Choosing Wisely: Things We Do For No Reason

The Things We Do for No Reason (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent black and white conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

CASE PRESENTATION

A 65‐year‐old man is admitted with pneumonia. Review of the medical record reveals a persistent macrocytic anemia (hematocrit 29%, hemoglobin 9.3 g/dL, mean corpuscular volume [MCV] 105 fL) with a low reticulocyte count and normal peripheral blood smear. The provider contemplates ordering a serum folate or red blood cell (RBC) folate test to workup the persistent macrocytic anemia.

BACKGROUND

Folate is a water‐soluble B vitamin essential for the synthesis of DNA and for converting homocysteine to methionine. Folate deficiency is causally linked with both neural tube defects and megaloblastic anemia. Low levels of folate are associated with cardiovascular disease, colon cancer, neuropathy, depression, hypercoagulability, and cognitive decline, though there is a paucity of evidence showing causation or risk reduction with folate supplementation.[1] In patients with inadequate folate intake, the earliest sign is a decline in serum folate levels, followed by a fall in RBC folate levels. Only weeks later do macrocytosis, megaloblastic bone marrow, and finally anemia occur.[2] Given that humans are unable to synthesize folate and are therefore dependent on dietary sources, those with inadequate intake or absorption are at risk of folate deficiency.

WHY FOLATE TESTING IS ORDERED

In hospitalized patients, the most common indication for folate testing is anemia, either with or without macrocytosis.[3, 4] Given that at least 10% to 15% of hospitalized patients are anemic,[5, 6] it is unsurprising that folate testing is frequently performed. Despite the link between folate deficiency and megaloblastic anemia, >85% of patients evaluated for folate deficiency have normocytic or microcytic anemia.[3, 4] In addition, a study found that 30% of all folate testing was performed not as part of an anemia workup but in the evaluation of other comorbidities (eg, dementia and altered mental status) that are not causally linked to folate deficiency.[7]

WHY THERE IS NO REASON TO ORDER FOLATE TESTING

There are 2 reasons why testing hospitalized patients for folate deficiency does not contribute value: (1) the poor characteristics of the tests used and (2) the low prevalence of folate deficiency in the postfortification era.

There is no accepted gold standard for the diagnosis of folate deficiency, though biological assays are considered more accurate than the now more commonly used protein binding assays.[8] The lack of a gold standard limits the ability to fully quantify the sensitivity and specificity of either serum or RBC folate testing, though falsely low and high serum folate results can be seen. Falsely low serum levels (false positives) are found with heavy alcohol use and with certain anticonvulsant or antineoplastic drug use.[9] The low levels in these patients indicate low serum folate but do not necessarily reflect tissue stores. Serum folate levels may fall rapidly within a few days of the start of low dietary folate intake, resulting in low serum folate levels that also do not represent true folate deficiency.[10] On the other hand, intake of folatethrough a meal or ingestion of an oral supplementdirectly preceding evaluation of serum folate can lead to falsely elevated levels (false negatives).[10]

Although RBC folate reflects body stores and is largely unaffected by diet, the available tests also lack sensitivity and specificity.[11] Furthermore, serum folate levels and RBC folate levels correlate well.[12] Because RBC folate testing is more expensive than serum folate testing, has results that correlate well with serum folate testing, and is without significantly better test characteristics, there is no added value to using RBC folate testing as compared to serum folate testing.

In addition to the issues with available diagnostic tests, numerous studies now indicate that the rate of folate deficiency in the United States is exceptionally low. This is largely driven by the United States Food and Drug Administration's mandate that all grain products be fortified with 0.14 mg of folic acid per gram of grains.[13] Fortification has been overwhelmingly successful at increasing folic acid intake[14, 15] and reducing the incidence of neural tube defects.[16] Although the serum and RBC folate tests are prone to inaccuracies for an individual patient, population trends postfortification, coupled with the data on intake and rates of neural tube defects, make a strong argument that the prevalence of deficiency has decreased dramatically.

Similar to these population‐based trends, studies of hospital‐based laboratories have shown a marked decrease in the rate of low serum and RBC folate levels, making for a very low pretest probability for folate deficiency (Table 1). Even before fortification had been fully implemented, a study of outpatients and inpatients cared for at 3 hospitals in Denver, Colorado in 1996 found that just 1.9% of patients had low serum folate levels and 4.4% had low RBC folate levels.[17] A retrospective study of 26,662 patients in 1998 showed a rate of serum deficiency (<2.7 ng/mL) of 0.3%.[18] The authors also found that despite a decline in rate of serum deficiency from 1.3% to 0.3% between 1994 and 1998, the total number of serum folate tests performed increased by 84%. A similar study found just 0.4% of 1007 patients with low serum folate levels (<3.0 ng/mL).[7] Parallel results have been seen in other countries after implementation of folate fortification with a cohort of 2154 Canadian patients reporting low serum folate (<6.8 nmol/L) and RBC folate (<417 nmol/L) levels in just 0.5% and 0.7% of patients, respectively.[19]

Few studies have looked exclusively at hospitalized and emergency room patients. In an evaluation of 2093 serum folate tests performed on hospitalized or emergency room patients (98.1% of whom were admitted) in 2011, only 2 (0.1%) deficient levels (<3 ng/mL) were identified, 1 of which was associated with a macrocytic anemia.[3] A similar study of RBC folate levels in 2562 patients at 3 Canadian hospitals found just 4 (0.16%) levels to be low (<254 nmol/L), only 1 of which was associated with macrocytic anemia.[20]

When examining only patients with macrocytic anemia, the rates of folate deficiency are only slightly higher than the general population. As noted above, each of the 2 studies of inpatients uncovered just 1 patient with macrocytic anemia and concomitant low serum or RBC folate levels.[3, 20] Other studies reveal rates of serum folate deficiency in patients with macrocytic anemia and macrocytosis of 2.8%[7] and 1%,[21] respectively, and RBC folate deficiency rates in patients with macrocytosis of 1.8%.[22] Patients with extreme macrocytosis (MCV >130) represent 1 subset of patients with a high pretest probability of low serum folate, with 1 study reporting low levels in 37% of patients.[23]

Despite the relatively inexpensive cost per serum and RBC folate test, expenses per test that result in an abnormally low level are significant. As the pretest probability for folate deficiency is extremely low, tests must be ordered on a large number of patients to find 1 patient with levels suggesting deficiency. For example, a study found that an institution charged $151 per serum folate test, which amounted to $158,000 per deficient result.[3] The institutional cost was <$2.00 per serum folate test and <$2093 per deficient result. Another study reported the institutional cost of RBC folate to be $12.54 per test and $8035 per deficient result.[20] The charges and costs are institution specific and will vary. However, in light of the low pretest probability of testing, any expense associated with these tests represents low value.

WHAT YOU SHOULD DO INSTEAD

The clinician in our case presentation is facing a common scenarioa patient with persistent anemia without a known etiology. The treatment of suspected or confirmed folate deficiency includes improving diet or adding a folic acid supplement, a low‐cost (as little $0.01 per tablet) intervention. Furthermore, other at‐risk patients (eg, those with sickle cell disease, alcoholism, or malabsorption) may be candidates for long‐term supplementation regardless of serum folate and/or RBC folate testing results.

Folate deficiency in patients living in the United States and Canada is exceedingly rare, making the pretest probability of testing low. Furthermore, even patients with typical hematologic characteristics for folate deficiency (anemia and macrocytosis) are unlikely to have folate deficiency. Importantly, there are no nonhematologic indications to test for folate deficiency, and testing those patients, just as in the general population, yields an extremely low rate of folate deficiency. The tests themselves are unreliable and inaccurate, and fortunately, treatment is cheap, easy to administer, and can be done empirically. In other words, testing for folate deficiency is a Thing We Do for No Reason.

RECOMMENDATIONS

In patients suspected of having folate deficiency or who are at high risk of folate deficiency (eg, diet poor in folate‐rich or folic acid fortified foods), treat with a diet containing folate or folic acid fortified foods and/or a supplement containing 400 to 1000 g of folic acid. Approximately 1 to 2 weeks following initiation of treatment, a complete blood count should be performed to evaluate for an appropriate increase in hematocrit/hemoglobin and decrease in MCV.[24] Once a full hematologic response is seen, treatment beyond this time is not required unless the cause (eg, malnutrition) persists.

Serum folate and RBC folate tests should not be routinely ordered. Even in those with macrocytic anemia, the pretest probability of folate deficiency remains low. Although testing may suggest a folate deficiency, it is still more likely there is another cause for the patient's anemia. This places providers at risk for premature closure. For patients such as the one presented in the case presentation, obtaining B12 levels is of greater importance, given the higher prevalence and the risks of untreated deficiency.

For patients in whom the pretest probability of folate deficiency is high (eg, those with an MCV >130), obtain fasting serum folate levels on samples taken before supplementation has begun or a diet administered.

Do you think this is a low‐value practice? Is this truly a Thing We Do for No Reason? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other Things We Do for No Reason topics by emailing [email protected].

The Things We Do for No Reason (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent black and white conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

CASE PRESENTATION

A 65‐year‐old man is admitted with pneumonia. Review of the medical record reveals a persistent macrocytic anemia (hematocrit 29%, hemoglobin 9.3 g/dL, mean corpuscular volume [MCV] 105 fL) with a low reticulocyte count and normal peripheral blood smear. The provider contemplates ordering a serum folate or red blood cell (RBC) folate test to workup the persistent macrocytic anemia.

BACKGROUND

Folate is a water‐soluble B vitamin essential for the synthesis of DNA and for converting homocysteine to methionine. Folate deficiency is causally linked with both neural tube defects and megaloblastic anemia. Low levels of folate are associated with cardiovascular disease, colon cancer, neuropathy, depression, hypercoagulability, and cognitive decline, though there is a paucity of evidence showing causation or risk reduction with folate supplementation.[1] In patients with inadequate folate intake, the earliest sign is a decline in serum folate levels, followed by a fall in RBC folate levels. Only weeks later do macrocytosis, megaloblastic bone marrow, and finally anemia occur.[2] Given that humans are unable to synthesize folate and are therefore dependent on dietary sources, those with inadequate intake or absorption are at risk of folate deficiency.

WHY FOLATE TESTING IS ORDERED

In hospitalized patients, the most common indication for folate testing is anemia, either with or without macrocytosis.[3, 4] Given that at least 10% to 15% of hospitalized patients are anemic,[5, 6] it is unsurprising that folate testing is frequently performed. Despite the link between folate deficiency and megaloblastic anemia, >85% of patients evaluated for folate deficiency have normocytic or microcytic anemia.[3, 4] In addition, a study found that 30% of all folate testing was performed not as part of an anemia workup but in the evaluation of other comorbidities (eg, dementia and altered mental status) that are not causally linked to folate deficiency.[7]

WHY THERE IS NO REASON TO ORDER FOLATE TESTING

There are 2 reasons why testing hospitalized patients for folate deficiency does not contribute value: (1) the poor characteristics of the tests used and (2) the low prevalence of folate deficiency in the postfortification era.

There is no accepted gold standard for the diagnosis of folate deficiency, though biological assays are considered more accurate than the now more commonly used protein binding assays.[8] The lack of a gold standard limits the ability to fully quantify the sensitivity and specificity of either serum or RBC folate testing, though falsely low and high serum folate results can be seen. Falsely low serum levels (false positives) are found with heavy alcohol use and with certain anticonvulsant or antineoplastic drug use.[9] The low levels in these patients indicate low serum folate but do not necessarily reflect tissue stores. Serum folate levels may fall rapidly within a few days of the start of low dietary folate intake, resulting in low serum folate levels that also do not represent true folate deficiency.[10] On the other hand, intake of folatethrough a meal or ingestion of an oral supplementdirectly preceding evaluation of serum folate can lead to falsely elevated levels (false negatives).[10]

Although RBC folate reflects body stores and is largely unaffected by diet, the available tests also lack sensitivity and specificity.[11] Furthermore, serum folate levels and RBC folate levels correlate well.[12] Because RBC folate testing is more expensive than serum folate testing, has results that correlate well with serum folate testing, and is without significantly better test characteristics, there is no added value to using RBC folate testing as compared to serum folate testing.

In addition to the issues with available diagnostic tests, numerous studies now indicate that the rate of folate deficiency in the United States is exceptionally low. This is largely driven by the United States Food and Drug Administration's mandate that all grain products be fortified with 0.14 mg of folic acid per gram of grains.[13] Fortification has been overwhelmingly successful at increasing folic acid intake[14, 15] and reducing the incidence of neural tube defects.[16] Although the serum and RBC folate tests are prone to inaccuracies for an individual patient, population trends postfortification, coupled with the data on intake and rates of neural tube defects, make a strong argument that the prevalence of deficiency has decreased dramatically.

Similar to these population‐based trends, studies of hospital‐based laboratories have shown a marked decrease in the rate of low serum and RBC folate levels, making for a very low pretest probability for folate deficiency (Table 1). Even before fortification had been fully implemented, a study of outpatients and inpatients cared for at 3 hospitals in Denver, Colorado in 1996 found that just 1.9% of patients had low serum folate levels and 4.4% had low RBC folate levels.[17] A retrospective study of 26,662 patients in 1998 showed a rate of serum deficiency (<2.7 ng/mL) of 0.3%.[18] The authors also found that despite a decline in rate of serum deficiency from 1.3% to 0.3% between 1994 and 1998, the total number of serum folate tests performed increased by 84%. A similar study found just 0.4% of 1007 patients with low serum folate levels (<3.0 ng/mL).[7] Parallel results have been seen in other countries after implementation of folate fortification with a cohort of 2154 Canadian patients reporting low serum folate (<6.8 nmol/L) and RBC folate (<417 nmol/L) levels in just 0.5% and 0.7% of patients, respectively.[19]

Few studies have looked exclusively at hospitalized and emergency room patients. In an evaluation of 2093 serum folate tests performed on hospitalized or emergency room patients (98.1% of whom were admitted) in 2011, only 2 (0.1%) deficient levels (<3 ng/mL) were identified, 1 of which was associated with a macrocytic anemia.[3] A similar study of RBC folate levels in 2562 patients at 3 Canadian hospitals found just 4 (0.16%) levels to be low (<254 nmol/L), only 1 of which was associated with macrocytic anemia.[20]

When examining only patients with macrocytic anemia, the rates of folate deficiency are only slightly higher than the general population. As noted above, each of the 2 studies of inpatients uncovered just 1 patient with macrocytic anemia and concomitant low serum or RBC folate levels.[3, 20] Other studies reveal rates of serum folate deficiency in patients with macrocytic anemia and macrocytosis of 2.8%[7] and 1%,[21] respectively, and RBC folate deficiency rates in patients with macrocytosis of 1.8%.[22] Patients with extreme macrocytosis (MCV >130) represent 1 subset of patients with a high pretest probability of low serum folate, with 1 study reporting low levels in 37% of patients.[23]

Despite the relatively inexpensive cost per serum and RBC folate test, expenses per test that result in an abnormally low level are significant. As the pretest probability for folate deficiency is extremely low, tests must be ordered on a large number of patients to find 1 patient with levels suggesting deficiency. For example, a study found that an institution charged $151 per serum folate test, which amounted to $158,000 per deficient result.[3] The institutional cost was <$2.00 per serum folate test and <$2093 per deficient result. Another study reported the institutional cost of RBC folate to be $12.54 per test and $8035 per deficient result.[20] The charges and costs are institution specific and will vary. However, in light of the low pretest probability of testing, any expense associated with these tests represents low value.

WHAT YOU SHOULD DO INSTEAD

The clinician in our case presentation is facing a common scenarioa patient with persistent anemia without a known etiology. The treatment of suspected or confirmed folate deficiency includes improving diet or adding a folic acid supplement, a low‐cost (as little $0.01 per tablet) intervention. Furthermore, other at‐risk patients (eg, those with sickle cell disease, alcoholism, or malabsorption) may be candidates for long‐term supplementation regardless of serum folate and/or RBC folate testing results.

Folate deficiency in patients living in the United States and Canada is exceedingly rare, making the pretest probability of testing low. Furthermore, even patients with typical hematologic characteristics for folate deficiency (anemia and macrocytosis) are unlikely to have folate deficiency. Importantly, there are no nonhematologic indications to test for folate deficiency, and testing those patients, just as in the general population, yields an extremely low rate of folate deficiency. The tests themselves are unreliable and inaccurate, and fortunately, treatment is cheap, easy to administer, and can be done empirically. In other words, testing for folate deficiency is a Thing We Do for No Reason.

RECOMMENDATIONS

In patients suspected of having folate deficiency or who are at high risk of folate deficiency (eg, diet poor in folate‐rich or folic acid fortified foods), treat with a diet containing folate or folic acid fortified foods and/or a supplement containing 400 to 1000 g of folic acid. Approximately 1 to 2 weeks following initiation of treatment, a complete blood count should be performed to evaluate for an appropriate increase in hematocrit/hemoglobin and decrease in MCV.[24] Once a full hematologic response is seen, treatment beyond this time is not required unless the cause (eg, malnutrition) persists.

Serum folate and RBC folate tests should not be routinely ordered. Even in those with macrocytic anemia, the pretest probability of folate deficiency remains low. Although testing may suggest a folate deficiency, it is still more likely there is another cause for the patient's anemia. This places providers at risk for premature closure. For patients such as the one presented in the case presentation, obtaining B12 levels is of greater importance, given the higher prevalence and the risks of untreated deficiency.

For patients in whom the pretest probability of folate deficiency is high (eg, those with an MCV >130), obtain fasting serum folate levels on samples taken before supplementation has begun or a diet administered.

Do you think this is a low‐value practice? Is this truly a Thing We Do for No Reason? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other Things We Do for No Reason topics by emailing [email protected].

The Things We Do for No Reason (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent black and white conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

CASE PRESENTATION

A 65‐year‐old man is admitted with pneumonia. Review of the medical record reveals a persistent macrocytic anemia (hematocrit 29%, hemoglobin 9.3 g/dL, mean corpuscular volume [MCV] 105 fL) with a low reticulocyte count and normal peripheral blood smear. The provider contemplates ordering a serum folate or red blood cell (RBC) folate test to workup the persistent macrocytic anemia.

BACKGROUND

Folate is a water‐soluble B vitamin essential for the synthesis of DNA and for converting homocysteine to methionine. Folate deficiency is causally linked with both neural tube defects and megaloblastic anemia. Low levels of folate are associated with cardiovascular disease, colon cancer, neuropathy, depression, hypercoagulability, and cognitive decline, though there is a paucity of evidence showing causation or risk reduction with folate supplementation.[1] In patients with inadequate folate intake, the earliest sign is a decline in serum folate levels, followed by a fall in RBC folate levels. Only weeks later do macrocytosis, megaloblastic bone marrow, and finally anemia occur.[2] Given that humans are unable to synthesize folate and are therefore dependent on dietary sources, those with inadequate intake or absorption are at risk of folate deficiency.

WHY FOLATE TESTING IS ORDERED

In hospitalized patients, the most common indication for folate testing is anemia, either with or without macrocytosis.[3, 4] Given that at least 10% to 15% of hospitalized patients are anemic,[5, 6] it is unsurprising that folate testing is frequently performed. Despite the link between folate deficiency and megaloblastic anemia, >85% of patients evaluated for folate deficiency have normocytic or microcytic anemia.[3, 4] In addition, a study found that 30% of all folate testing was performed not as part of an anemia workup but in the evaluation of other comorbidities (eg, dementia and altered mental status) that are not causally linked to folate deficiency.[7]

WHY THERE IS NO REASON TO ORDER FOLATE TESTING

There are 2 reasons why testing hospitalized patients for folate deficiency does not contribute value: (1) the poor characteristics of the tests used and (2) the low prevalence of folate deficiency in the postfortification era.

There is no accepted gold standard for the diagnosis of folate deficiency, though biological assays are considered more accurate than the now more commonly used protein binding assays.[8] The lack of a gold standard limits the ability to fully quantify the sensitivity and specificity of either serum or RBC folate testing, though falsely low and high serum folate results can be seen. Falsely low serum levels (false positives) are found with heavy alcohol use and with certain anticonvulsant or antineoplastic drug use.[9] The low levels in these patients indicate low serum folate but do not necessarily reflect tissue stores. Serum folate levels may fall rapidly within a few days of the start of low dietary folate intake, resulting in low serum folate levels that also do not represent true folate deficiency.[10] On the other hand, intake of folatethrough a meal or ingestion of an oral supplementdirectly preceding evaluation of serum folate can lead to falsely elevated levels (false negatives).[10]

Although RBC folate reflects body stores and is largely unaffected by diet, the available tests also lack sensitivity and specificity.[11] Furthermore, serum folate levels and RBC folate levels correlate well.[12] Because RBC folate testing is more expensive than serum folate testing, has results that correlate well with serum folate testing, and is without significantly better test characteristics, there is no added value to using RBC folate testing as compared to serum folate testing.

In addition to the issues with available diagnostic tests, numerous studies now indicate that the rate of folate deficiency in the United States is exceptionally low. This is largely driven by the United States Food and Drug Administration's mandate that all grain products be fortified with 0.14 mg of folic acid per gram of grains.[13] Fortification has been overwhelmingly successful at increasing folic acid intake[14, 15] and reducing the incidence of neural tube defects.[16] Although the serum and RBC folate tests are prone to inaccuracies for an individual patient, population trends postfortification, coupled with the data on intake and rates of neural tube defects, make a strong argument that the prevalence of deficiency has decreased dramatically.

Similar to these population‐based trends, studies of hospital‐based laboratories have shown a marked decrease in the rate of low serum and RBC folate levels, making for a very low pretest probability for folate deficiency (Table 1). Even before fortification had been fully implemented, a study of outpatients and inpatients cared for at 3 hospitals in Denver, Colorado in 1996 found that just 1.9% of patients had low serum folate levels and 4.4% had low RBC folate levels.[17] A retrospective study of 26,662 patients in 1998 showed a rate of serum deficiency (<2.7 ng/mL) of 0.3%.[18] The authors also found that despite a decline in rate of serum deficiency from 1.3% to 0.3% between 1994 and 1998, the total number of serum folate tests performed increased by 84%. A similar study found just 0.4% of 1007 patients with low serum folate levels (<3.0 ng/mL).[7] Parallel results have been seen in other countries after implementation of folate fortification with a cohort of 2154 Canadian patients reporting low serum folate (<6.8 nmol/L) and RBC folate (<417 nmol/L) levels in just 0.5% and 0.7% of patients, respectively.[19]

Few studies have looked exclusively at hospitalized and emergency room patients. In an evaluation of 2093 serum folate tests performed on hospitalized or emergency room patients (98.1% of whom were admitted) in 2011, only 2 (0.1%) deficient levels (<3 ng/mL) were identified, 1 of which was associated with a macrocytic anemia.[3] A similar study of RBC folate levels in 2562 patients at 3 Canadian hospitals found just 4 (0.16%) levels to be low (<254 nmol/L), only 1 of which was associated with macrocytic anemia.[20]

When examining only patients with macrocytic anemia, the rates of folate deficiency are only slightly higher than the general population. As noted above, each of the 2 studies of inpatients uncovered just 1 patient with macrocytic anemia and concomitant low serum or RBC folate levels.[3, 20] Other studies reveal rates of serum folate deficiency in patients with macrocytic anemia and macrocytosis of 2.8%[7] and 1%,[21] respectively, and RBC folate deficiency rates in patients with macrocytosis of 1.8%.[22] Patients with extreme macrocytosis (MCV >130) represent 1 subset of patients with a high pretest probability of low serum folate, with 1 study reporting low levels in 37% of patients.[23]

Despite the relatively inexpensive cost per serum and RBC folate test, expenses per test that result in an abnormally low level are significant. As the pretest probability for folate deficiency is extremely low, tests must be ordered on a large number of patients to find 1 patient with levels suggesting deficiency. For example, a study found that an institution charged $151 per serum folate test, which amounted to $158,000 per deficient result.[3] The institutional cost was <$2.00 per serum folate test and <$2093 per deficient result. Another study reported the institutional cost of RBC folate to be $12.54 per test and $8035 per deficient result.[20] The charges and costs are institution specific and will vary. However, in light of the low pretest probability of testing, any expense associated with these tests represents low value.

WHAT YOU SHOULD DO INSTEAD

The clinician in our case presentation is facing a common scenarioa patient with persistent anemia without a known etiology. The treatment of suspected or confirmed folate deficiency includes improving diet or adding a folic acid supplement, a low‐cost (as little $0.01 per tablet) intervention. Furthermore, other at‐risk patients (eg, those with sickle cell disease, alcoholism, or malabsorption) may be candidates for long‐term supplementation regardless of serum folate and/or RBC folate testing results.

Folate deficiency in patients living in the United States and Canada is exceedingly rare, making the pretest probability of testing low. Furthermore, even patients with typical hematologic characteristics for folate deficiency (anemia and macrocytosis) are unlikely to have folate deficiency. Importantly, there are no nonhematologic indications to test for folate deficiency, and testing those patients, just as in the general population, yields an extremely low rate of folate deficiency. The tests themselves are unreliable and inaccurate, and fortunately, treatment is cheap, easy to administer, and can be done empirically. In other words, testing for folate deficiency is a Thing We Do for No Reason.

RECOMMENDATIONS

In patients suspected of having folate deficiency or who are at high risk of folate deficiency (eg, diet poor in folate‐rich or folic acid fortified foods), treat with a diet containing folate or folic acid fortified foods and/or a supplement containing 400 to 1000 g of folic acid. Approximately 1 to 2 weeks following initiation of treatment, a complete blood count should be performed to evaluate for an appropriate increase in hematocrit/hemoglobin and decrease in MCV.[24] Once a full hematologic response is seen, treatment beyond this time is not required unless the cause (eg, malnutrition) persists.

Serum folate and RBC folate tests should not be routinely ordered. Even in those with macrocytic anemia, the pretest probability of folate deficiency remains low. Although testing may suggest a folate deficiency, it is still more likely there is another cause for the patient's anemia. This places providers at risk for premature closure. For patients such as the one presented in the case presentation, obtaining B12 levels is of greater importance, given the higher prevalence and the risks of untreated deficiency.

For patients in whom the pretest probability of folate deficiency is high (eg, those with an MCV >130), obtain fasting serum folate levels on samples taken before supplementation has begun or a diet administered.

Do you think this is a low‐value practice? Is this truly a Thing We Do for No Reason? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other Things We Do for No Reason topics by emailing [email protected].

The Things We Do for No Reason (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent black and white conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

CASE PRESENTATION

A 54‐year‐old woman presented to the emergency department (ED) with shortness of breath. She reported that her primary care physician diagnosed her with chronic obstructive pulmonary disease (COPD). Her physician had prescribed her an albuterol inhaler to use as needed for shortness of breath. Over the past few weeks she had been trying to use the inhaler, but she noted that it did not seem to help her increasing wheezing, coughing, and sputum production. In the ED, she received continuous albuterol treatments via nebulizer, Solu‐Medrol 125 mg intravenously, antibiotics, and a chest x‐ray. She was admitted to the hospital medicine service for COPD exacerbation and started on nebulized bronchodilator treatments every 4 hours. By the fourth day of her hospital stay, she was discharged to home with an albuterol inhaler, oral prednisone, oral doxycycline, and a follow‐up appointment. Dedicated patient education regarding proper inhaler administration did not occur during hospitalization.

WHY YOU MIGHT THINK NEBULIZED TREATMENTS IN INPATIENTS ARE HELPFUL

Inhaled bronchodilators are a mainstay of therapy for acute obstructive pulmonary diseases, including COPD and asthma exacerbations.[1, 2] Inhaled bronchodilators may be delivered by metered‐dose inhalers (MDIs) or via wet nebulizers powered by compressed air or oxygen. Current practice patterns in EDs and hospital wards tend to favor the use of nebulizers due to many apparent advantages of these devices.[3] For instance, nebulizers do not require any special inhalation technique and can be effectively used by patients at any age.[3, 4] There is also a common perception that nebulizers are more effective, possibly stemming from the assumption that hospitalized patients have already failed their outpatient MDI therapy and an almost mystical belief in the healing power of mist. Moreover, many clinicians have been trained to routinely use nebulizer therapies and may lack sufficient knowledge or comfort about the relative efficacy and equivalence dosing of MDI therapies.

WHY NEBULIZERS ARE NOT BETTER THAN MDIs FOR PATIENTS HOSPITALIZED WITH OBSTRUCTIVE PULMONARY SYMPTOMS

Decades of research support that MDIs are effective, efficient, and less costly (depending on circumstances) than nebulizers for the routine treatment of obstructive pulmonary exacerbations.[3, 4, 5, 6, 7, 8, 9, 10, 11] The clinical effectiveness of MDIs has been shown in studies across populations of adults with acute COPD symptoms,[3, 4, 7, 8] as well as children and adults with asthma exacerbations.[3, 4, 5, 6, 9, 10] A 2005 joint report by the American College of Chest Physicians (ACCP) and the American College of Asthma, Allergy and Immunology (ACAAI), concluded none of the pooled meta‐analyses showed a significant difference between devices in any efficacy outcome in any patient group for each of the clinical settings.[4] Many different outcomes have been investigated, including forced expiratory volumes (FEV), peak flows, symptoms and specific symptom scores, and physical findings.[4]

Compared to MDIs, there are a number of drawbacks to the use of nebulizers: nebulizers are more expensive to buy and maintain, are less portable, and take longer to set up, use, and clean following each use.[12] In addition, nebulizers have been associated with greater increases in heart rate and tremors compared to MDIs, suggesting nebulizers lead to higher systemically absorbed ‐agonist doses.[4]

Of note, nearly all of the clinical effectiveness studies administered MDIs with a valved holding chamber or spacer, facilitating the delivery of drug to the airways.[3, 4] Although valved holding chambers are commonly referred to as a spacer, a true spacer does not have a valve and is rarely used today.[12]

THE EVIDENCE EXAMINING NEBULIZERS VERSUS MDIs IN PATIENTS WITH ASTHMA OR COPD EXACERBATIONS

A 2013 Cochrane review sought to establish the relative efficacy of MDIs with holding chambers versus nebulizers for children and adults who presented to a community setting or emergency department with acute asthma.[6] The review included a total of 1897 children and 729 adults in 39 randomized controlled trials. The authors judged the overall evidence to be of moderate quality. Children with acute asthma treated with MDIs in the ED had shorter lengths of stay in the ED (70 minutes vs 103 minutes), similar peak flow and FEV measurements, lower heart rates, and less tremor compared to children treated with nebulizers.[5, 6] There were no significant differences found between devices for the treatment of adult patients with asthma.[6]

In a separate double‐blind, randomized, placebo‐controlled study evaluating albuterol administered by nebulizer versus MDI with spacer for children <2 years old presenting to an ED with wheezing, the use of MDIs with a spacer and facemask was equally efficacious and may have led to fewer hospital admissions.[10]

Mandelberg et al. performed a double‐blind, randomized, placebo‐controlled trial for unselected adult patients presenting to an ED with obstructive pulmonary symptoms.[8] Patients received either 2 puffs of a placebo MDI with a spacer along with nebulized salbutamol 0.5 mL in 1.5 mL saline solution (n=25), or a salbutamol MDI along with a nebulized placebo saline solution (n=25). Treatments were repeated every 15 minutes up to 3 times, unless side effects occurred. Spirometric measurements were performed following each treatment. No differences were seen between the groups at any point during the study period. The authors concluded, Even in the setting of the unselected group of patient referrals to the [Department of Emergency Medicine] for episodes of severe airflow limitation, the clinical and objective bronchodilator responses to the administration of salbutamol are independent of the method of delivery: MDI with large spacer or aerosol nebulization.[8]

There are surprisingly few studies examining the use of nebulizers versus MDIs in the inpatient setting for both children and adults. Dolovich et al. reviewed 6 studies that included 253 total patients and reported no significant differences in pulmonary function between devices.[4] Based on these findings, the ACCP/ACAAI group recommended both nebulizers and MDIs with spacers/holding chambers are appropriate for use in the inpatient setting. Quality of evidence: good.[4]

WHY USE MDIs FOR INPATIENTS

If MDI and nebulizer treatments are equally effective, why change current practice? The use of MDIs, rather than nebulizers, in hospitals could lead to fewer side effects such as tachycardia, arrhythmias, and tremors. MDIs are also more portable and do not require specialized set‐up. Furthermore, MDI administrations during hospitalization may provide a golden opportunity to have respiratory therapists, pharmacists, or other health professionals spend time teaching patients proper inhaler usage, rather than providing time‐consuming nebulizer treatments.[13] In a recent study, approximately 86% of hospitalized patients with asthma or COPD could not demonstrate appropriate use of an MDI. However, 100% of patients were able to achieve mastery following a short teach‐back session.[14] It is conceivable that transitioning patients to MDIs earlier during hospitalization and providing them with education regarding proper MDI administration could instill confidence in their use of inhalers and result in downstream effects such as shorter lengths of stay, less frequent hospital readmissions, or improved quality of life.

MDI use may result in cost savings in certain settings, although the relative costs of nebulizer versus MDI treatments depends on many institution‐specific factors. Such factors include the institutional policies on who delivers the nebulizer or the MDI and how they are compensated and staffed. For example in the Nebs No More After 24 program initiated at the University of California, San Francisco, the vast majority of the realized cost savings are due to the reduction in respiratory therapist time spent delivering MDIs, which reflects the local policies and compensation structure.[13] Previous inpatient interventions to convert from nebulizers to MDIs also showed cost savings resulting from decreased labor needs.[15] In some hospitals, nurses deliver nebulizer treatments, whereas in others only respiratory therapists are allowed to provide nebulizers. Moreover, whether the MDI can go home with the patient upon discharge depends on whether the hospital has a dispensing pharmacy or not. Formal economic evaluations specific to the local institution are necessary.

WHAT WE SHOULD DO INSTEAD: ENCOURAGE THE USE OF MDIs FOR INPATIENTS

For effective inpatient MDI treatments, MDI technique must be good. Thus, it is vital to enlist the right people to provide proper MDI teaching and supervision. Respiratory therapists are generally trained for this task, and may be complemented by appropriately trained physicians, nurses, or pharmacists. Many institutions have successfully implemented respiratory therapist‐driven protocols for the administration of MDIs, which has led to measurable improvements in the utilization of appropriate respiratory care resources.[15, 16] At University of California, San Francisco, this was accomplished by recruiting respiratory therapists and nurses to help support the transition of patients from nebulizers to MDIs and to provide bedside teaching on proper MDI usage. The institution then launched a Nebs No More After 24 campaign that sought to transition patients from nebulizers to MDIs within 24 hours of hospitalization. This campaign included an educational program for physicians, prepared facilitator guides to assist attending physicians with teaching about the new initiative, publicity efforts including pens and strategically placed posters, and regular feedback regarding nebulizer utilization on the pilot ward. Although the evidence suggests that patients can be started on MDIs immediately upon presentation to the ED, the UCSF campaign focused on transitioning patients within 24 hours so to alleviate concerns about transitions in care between the ED and the medical ward, as well as between overnight and day teams. MDIs are only as or more effective than nebulizers if the correct administration technique is employed. The 24‐hour transition period allows for MDI teaching and transition during regular daytime hours.

Inpatient use of nebulizers may be more appropriate than MDIs for patients with dementia or altered mental status, as well as those in extreme distress resulting in an inability to coordinate inhaler usage. Very low health literacy may be an additional barrier to appropriate MDI teaching and usage.

RECOMMENDATIONS

In patients with obstructive pulmonary symptoms, transition patients from nebulizers to MDIs early in their hospital course, unless the patient is unable to use an inhaler due to altered mental status, dementia, or other circumstances. Ensure that patients are instructed and supervised on proper MDI technique. Enlisting respiratory therapists and appropriately trained staff (pharmacists, nurses, physicians) is key to the successful use of MDIs. Frequency and dosage of MDIs used should be comparable to that of nebulized treatments. Although studies have used a relatively wide range of albuterol MDI dosing, prior programs have determined a dose of albuterol 4 puffs via MDI as being equivalent to the standard albuterol 2.5 mg nebulizer dosage.[17, 18] Some studies have advocated for using a range of 2 to 10 puffs albuterol MDI, with the actual dose based on clinical response.[17] One study in children with mild acute asthma found that 2 puffs of albuterol by MDI was just as effective as higher doses delivered by MDI (610 puffs) or by nebulizer.[19]

CONCLUSION

MDIs with holding chambers are clinically equivalent to nebulizer therapy for the treatment of both children and adults with obstructive pulmonary symptoms, as long as MDI technique and MDI dosing is adequate. This is based on good data in the ED setting but fewer studies in adult inpatients. There are a number of advantages to the use of inpatient MDIs over nebulizers; MDIs are more portable, often less expensive to use, may result in fewer side effects, and will hopefully improve outpatient MDI technique. The delivery of MDIs during hospitalization should be accompanied with patient education regarding proper administration technique.

Do you think this is a low‐value practice? Is this truly a Thing We Do for No Reason? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other Things We Do for No Reason topics by emailing [email protected]

The Things We Do for No Reason (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent black and white conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

CASE PRESENTATION

A 54‐year‐old woman presented to the emergency department (ED) with shortness of breath. She reported that her primary care physician diagnosed her with chronic obstructive pulmonary disease (COPD). Her physician had prescribed her an albuterol inhaler to use as needed for shortness of breath. Over the past few weeks she had been trying to use the inhaler, but she noted that it did not seem to help her increasing wheezing, coughing, and sputum production. In the ED, she received continuous albuterol treatments via nebulizer, Solu‐Medrol 125 mg intravenously, antibiotics, and a chest x‐ray. She was admitted to the hospital medicine service for COPD exacerbation and started on nebulized bronchodilator treatments every 4 hours. By the fourth day of her hospital stay, she was discharged to home with an albuterol inhaler, oral prednisone, oral doxycycline, and a follow‐up appointment. Dedicated patient education regarding proper inhaler administration did not occur during hospitalization.

WHY YOU MIGHT THINK NEBULIZED TREATMENTS IN INPATIENTS ARE HELPFUL

Inhaled bronchodilators are a mainstay of therapy for acute obstructive pulmonary diseases, including COPD and asthma exacerbations.[1, 2] Inhaled bronchodilators may be delivered by metered‐dose inhalers (MDIs) or via wet nebulizers powered by compressed air or oxygen. Current practice patterns in EDs and hospital wards tend to favor the use of nebulizers due to many apparent advantages of these devices.[3] For instance, nebulizers do not require any special inhalation technique and can be effectively used by patients at any age.[3, 4] There is also a common perception that nebulizers are more effective, possibly stemming from the assumption that hospitalized patients have already failed their outpatient MDI therapy and an almost mystical belief in the healing power of mist. Moreover, many clinicians have been trained to routinely use nebulizer therapies and may lack sufficient knowledge or comfort about the relative efficacy and equivalence dosing of MDI therapies.

WHY NEBULIZERS ARE NOT BETTER THAN MDIs FOR PATIENTS HOSPITALIZED WITH OBSTRUCTIVE PULMONARY SYMPTOMS

Decades of research support that MDIs are effective, efficient, and less costly (depending on circumstances) than nebulizers for the routine treatment of obstructive pulmonary exacerbations.[3, 4, 5, 6, 7, 8, 9, 10, 11] The clinical effectiveness of MDIs has been shown in studies across populations of adults with acute COPD symptoms,[3, 4, 7, 8] as well as children and adults with asthma exacerbations.[3, 4, 5, 6, 9, 10] A 2005 joint report by the American College of Chest Physicians (ACCP) and the American College of Asthma, Allergy and Immunology (ACAAI), concluded none of the pooled meta‐analyses showed a significant difference between devices in any efficacy outcome in any patient group for each of the clinical settings.[4] Many different outcomes have been investigated, including forced expiratory volumes (FEV), peak flows, symptoms and specific symptom scores, and physical findings.[4]

Compared to MDIs, there are a number of drawbacks to the use of nebulizers: nebulizers are more expensive to buy and maintain, are less portable, and take longer to set up, use, and clean following each use.[12] In addition, nebulizers have been associated with greater increases in heart rate and tremors compared to MDIs, suggesting nebulizers lead to higher systemically absorbed ‐agonist doses.[4]

Of note, nearly all of the clinical effectiveness studies administered MDIs with a valved holding chamber or spacer, facilitating the delivery of drug to the airways.[3, 4] Although valved holding chambers are commonly referred to as a spacer, a true spacer does not have a valve and is rarely used today.[12]

THE EVIDENCE EXAMINING NEBULIZERS VERSUS MDIs IN PATIENTS WITH ASTHMA OR COPD EXACERBATIONS

A 2013 Cochrane review sought to establish the relative efficacy of MDIs with holding chambers versus nebulizers for children and adults who presented to a community setting or emergency department with acute asthma.[6] The review included a total of 1897 children and 729 adults in 39 randomized controlled trials. The authors judged the overall evidence to be of moderate quality. Children with acute asthma treated with MDIs in the ED had shorter lengths of stay in the ED (70 minutes vs 103 minutes), similar peak flow and FEV measurements, lower heart rates, and less tremor compared to children treated with nebulizers.[5, 6] There were no significant differences found between devices for the treatment of adult patients with asthma.[6]

In a separate double‐blind, randomized, placebo‐controlled study evaluating albuterol administered by nebulizer versus MDI with spacer for children <2 years old presenting to an ED with wheezing, the use of MDIs with a spacer and facemask was equally efficacious and may have led to fewer hospital admissions.[10]

Mandelberg et al. performed a double‐blind, randomized, placebo‐controlled trial for unselected adult patients presenting to an ED with obstructive pulmonary symptoms.[8] Patients received either 2 puffs of a placebo MDI with a spacer along with nebulized salbutamol 0.5 mL in 1.5 mL saline solution (n=25), or a salbutamol MDI along with a nebulized placebo saline solution (n=25). Treatments were repeated every 15 minutes up to 3 times, unless side effects occurred. Spirometric measurements were performed following each treatment. No differences were seen between the groups at any point during the study period. The authors concluded, Even in the setting of the unselected group of patient referrals to the [Department of Emergency Medicine] for episodes of severe airflow limitation, the clinical and objective bronchodilator responses to the administration of salbutamol are independent of the method of delivery: MDI with large spacer or aerosol nebulization.[8]

There are surprisingly few studies examining the use of nebulizers versus MDIs in the inpatient setting for both children and adults. Dolovich et al. reviewed 6 studies that included 253 total patients and reported no significant differences in pulmonary function between devices.[4] Based on these findings, the ACCP/ACAAI group recommended both nebulizers and MDIs with spacers/holding chambers are appropriate for use in the inpatient setting. Quality of evidence: good.[4]

WHY USE MDIs FOR INPATIENTS

If MDI and nebulizer treatments are equally effective, why change current practice? The use of MDIs, rather than nebulizers, in hospitals could lead to fewer side effects such as tachycardia, arrhythmias, and tremors. MDIs are also more portable and do not require specialized set‐up. Furthermore, MDI administrations during hospitalization may provide a golden opportunity to have respiratory therapists, pharmacists, or other health professionals spend time teaching patients proper inhaler usage, rather than providing time‐consuming nebulizer treatments.[13] In a recent study, approximately 86% of hospitalized patients with asthma or COPD could not demonstrate appropriate use of an MDI. However, 100% of patients were able to achieve mastery following a short teach‐back session.[14] It is conceivable that transitioning patients to MDIs earlier during hospitalization and providing them with education regarding proper MDI administration could instill confidence in their use of inhalers and result in downstream effects such as shorter lengths of stay, less frequent hospital readmissions, or improved quality of life.

MDI use may result in cost savings in certain settings, although the relative costs of nebulizer versus MDI treatments depends on many institution‐specific factors. Such factors include the institutional policies on who delivers the nebulizer or the MDI and how they are compensated and staffed. For example in the Nebs No More After 24 program initiated at the University of California, San Francisco, the vast majority of the realized cost savings are due to the reduction in respiratory therapist time spent delivering MDIs, which reflects the local policies and compensation structure.[13] Previous inpatient interventions to convert from nebulizers to MDIs also showed cost savings resulting from decreased labor needs.[15] In some hospitals, nurses deliver nebulizer treatments, whereas in others only respiratory therapists are allowed to provide nebulizers. Moreover, whether the MDI can go home with the patient upon discharge depends on whether the hospital has a dispensing pharmacy or not. Formal economic evaluations specific to the local institution are necessary.

WHAT WE SHOULD DO INSTEAD: ENCOURAGE THE USE OF MDIs FOR INPATIENTS

For effective inpatient MDI treatments, MDI technique must be good. Thus, it is vital to enlist the right people to provide proper MDI teaching and supervision. Respiratory therapists are generally trained for this task, and may be complemented by appropriately trained physicians, nurses, or pharmacists. Many institutions have successfully implemented respiratory therapist‐driven protocols for the administration of MDIs, which has led to measurable improvements in the utilization of appropriate respiratory care resources.[15, 16] At University of California, San Francisco, this was accomplished by recruiting respiratory therapists and nurses to help support the transition of patients from nebulizers to MDIs and to provide bedside teaching on proper MDI usage. The institution then launched a Nebs No More After 24 campaign that sought to transition patients from nebulizers to MDIs within 24 hours of hospitalization. This campaign included an educational program for physicians, prepared facilitator guides to assist attending physicians with teaching about the new initiative, publicity efforts including pens and strategically placed posters, and regular feedback regarding nebulizer utilization on the pilot ward. Although the evidence suggests that patients can be started on MDIs immediately upon presentation to the ED, the UCSF campaign focused on transitioning patients within 24 hours so to alleviate concerns about transitions in care between the ED and the medical ward, as well as between overnight and day teams. MDIs are only as or more effective than nebulizers if the correct administration technique is employed. The 24‐hour transition period allows for MDI teaching and transition during regular daytime hours.

Inpatient use of nebulizers may be more appropriate than MDIs for patients with dementia or altered mental status, as well as those in extreme distress resulting in an inability to coordinate inhaler usage. Very low health literacy may be an additional barrier to appropriate MDI teaching and usage.

RECOMMENDATIONS

In patients with obstructive pulmonary symptoms, transition patients from nebulizers to MDIs early in their hospital course, unless the patient is unable to use an inhaler due to altered mental status, dementia, or other circumstances. Ensure that patients are instructed and supervised on proper MDI technique. Enlisting respiratory therapists and appropriately trained staff (pharmacists, nurses, physicians) is key to the successful use of MDIs. Frequency and dosage of MDIs used should be comparable to that of nebulized treatments. Although studies have used a relatively wide range of albuterol MDI dosing, prior programs have determined a dose of albuterol 4 puffs via MDI as being equivalent to the standard albuterol 2.5 mg nebulizer dosage.[17, 18] Some studies have advocated for using a range of 2 to 10 puffs albuterol MDI, with the actual dose based on clinical response.[17] One study in children with mild acute asthma found that 2 puffs of albuterol by MDI was just as effective as higher doses delivered by MDI (610 puffs) or by nebulizer.[19]

CONCLUSION

MDIs with holding chambers are clinically equivalent to nebulizer therapy for the treatment of both children and adults with obstructive pulmonary symptoms, as long as MDI technique and MDI dosing is adequate. This is based on good data in the ED setting but fewer studies in adult inpatients. There are a number of advantages to the use of inpatient MDIs over nebulizers; MDIs are more portable, often less expensive to use, may result in fewer side effects, and will hopefully improve outpatient MDI technique. The delivery of MDIs during hospitalization should be accompanied with patient education regarding proper administration technique.

Do you think this is a low‐value practice? Is this truly a Thing We Do for No Reason? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other Things We Do for No Reason topics by emailing [email protected]

The Things We Do for No Reason (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent black and white conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

CASE PRESENTATION

A 54‐year‐old woman presented to the emergency department (ED) with shortness of breath. She reported that her primary care physician diagnosed her with chronic obstructive pulmonary disease (COPD). Her physician had prescribed her an albuterol inhaler to use as needed for shortness of breath. Over the past few weeks she had been trying to use the inhaler, but she noted that it did not seem to help her increasing wheezing, coughing, and sputum production. In the ED, she received continuous albuterol treatments via nebulizer, Solu‐Medrol 125 mg intravenously, antibiotics, and a chest x‐ray. She was admitted to the hospital medicine service for COPD exacerbation and started on nebulized bronchodilator treatments every 4 hours. By the fourth day of her hospital stay, she was discharged to home with an albuterol inhaler, oral prednisone, oral doxycycline, and a follow‐up appointment. Dedicated patient education regarding proper inhaler administration did not occur during hospitalization.

WHY YOU MIGHT THINK NEBULIZED TREATMENTS IN INPATIENTS ARE HELPFUL

Inhaled bronchodilators are a mainstay of therapy for acute obstructive pulmonary diseases, including COPD and asthma exacerbations.[1, 2] Inhaled bronchodilators may be delivered by metered‐dose inhalers (MDIs) or via wet nebulizers powered by compressed air or oxygen. Current practice patterns in EDs and hospital wards tend to favor the use of nebulizers due to many apparent advantages of these devices.[3] For instance, nebulizers do not require any special inhalation technique and can be effectively used by patients at any age.[3, 4] There is also a common perception that nebulizers are more effective, possibly stemming from the assumption that hospitalized patients have already failed their outpatient MDI therapy and an almost mystical belief in the healing power of mist. Moreover, many clinicians have been trained to routinely use nebulizer therapies and may lack sufficient knowledge or comfort about the relative efficacy and equivalence dosing of MDI therapies.

WHY NEBULIZERS ARE NOT BETTER THAN MDIs FOR PATIENTS HOSPITALIZED WITH OBSTRUCTIVE PULMONARY SYMPTOMS

Decades of research support that MDIs are effective, efficient, and less costly (depending on circumstances) than nebulizers for the routine treatment of obstructive pulmonary exacerbations.[3, 4, 5, 6, 7, 8, 9, 10, 11] The clinical effectiveness of MDIs has been shown in studies across populations of adults with acute COPD symptoms,[3, 4, 7, 8] as well as children and adults with asthma exacerbations.[3, 4, 5, 6, 9, 10] A 2005 joint report by the American College of Chest Physicians (ACCP) and the American College of Asthma, Allergy and Immunology (ACAAI), concluded none of the pooled meta‐analyses showed a significant difference between devices in any efficacy outcome in any patient group for each of the clinical settings.[4] Many different outcomes have been investigated, including forced expiratory volumes (FEV), peak flows, symptoms and specific symptom scores, and physical findings.[4]

Compared to MDIs, there are a number of drawbacks to the use of nebulizers: nebulizers are more expensive to buy and maintain, are less portable, and take longer to set up, use, and clean following each use.[12] In addition, nebulizers have been associated with greater increases in heart rate and tremors compared to MDIs, suggesting nebulizers lead to higher systemically absorbed ‐agonist doses.[4]

Of note, nearly all of the clinical effectiveness studies administered MDIs with a valved holding chamber or spacer, facilitating the delivery of drug to the airways.[3, 4] Although valved holding chambers are commonly referred to as a spacer, a true spacer does not have a valve and is rarely used today.[12]

THE EVIDENCE EXAMINING NEBULIZERS VERSUS MDIs IN PATIENTS WITH ASTHMA OR COPD EXACERBATIONS

A 2013 Cochrane review sought to establish the relative efficacy of MDIs with holding chambers versus nebulizers for children and adults who presented to a community setting or emergency department with acute asthma.[6] The review included a total of 1897 children and 729 adults in 39 randomized controlled trials. The authors judged the overall evidence to be of moderate quality. Children with acute asthma treated with MDIs in the ED had shorter lengths of stay in the ED (70 minutes vs 103 minutes), similar peak flow and FEV measurements, lower heart rates, and less tremor compared to children treated with nebulizers.[5, 6] There were no significant differences found between devices for the treatment of adult patients with asthma.[6]

In a separate double‐blind, randomized, placebo‐controlled study evaluating albuterol administered by nebulizer versus MDI with spacer for children <2 years old presenting to an ED with wheezing, the use of MDIs with a spacer and facemask was equally efficacious and may have led to fewer hospital admissions.[10]

Mandelberg et al. performed a double‐blind, randomized, placebo‐controlled trial for unselected adult patients presenting to an ED with obstructive pulmonary symptoms.[8] Patients received either 2 puffs of a placebo MDI with a spacer along with nebulized salbutamol 0.5 mL in 1.5 mL saline solution (n=25), or a salbutamol MDI along with a nebulized placebo saline solution (n=25). Treatments were repeated every 15 minutes up to 3 times, unless side effects occurred. Spirometric measurements were performed following each treatment. No differences were seen between the groups at any point during the study period. The authors concluded, Even in the setting of the unselected group of patient referrals to the [Department of Emergency Medicine] for episodes of severe airflow limitation, the clinical and objective bronchodilator responses to the administration of salbutamol are independent of the method of delivery: MDI with large spacer or aerosol nebulization.[8]

There are surprisingly few studies examining the use of nebulizers versus MDIs in the inpatient setting for both children and adults. Dolovich et al. reviewed 6 studies that included 253 total patients and reported no significant differences in pulmonary function between devices.[4] Based on these findings, the ACCP/ACAAI group recommended both nebulizers and MDIs with spacers/holding chambers are appropriate for use in the inpatient setting. Quality of evidence: good.[4]

WHY USE MDIs FOR INPATIENTS

If MDI and nebulizer treatments are equally effective, why change current practice? The use of MDIs, rather than nebulizers, in hospitals could lead to fewer side effects such as tachycardia, arrhythmias, and tremors. MDIs are also more portable and do not require specialized set‐up. Furthermore, MDI administrations during hospitalization may provide a golden opportunity to have respiratory therapists, pharmacists, or other health professionals spend time teaching patients proper inhaler usage, rather than providing time‐consuming nebulizer treatments.[13] In a recent study, approximately 86% of hospitalized patients with asthma or COPD could not demonstrate appropriate use of an MDI. However, 100% of patients were able to achieve mastery following a short teach‐back session.[14] It is conceivable that transitioning patients to MDIs earlier during hospitalization and providing them with education regarding proper MDI administration could instill confidence in their use of inhalers and result in downstream effects such as shorter lengths of stay, less frequent hospital readmissions, or improved quality of life.

MDI use may result in cost savings in certain settings, although the relative costs of nebulizer versus MDI treatments depends on many institution‐specific factors. Such factors include the institutional policies on who delivers the nebulizer or the MDI and how they are compensated and staffed. For example in the Nebs No More After 24 program initiated at the University of California, San Francisco, the vast majority of the realized cost savings are due to the reduction in respiratory therapist time spent delivering MDIs, which reflects the local policies and compensation structure.[13] Previous inpatient interventions to convert from nebulizers to MDIs also showed cost savings resulting from decreased labor needs.[15] In some hospitals, nurses deliver nebulizer treatments, whereas in others only respiratory therapists are allowed to provide nebulizers. Moreover, whether the MDI can go home with the patient upon discharge depends on whether the hospital has a dispensing pharmacy or not. Formal economic evaluations specific to the local institution are necessary.

WHAT WE SHOULD DO INSTEAD: ENCOURAGE THE USE OF MDIs FOR INPATIENTS

For effective inpatient MDI treatments, MDI technique must be good. Thus, it is vital to enlist the right people to provide proper MDI teaching and supervision. Respiratory therapists are generally trained for this task, and may be complemented by appropriately trained physicians, nurses, or pharmacists. Many institutions have successfully implemented respiratory therapist‐driven protocols for the administration of MDIs, which has led to measurable improvements in the utilization of appropriate respiratory care resources.[15, 16] At University of California, San Francisco, this was accomplished by recruiting respiratory therapists and nurses to help support the transition of patients from nebulizers to MDIs and to provide bedside teaching on proper MDI usage. The institution then launched a Nebs No More After 24 campaign that sought to transition patients from nebulizers to MDIs within 24 hours of hospitalization. This campaign included an educational program for physicians, prepared facilitator guides to assist attending physicians with teaching about the new initiative, publicity efforts including pens and strategically placed posters, and regular feedback regarding nebulizer utilization on the pilot ward. Although the evidence suggests that patients can be started on MDIs immediately upon presentation to the ED, the UCSF campaign focused on transitioning patients within 24 hours so to alleviate concerns about transitions in care between the ED and the medical ward, as well as between overnight and day teams. MDIs are only as or more effective than nebulizers if the correct administration technique is employed. The 24‐hour transition period allows for MDI teaching and transition during regular daytime hours.

Inpatient use of nebulizers may be more appropriate than MDIs for patients with dementia or altered mental status, as well as those in extreme distress resulting in an inability to coordinate inhaler usage. Very low health literacy may be an additional barrier to appropriate MDI teaching and usage.

RECOMMENDATIONS

In patients with obstructive pulmonary symptoms, transition patients from nebulizers to MDIs early in their hospital course, unless the patient is unable to use an inhaler due to altered mental status, dementia, or other circumstances. Ensure that patients are instructed and supervised on proper MDI technique. Enlisting respiratory therapists and appropriately trained staff (pharmacists, nurses, physicians) is key to the successful use of MDIs. Frequency and dosage of MDIs used should be comparable to that of nebulized treatments. Although studies have used a relatively wide range of albuterol MDI dosing, prior programs have determined a dose of albuterol 4 puffs via MDI as being equivalent to the standard albuterol 2.5 mg nebulizer dosage.[17, 18] Some studies have advocated for using a range of 2 to 10 puffs albuterol MDI, with the actual dose based on clinical response.[17] One study in children with mild acute asthma found that 2 puffs of albuterol by MDI was just as effective as higher doses delivered by MDI (610 puffs) or by nebulizer.[19]

CONCLUSION

MDIs with holding chambers are clinically equivalent to nebulizer therapy for the treatment of both children and adults with obstructive pulmonary symptoms, as long as MDI technique and MDI dosing is adequate. This is based on good data in the ED setting but fewer studies in adult inpatients. There are a number of advantages to the use of inpatient MDIs over nebulizers; MDIs are more portable, often less expensive to use, may result in fewer side effects, and will hopefully improve outpatient MDI technique. The delivery of MDIs during hospitalization should be accompanied with patient education regarding proper administration technique.

Do you think this is a low‐value practice? Is this truly a Thing We Do for No Reason? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other Things We Do for No Reason topics by emailing [email protected]