared a detailed summary in the first person, using the participant's own words, according to an established process in phenomenological research13 (Figure 1). These narrative summaries allowed for the development of a holistic view of the participant, the creation of a narrative structure, and the fostering of an empathic bridge,13 a connection between the experiences of the participant and those of the reviewer. The summaries were read aloud at research meetings allowing for discussion, and the content of the summaries were modified based on the consensus of the group.

Figure 1

Next, we randomly rotated the narrative summaries so that each of the 4 analysts became an expert for 2 additional participants in order to critically evaluate the compiled narratives, and develop a structural summary14a summary of the prevalent themes. We extracted content from the narrative summaries based on these common themes, and returned to the transcripts as needed for relevant quotations. This inductive process allowed unique participant narratives to come through unconstrained by a predetermined coding structure.

The team reached consensus on organizing themes following the chronology of childhood to adulthood. This model was utilized to preserve the narrative basis of the methodology, and to ultimately elucidate the antecedents, subjective experience, and consequences of EHHU. An audit trail was maintained throughout the data analysis process.

RESULTS

Table 1 displays demographic, clinical, and hospitalization data for the 8 participants. These patients represented approximately 8% of the population with sickle cell disease at the study institution, but accounted for 57% of hospital days among sickle cell disease patients over a 3‐year period, with cumulative hospital days near or above 100 days per patient each year. Greater than 90% of admissions were for vaso‐occlusive crises without other SCD‐related complications. However, many participants had complicated medical histories, including avascular necrosis, acute chest syndrome, and leg ulcers.

Participant interviews presented a common narrative of the evolution of EHHU from a young age, culminating in a universally negative description of hospitalization: It's like jail. (participant 2); It's like a massacre, coming in the hospital; I get tortured. (participant 1). Saturation was reached on major themes, which fit into 3 general categories: pain and opioid medication use, interpersonal relationships, and personal development.

DISCUSSION

Our study population represents a unique and understudied group among patients with SCD. While several themes from prior research on individuals with SCD were presentreciprocal mistrust between patients and providers surrounding opioid analgesics and pain reporting,15, 16 racial and disease‐related bias,17 patient dissatisfaction with clinical services,18the common narrative of thwarted personal development in the setting of a long history of hospitalization and opioid use was striking.

The developmental perspective posits that age‐appropriate tasks govern basic capacities and skills (academic, interpersonal, affective, and cognitive) honed through institutional interactions (family, school, and community), which allow individuals to develop autonomy that guides them into effective participation in social groups and civil society, and eventually to becoming guarantors for the next generation. Our participants described problems such as social isolation, depression, and dependence on medications, all linked to their description of recurrent stays in the hospital during childhood and adolescence, where missed vocational and social opportunities left their indelible mark. Participants expressed an awareness of their inability to lead productive lives, and the perception that they were burdensome to their caregivers and the hospital.

While previous research has correlated high hospital utilization in SCD with factors like poor coping strategies,1921 high levels of stress,22 and inadequate support,17 our interviews suggest that such psychosocial difficulties may be consequences as well as causes of hospitalization, creating an accelerating downward spiral of dysfunction. At the center of this spiral is participants' ongoing experience of pain, which may be related to SCD, medications, or neither.23 Additionally, chronic anemia, opioid exposure, airway disease, and cerebrovascular disease are all implicated in impaired neuropsychological functioning in children and adolescents with sickle cell disease.24, 25

Clinical features of SCD remain relevant to hospitalization in adulthood. Chart review revealed that the vast majority of inpatient admissions were due to vaso‐occlusive crises uncomplicated by SCD‐related pathology, such as aseptic necrosis of bone or acute chest syndrome. This finding is consistent with previous work,9 which correlated new onset of high hospital use with SCD‐related complications, but not reliably with persistent EHHU, our study population.

The double‐edged sword of opioid use26 was starkly evident in participants' narratives. Crippling vaso‐occlusive crises were competently treated with opioids starting in childhood, but then a cycle of increasing outpatient doses of opioids and more frequent and longer courses of inpatient intravenous opioids followed. Participants felt judged and stigmatized for seeking one of the few treatment options they had been offered, resulting in confusion and bitterness at times. Other potential complications of long‐term opioid therapy less well known to patients and providers such as hypogonadism and hyperalgesia27may have played a role in the patient experience and should be examined in future research. In addition, undertreatment of pain may lead to pseudoaddiction,28 underscoring the complexity of delineating the pathologies of dependence, addiction, withdrawal, acute pain, and chronic pain.

Our study is limited primarily by the fact that it was conducted with a small number of participants. It is also possible that institutional variation, especially with regard to pain management, makes it difficult to generalize our hypotheses. Similarly, our participants grew up in similar environments outside the hospital, which may differ significantly from environments of other individuals with EHHU. Lastly, participants were all interviewed as inpatients, and the acuteness of their illness may have influenced responses. Despite these limitations, we achieved saturation on the major themes, and there was substantial agreement in their experiences of their illness.

Breaking the cycle of alienation from the external world and dependence on the hospital necessitates an acknowledgement of the role of the hospital, pain, and opioid use in the long‐term development of individuals with EHHU. Further research should test this developmental hypothesis, and focus on early interventions and the critical transition from pediatric to adult care.25 Longitudinal quantitative analysis could include psychosocial variables in SCD in the attempt to predict EHHU as has been accomplished in the chronic pain literature.29 Additionally, a comprehensive qualitative approach including the perspectives of caregivers, family members, and comparison to low hospital utilizers will better inform interventions aimed at ameliorating EHHU. It is particularly important to understand the similarities and differences in the long‐term development of patients with SCD who demonstrate EHHU versus low hospital use. The optimal strategy for opioid use in the long‐term management of pain in patients with SCD remains to be determined. Alternatives to opioids should be investigated in a controlled trial, and institutional differences should be examined as they relate to EHHU and pain‐management strategies. Lastly, our results suggest that psychosocial and skill rehabilitation may mitigate EHHU, and that multidisciplinary resources proactively directed towards this population will reduce hospitalization.30

Physician handoff is a common and essential component of daily patient care that includes transfer of important clinical patient information and accountability of patient care. Thus, high‐quality physician handoffs are crucial to ensure patient safety and continuity of patient care, especially with the new resident work hour restriction in North America.[1, 2] As such, healthcare organizations including the World Health Organization[3] have issued specific goals and organizational challenges to improve the effectiveness and coordination of communication among the care/service providers and with the recipients of care/service across the continuum in healthcare.[4, 5]

It has been well‐documented that physician handoffs in hospital settings are often unstructured and not standardized, which leads to medical errors and jeopardizes patient safety.[2, 6, 7, 8, 9, 10, 11, 12] This lack of standardization of physician handoff for hospitalized patients occurs in every major in‐hospital service and affects trainees and staff.[2, 6, 7, 9, 10, 12, 13] It has been demonstrated in healthcare and in other domains that a standardized handoff protocol that involves both verbal communication and written handoff documents is likely to be an effective method of handoff to decrease miscommunication and associated errors.[14, 15, 16, 17] Computerized physician handoff tools (CHTs) have been increasingly deployed to address these challenges and have quickly gained popularity among physicians for documenting patient information during physician handoff for hospitalized patients.[18] CHTs can be an complementary part of electronic medical record (EMR) systems, but not a substitute since their focus is to deliver concise and essential information vital for patient care during interfaces of patient care.

Two recent systematic reviews have examined information technology (IT) systems to promote the handoff process in healthcare.[17, 19] However, to our knowledge, there has not been a systematic review of the potential role of CHT in physician handoff and quality of patient care for hospitalized patients. We therefore conducted a systematic review to examine the current evidence for CHTs in physician handoff for hospitalized patients, focusing specifically on potential effects on continuity of patient care, physician work efficiency, quality of handoffs, and patient outcomes.

METHODS

RESULTS

Study Selection

A total of 1026 citations were identified in the initial search, of which 1006 studies did not evaluate CHT and were excluded by title and abstract screening. Of the 20 studies evaluated further by full‐text review, 5 were selected for the final analysis. One additional study was identified by hand searching references. The kappa score of inter‐reviewer agreement on article selection in the first stage of screening was 0.7, and for the second stage of article selection, kappa was 1.0. The reasons for exclusion in the second selection step are presented in Figure 1.

Figure 1

DISCUSSION

Our systematic review identified 6 controlled studies of CHT. Outcome parameters reported in these studies included quality of the handoff (including completeness, accuracy, and consistency), physician time management, continuity of care, adverse events, and missed patients. Our results suggest that while CHT are a promising tool, further evaluation using rigorous study methodologies is needed. These findings are somewhat surprising given increasing popularity of CHTs in daily patient care.[19, 24, 26, 27, 28] This might be due to the fact that IT adoption and use in healthcare is still in a phase of relative infancy,[29] and that the success of adopting IT systems in healthcare depends on various factors.[30]

CONCLUSIONS AND IMPLICATIONS FOR PRACTICE

Although the current literature suggests that implementation of CHTs is likely to improve physician work efficiency, satisfaction, and quality of patient care during physician handoff for hospitalized patients, the evidence supporting these potential benefits is limited. Furthermore, it is unknown what impacts CHTs may have on clinical outcomes, such as hospital length of stay and mortality. Further studies with larger sample size, multiple center involvement, and more objective patient outcome measurements are therefore needed to evaluate the roles of CHTs in physician handoff and improving the quality of patient care.

In the absence of larger studies evaluating major clinical outcomes, such as length of stay and mortality, hospitals considering innovations in the domain of computerized platforms for physician handoffs will need to consider the pros and cons of immediate system implementation on the basis of the evidence presented here versus waiting until there is more evidence from more definitive studies. In addition, our study suggests that organizations engage physicians during CHT design and develop a standardized CHT protocol that is interfaced with hospital IT systems and includes key components of handoff information, but provides flexibility to meet service‐specific needs. The evidence summarized here, while far from definitive for major outcomes, is nonetheless rather positive for the general benefits of CHTan impetus for careful design, implementation, and modification, whenever and wherever possible. Any such system implementations should, however, incorporate an evaluative component so that the evidence‐base surrounding CHT can be enhanced.

Physician handoff is a common and essential component of daily patient care that includes transfer of important clinical patient information and accountability of patient care. Thus, high‐quality physician handoffs are crucial to ensure patient safety and continuity of patient care, especially with the new resident work hour restriction in North America.[1, 2] As such, healthcare organizations including the World Health Organization[3] have issued specific goals and organizational challenges to improve the effectiveness and coordination of communication among the care/service providers and with the recipients of care/service across the continuum in healthcare.[4, 5]

It has been well‐documented that physician handoffs in hospital settings are often unstructured and not standardized, which leads to medical errors and jeopardizes patient safety.[2, 6, 7, 8, 9, 10, 11, 12] This lack of standardization of physician handoff for hospitalized patients occurs in every major in‐hospital service and affects trainees and staff.[2, 6, 7, 9, 10, 12, 13] It has been demonstrated in healthcare and in other domains that a standardized handoff protocol that involves both verbal communication and written handoff documents is likely to be an effective method of handoff to decrease miscommunication and associated errors.[14, 15, 16, 17] Computerized physician handoff tools (CHTs) have been increasingly deployed to address these challenges and have quickly gained popularity among physicians for documenting patient information during physician handoff for hospitalized patients.[18] CHTs can be an complementary part of electronic medical record (EMR) systems, but not a substitute since their focus is to deliver concise and essential information vital for patient care during interfaces of patient care.

Two recent systematic reviews have examined information technology (IT) systems to promote the handoff process in healthcare.[17, 19] However, to our knowledge, there has not been a systematic review of the potential role of CHT in physician handoff and quality of patient care for hospitalized patients. We therefore conducted a systematic review to examine the current evidence for CHTs in physician handoff for hospitalized patients, focusing specifically on potential effects on continuity of patient care, physician work efficiency, quality of handoffs, and patient outcomes.

METHODS

RESULTS

Study Selection

A total of 1026 citations were identified in the initial search, of which 1006 studies did not evaluate CHT and were excluded by title and abstract screening. Of the 20 studies evaluated further by full‐text review, 5 were selected for the final analysis. One additional study was identified by hand searching references. The kappa score of inter‐reviewer agreement on article selection in the first stage of screening was 0.7, and for the second stage of article selection, kappa was 1.0. The reasons for exclusion in the second selection step are presented in Figure 1.

Figure 1

DISCUSSION

Our systematic review identified 6 controlled studies of CHT. Outcome parameters reported in these studies included quality of the handoff (including completeness, accuracy, and consistency), physician time management, continuity of care, adverse events, and missed patients. Our results suggest that while CHT are a promising tool, further evaluation using rigorous study methodologies is needed. These findings are somewhat surprising given increasing popularity of CHTs in daily patient care.[19, 24, 26, 27, 28] This might be due to the fact that IT adoption and use in healthcare is still in a phase of relative infancy,[29] and that the success of adopting IT systems in healthcare depends on various factors.[30]

CONCLUSIONS AND IMPLICATIONS FOR PRACTICE

Although the current literature suggests that implementation of CHTs is likely to improve physician work efficiency, satisfaction, and quality of patient care during physician handoff for hospitalized patients, the evidence supporting these potential benefits is limited. Furthermore, it is unknown what impacts CHTs may have on clinical outcomes, such as hospital length of stay and mortality. Further studies with larger sample size, multiple center involvement, and more objective patient outcome measurements are therefore needed to evaluate the roles of CHTs in physician handoff and improving the quality of patient care.

In the absence of larger studies evaluating major clinical outcomes, such as length of stay and mortality, hospitals considering innovations in the domain of computerized platforms for physician handoffs will need to consider the pros and cons of immediate system implementation on the basis of the evidence presented here versus waiting until there is more evidence from more definitive studies. In addition, our study suggests that organizations engage physicians during CHT design and develop a standardized CHT protocol that is interfaced with hospital IT systems and includes key components of handoff information, but provides flexibility to meet service‐specific needs. The evidence summarized here, while far from definitive for major outcomes, is nonetheless rather positive for the general benefits of CHTan impetus for careful design, implementation, and modification, whenever and wherever possible. Any such system implementations should, however, incorporate an evaluative component so that the evidence‐base surrounding CHT can be enhanced.

Physician handoff is a common and essential component of daily patient care that includes transfer of important clinical patient information and accountability of patient care. Thus, high‐quality physician handoffs are crucial to ensure patient safety and continuity of patient care, especially with the new resident work hour restriction in North America.[1, 2] As such, healthcare organizations including the World Health Organization[3] have issued specific goals and organizational challenges to improve the effectiveness and coordination of communication among the care/service providers and with the recipients of care/service across the continuum in healthcare.[4, 5]

It has been well‐documented that physician handoffs in hospital settings are often unstructured and not standardized, which leads to medical errors and jeopardizes patient safety.[2, 6, 7, 8, 9, 10, 11, 12] This lack of standardization of physician handoff for hospitalized patients occurs in every major in‐hospital service and affects trainees and staff.[2, 6, 7, 9, 10, 12, 13] It has been demonstrated in healthcare and in other domains that a standardized handoff protocol that involves both verbal communication and written handoff documents is likely to be an effective method of handoff to decrease miscommunication and associated errors.[14, 15, 16, 17] Computerized physician handoff tools (CHTs) have been increasingly deployed to address these challenges and have quickly gained popularity among physicians for documenting patient information during physician handoff for hospitalized patients.[18] CHTs can be an complementary part of electronic medical record (EMR) systems, but not a substitute since their focus is to deliver concise and essential information vital for patient care during interfaces of patient care.

Two recent systematic reviews have examined information technology (IT) systems to promote the handoff process in healthcare.[17, 19] However, to our knowledge, there has not been a systematic review of the potential role of CHT in physician handoff and quality of patient care for hospitalized patients. We therefore conducted a systematic review to examine the current evidence for CHTs in physician handoff for hospitalized patients, focusing specifically on potential effects on continuity of patient care, physician work efficiency, quality of handoffs, and patient outcomes.

METHODS

RESULTS

Study Selection

A total of 1026 citations were identified in the initial search, of which 1006 studies did not evaluate CHT and were excluded by title and abstract screening. Of the 20 studies evaluated further by full‐text review, 5 were selected for the final analysis. One additional study was identified by hand searching references. The kappa score of inter‐reviewer agreement on article selection in the first stage of screening was 0.7, and for the second stage of article selection, kappa was 1.0. The reasons for exclusion in the second selection step are presented in Figure 1.

Figure 1

DISCUSSION

Our systematic review identified 6 controlled studies of CHT. Outcome parameters reported in these studies included quality of the handoff (including completeness, accuracy, and consistency), physician time management, continuity of care, adverse events, and missed patients. Our results suggest that while CHT are a promising tool, further evaluation using rigorous study methodologies is needed. These findings are somewhat surprising given increasing popularity of CHTs in daily patient care.[19, 24, 26, 27, 28] This might be due to the fact that IT adoption and use in healthcare is still in a phase of relative infancy,[29] and that the success of adopting IT systems in healthcare depends on various factors.[30]

CONCLUSIONS AND IMPLICATIONS FOR PRACTICE

Although the current literature suggests that implementation of CHTs is likely to improve physician work efficiency, satisfaction, and quality of patient care during physician handoff for hospitalized patients, the evidence supporting these potential benefits is limited. Furthermore, it is unknown what impacts CHTs may have on clinical outcomes, such as hospital length of stay and mortality. Further studies with larger sample size, multiple center involvement, and more objective patient outcome measurements are therefore needed to evaluate the roles of CHTs in physician handoff and improving the quality of patient care.

In the absence of larger studies evaluating major clinical outcomes, such as length of stay and mortality, hospitals considering innovations in the domain of computerized platforms for physician handoffs will need to consider the pros and cons of immediate system implementation on the basis of the evidence presented here versus waiting until there is more evidence from more definitive studies. In addition, our study suggests that organizations engage physicians during CHT design and develop a standardized CHT protocol that is interfaced with hospital IT systems and includes key components of handoff information, but provides flexibility to meet service‐specific needs. The evidence summarized here, while far from definitive for major outcomes, is nonetheless rather positive for the general benefits of CHTan impetus for careful design, implementation, and modification, whenever and wherever possible. Any such system implementations should, however, incorporate an evaluative component so that the evidence‐base surrounding CHT can be enhanced.

Hospitalized patients have increased rates of sleep disturbances.1, 2 Sleep disturbances are perceived to be disruptive to both patients and staff, a putative reason for the high rates of hypnotic use in hospitalized patients.3, 4 Zolpidem, a short‐acting, non‐benzodiazepine, benzodiazepine receptor agonist that acts at the ‐aminobutyric acid (GABA)‐A receptor complex, is the most commonly prescribed hypnotic agent in the United States.5, 6 It is also extremely commonly used in inpatient settings. Although zolpidem is thought to have a relatively benign side‐effect profile, it has been found to impair balance in healthy volunteers, even after a single dose.7 Zolpidem use has been found to be higher in community‐dwelling adults who sustained a hip fracture.8, 9

Falls in the inpatient setting are associated with significantly increased morbidity, serious injury, and can result in a prolonged hospital stay and increased healthcare expenditure.10, 11 It is for these reasons that fall reduction is one of the target aims of the Department of Health and Human Services Partnership for Patients.10 While many fall prevention programs have been shown to be effective, they are resource intensive.11 If zolpidem use were associated with increased rates of falls in hospitalized patients, decreasing zolpidem prescription could be an easy and effective intervention in order to reduce fall risk.

A previous case‐control study showed increased zolpidem use in geriatric inpatients who sustained a fall.8 However, the literature linking zolpidem use with an increased fall risk in hospitalized patients is based upon a small sample and does not correct for potential confounders, such as other medication use, delirium, or insomnia.8

We aimed to conduct a cohort study in a large inpatient teaching hospital to ascertain whether zolpidem is associated with increased rates of falls after accounting for age, sex, insomnia, delirium, and use of other medications previously shown to be associated with increased fall risk.

METHODS

All inpatients 18 years or older, admitted in 2010 to hospitals at Mayo Clinic, Rochester, MN, who were prescribed zolpidem were eligible for inclusion in the study. We excluded all patients who were pregnant and those in the intensive care unit (ICU) setting. We compared the group that was prescribed zolpidem and received it, to the group that was prescribed zolpidem but did not receive the medication. We restricted the analysis to patients who were prescribed zolpidem because there may be systematic differences between patients eligible to receive zolpidem and patients in whom zolpidem is not prescribed at all. Our institutional admission order sets provide physicians and other healthcare providers an option of selecting as‐needed zolpidem or trazodone as sleep aids. Zolpidem was the most common sleep aid that was prescribed to inpatients with a ratio of zolpidem to trazodone prescriptions being 2:1.

We used the pharmacy database to identify all eligible inpatients who were prescribed or administered either scheduled or as needed (PRN) zolpidem during the study period. All details regarding zolpidem prescription and administration were obtained from the inpatient pharmacy electronic database. This database includes all zolpidem orders that were placed in the inpatient setting. The database also includes details of dose and time of all zolpidem administrations.

The institution uses electronic medication profiles, and automated dispensing machines with patient profiles and point‐of‐care barcode scan technology, which forces highly accurate electronic documentation of the medication administered. The documentation of medication not given or patient refusal would be documented as not administered.

We reviewed the electronic medical record to ascertain demographics, as well as diagnoses of visual impairment, gait abnormality, cognitive impairment/dementia, insomnia, and delirium, based on International Classification of Diseases, Ninth Revision (ICD‐9) diagnosis codes for these conditions (see Supporting Information, Appendix 1, in the online version of this article). These diagnostic codes were electronically abstracted from the medical record. The diagnosis codes are entered by medical coding specialists based on review of all provider notes. Hospital length of stay, Charlson comorbidity index scores, and Hendrich's fall risk scores from day of admission were abstracted from the individual electronic medical records. The nursing staff at our institution perform all the requisite assessments and electronically input all components required to calculate a Hendrich's fall risk score upon admission.

The Charlson index is a composite score calculated based on a patient's medical comorbidities. Each comorbidity is designated a score of 1, 2, 3, or 6 based on the risk of mortality associated with that condition.12 The Hendrich's fall risk is calculated based on the patient's current medication regimen, level of alertness, current medical condition, and the get up and go test.13A score of 5 or greater indicates increased risk of falling. These scores from the day of admission were available for all patients and were extracted from the nursing flow sheet.

At our institution, all falls are required to be called into a central event reporting system, and each fall receives an analysis regarding risk factors and proximal causes. We obtained details of all inpatient falls from this event system. The medication administration record, a part of the patient's electronic medical record, was accessed to identify all medications administered in the 24 hours prior to the fall. Medications were grouped into their respective pharmacologic classes. Antidepressants, antipsychotics, antihistamines, sedative antidepressants (this class included trazodone and mirtazapine), benzodiazepines, and opioids were included in the analyses. These medications have previously been shown to be associated with increased risk of falls.14

Statistical analyses were performed using JMP (version 9.03, Cary, NC). Univariate analyses were performed to calculate the odds ratio of falling in inpatients who were administered zolpidem, in male patients, those admitted to a surgical floor, and in those that had a diagnosis of insomnia, visual impairment, gait abnormality, cognitive impairment/dementia, or delirium. Hospital length of stay, age, zolpidem dose, Charlson comorbidity index scores, and Hendrich's fall risk scores were treated as continuous variables, and odds ratio of falling per unit increase was calculated for each of these variables.

Multivariable logistic regression analysis was performed to calculate the odds of falling in patients who received zolpidem, after accounting for age, gender, insomnia, visual impairment, gait abnormality, cognitive impairment/dementia, delirium, hospital length of stay, zolpidem dose, Charlson comorbidity index scores, and Hendrich's fall risk scores. Logistic regression analyses was repeated with only those factors that were significantly associated (P < 0.05) with falls or factors where the association was close to statistical significance (P < 0.08).

To account for the presence of other medications that might have increased fall risk, separate analyses using the MannWhitney U test comparing medication use in all hospitalized patients who sustained a fall were performed. We compared the rates of use of antidepressants, antipsychotics, antihistamines, sedative antidepressants (this class included trazodone and mirtazapine), benzodiazepines, and opioid medication in patients who were administered zolpidem to those patients not administered zolpidem in the 24 hours prior to sustaining a fall. This study had the requisite institutional review board approval.

RESULTS

There were 41,947 eligible admissions during the study period. Of these, a total of 16,320 (38.9%; mean age 54.7 18 years) patients were prescribed zolpidem. Among these patients, 4962 (30.4% of those prescribed, or 11.8% of all admissions) were administered zolpidem during the study period (Figure 1). The majority (88%) of zolpidem prescriptions were for PRN or as needed use. Patients who received zolpidem were older than those who were prescribed the medication but did not receive it (56.84 17.2 years vs 53.79 18.31 years; P < 0.001).

Figure 1

Patients who were prescribed and received zolpidem were more likely to be male, or have insomnia or delirium. They had higher Charlson comorbidity index scores and were more likely to be on a surgical floor. There was no statistically significant difference between patients who received zolpidem and patients who were prescribed but did not receive zolpidem in terms of their fall risk scores, length of hospital stay, rates of visual impairment, gait abnormalities, and cognitive impairment/dementia (all P > 0.05) (Table 1).

During the study period, there were a total of 672 total falls, with 609 unique patients falls (fall rate of 1.45/100 patients). Those who were administered zolpidem had an increased risk of falling compared to patients who were prescribed, but were not administered, zolpidem (fall rate of 3.04/100 patients vs 0.71/100 patients; odds ratio [OR] = 4.37, 95% confidence interval [CI] = 3.335.74; P < 0.001). Additionally, patients who received zolpidem had an increased risk of falling, as opposed to all other adult inpatients who did not receive zolpidemwhether prescribed zolpidem or not (3.04 falls/100 patients vs 1.24 falls/100 patients; OR = 2.50, 95% CI = 2.083.02; P < 0.001). The absolute increase in risk of sustaining a fall after receiving zolpidem as compared to all other adult inpatients was 1.8%, revealing a number needed to harm of 55.

During the study period, a total of 21,354 doses of zolpidem were administered, revealing a fall rate of 0.007 falls per dose of zolpidem administered (151/21,354). This was significantly greater than the baseline fall risk of 0.0028 falls per day of hospitalization (672/240,015 total hospital days) (P < 0.0001).

On univariate analyses, zolpidem use (OR = 4.37; 95% CI = 3.345.76; P < 0.001), male sex (OR = 1.36; 95% CI = 1.051.76; P = 0.02), insomnia (OR = 2.37; 95% CI = 1.813.08; P < 0.01), and delirium (OR = 4.96; 95% CI = 3.526.86; P < 0.001) were significantly associated with increased falls, as were increasing age, Charlson comorbidity index scores, fall risk scores, and dose of zolpidem (Table 2). While the association between the presence of cognitive impairment/dementia and falling was close to significant (OR = 2.89; 95% CI = 0.886.98; P = 0.075), the association between fall risk and the presence of visual impairment, gait abnormalities, and being on a surgical floor was not statistically significant.

Zolpidem use continued to be significantly associated with increased fall risk (adjusted OR = 6.39; 95% CI = 3.0714.49; P < 0.001) after multivariable logistic regression analyses accounting for all factors where the association with increased fall risk was statistically significant or close to significant on univariate analyses (Table 3). On further analyses, of all adult non‐ICU, non‐pregnant inpatients who sustained a fall, those who sustained a fall after receiving zolpidem did not differ from other inpatients who did not sustain a fall in terms of their age (59.6 17.95 vs 63.2 16.8 years; P = 0.07), antidepressant (42.62% vs 39.70%; P = 0.39), antipsychotic (9.83% vs 13.78%; P = 0.24), antihistamine (6.55% vs 3.49%; P = 0.10), sedative antidepressant (14.75% vs 15.80%; P = 0.31), benzodiazepine (36.06% vs 26.86%; P = 0.83), or opioid use (55.73% vs 43.01%; P = 0.66).

DISCUSSION

In this study, zolpidem use was associated with an increased risk of falling in hospitalized patients. We calculate that for every 55 inpatients administered zolpidem, we might expect one more fall than would otherwise have occurred. To our knowledge, this is the largest study examining the association between zolpidem use and falls in an inpatient setting. Previous literature have not accounted for the presence of several other factors that could increase fall risk in hospitalized patients using zolpidem, such as visual impairment, gait abnormalities, and type of admission. In our study, insomnia and delirium were associated with higher rates of falls, however, the risk of sustaining a fall after receiving zolpidem continued to remain elevated even after accounting for these and multiple other risk factors.

Previous research in healthy volunteers found that subjects who received zolpidem experienced increased difficulty maintaining their balance.15, 16 The subject's ability to correct their balance, with their eyes closed and also with their eyes open, was adversely affected, indicating that both proprioception and visually enabled balance correction were impacted. Navigating obstacles in a hospital setting, where the patient is in a novel environment and on other medications that could impact balance, is potentially made significantly worse by zolpidem, thus resulting in an increased fall risk.

While a previous case‐control study of inpatients, 65 years and older, reported increased rates of zolpidem use among inpatients who sustained a fall, it did not report whether this association continued to remain significant after accounting for potential confounders.9 Another study, in a similar age group and carried out in an ambulatory community setting, found that patients who sustained a hip fracture were more likely to have received zolpidem in the 6 months prior to their fall.8 In this study, zolpidem use continued to be significantly associated with hip fractures after accounting for potential confounders such as the use of other medication, age, comorbidity index score, the number of hospital days, and the number of nursing days. Our study differs from these studies in that it was a cohort study in an inpatient setting, and we included all non‐pregnant adult hospitalized patients outside of the ICU. Also, we examined medication administration in the 24 hours prior to a fall rather than medications simply prescribed in the months prior to a fall.8 In our cohort of adult inpatients, the odds of zolpidem use among patients who fell was greater than those previously reported. This could indicate increased vulnerability in hospitalized patients compared to community‐dwelling elderly.

Insomnia, older age, and delirium have all been shown to be associated with an increased risk of falls in previous research.1517 In one study of community‐dwelling older adults, the authors found a higher risk of falling in subjects with insomnia, but not in those who received a hypnotic agent.15 Delirium increases the likelihood of nocturnal wandering, also associated with increased risk of fall. Our inpatient cohort study confirms these prior findings: insomnia, delirium, and older age were all associated with an increased risk of falling. However, zolpidem use continued to remain a significant risk factor for falls even after accounting for these risk factors.

Hospitalized patients are more likely to be physically compromised and on a greater number of medications compared to community‐dwelling subjects, and hence at increased risk of falling. Multiple classes of medications have been shown to be associated with an increased fall risk in hospitalized patients.14 In our study, the patients who sustained a fall after receiving zolpidem did not differ from other patients who sustained a fall in terms of their medication use. Zolpidem thus appears to increase the risk of falling beyond that attributable to other medications in hospitalized patients.

A recent United States Preventive Services Task Force on Prevention of Falls in Community Dwelling Older Adults recommendation indicates that withdrawal of medication alone does not appear to have a significant impact on fall rates.18 Another study indicates that reduced benozodiazepine use did not significantly reduce the rates of hip fractures in the community.19 While these studies indicate that fall risk is multifactorial and requires a complex set of interventions, our results indicate that there might be an association between zolpidem administration and falls in an inpatient setting. Changing order sets so that zolpidem use is not encouraged could potentially reduce fall rates in hospitalized patients, a step that we have already taken in our institution based upon these findings. Other potential measures to reduce fall risk include the use of fall precautions in patients who are prescribed zolpidem or use of non‐pharmacologic treatments for insomnia. However, these interventions would need to be empirically tested before they could be recommended with confidence.

The results of this study must be viewed in the light of some limitations. Although we included age, sex, zolpidem dose, length of hospital stay, Charlson comorbidity index score, fall risk score, and diagnoses of insomnia, visual impairment, gait abnormality, cognitive impairment/dementia, and delirium in our analyses, we were unable to account for the degree of severity of these conditions. There could also be other possible medical conditions that result in an increased risk of falling that were not accounted for in our analyses. While we did attempt to correct for insomnia and delirium diagnoses, transient complaints of insomnia or altered mental status may have been missed by our retrospective methodology, and perhaps could co‐associate with risk of falling. Furthermore, administration of zolpidem was associated with a higher risk of falls when compared to other patients who were prescribed zolpidem, and also when compared to all other patients regardless of zolpidem prescription. We used ICD‐9 codes to identify patients with insomnia, delirium, visual impairment, and gait abnormalities, and these could be prone to misclassification and possible ascertainment bias. Finally, we were unable to account for use of medications that might potentially increase the risk of falling in the entire cohort. We were, however, able to account for this in the subset of patients who sustained a fall, and did not note a difference between the group that received zolpidem and the group that did not. In these analyses, we were able to account for administration of these other medications, but not the dose or cumulative dose.

CONCLUSIONS

Our study, the largest in an inpatient cohort, reveals that zolpidem administration is associated with increased risk of falling even after accounting for insomnia, delirium, and multiple other risk factors. Patients who sustained a fall after receiving zolpidem did not differ from other patients who sustained a fall, in terms of age or use of other medications conferring increased fall risk. Although insomnia and delirium are also associated with an increased risk of falling, addition of zolpidem in this situation appears to result in a further increase in fall risk. Presently, because there is limited evidence to recommend other hypnotic agents as safer alternatives in inpatient settings, non‐pharmacological measures to improve the sleep of hospitalized patients should be investigated as preferred methods to provide safe relief from complaints of disturbed sleep.