Original Research

Topical medication is a mainstay in the treatment of dermatologic conditions. Adherence to medication regimens can be challenging in patients requiring long-term topical treatment, and nonadherence is multifactorial. A major modifiable contributing factor is patient dissatisfaction with the vehicle used. Medications often have options for different topical preparations. Therefore, it is important to consider patient preference when prescribing topical treatments to maximize adherence, ensure patient satisfaction, and optimize outcomes.

We hypothesized that notable differences exist among demographic groups regarding preference for topical vehicles. Little research has been conducted to delineate trends. This study aimed to identify variations in preference for creams, lotions, and ointments by age, gender, and ethnicity.

Methods

Data were collected through surveys distributed to all patients seen at the Truman Medical Center University Health Dermatology Clinic in Kansas City, Missouri, between September 2018 and June 2019. The study was approved by the University of Missouri Kansas City institutional review board. An estimated response rate of 95% was achieved. Each patient was informed that the survey was voluntary and anonymous, and declining to complete the survey had no effect on the care provided. Each patient completed only 1 survey and returned it to a collection box before departing from clinic.

In the survey, patients provided demographic information, including age, gender, and ethnicity. Age groups included patients younger than 40 years, 40 to 60 years, and older than 60 years. Gender groups included male and female. Ethnicity included white, black, Hispanic/Latino, and Asian/Pacific Islander or other. Patients then chose 1 of 3 options for topical vehicle preference: cream, lotion, or ointment. Each of these options was accompanied by a brief description of the vehicle, a photograph, and examples of common commercial products to aid in decision-making. The expected values were calculated based on a probability distribution under the assumption that variables have no association. Therefore, the discrepancy between the expected value and the observed value was used to describe the significance of the association between variables. 

Data were analyzed using χ² tests with the aid of a statistician. P<.05 was considered statistically significant.

Results

A total of 404 surveys were collected and recorded. Data showed statistically significant trends in each demographic parameter.

Age
First, we analyzed differences in preference based on age (Table 1). Of 404 patients, 163 were younger than 40 years, 171 were aged 40 to 60 years, and 70 were older than 60 years. Patients younger than 40 years preferred lotion (68 vs 46.0 expected). Patients aged 40 to 60 years showed preference for cream (83 vs 76.6 expected) and ointment (56 vs 46.1 expected). Patients older than 60 years preferred cream (41 vs 31.4 expected). These findings were statistically significant (P<.0001).

Comment

Topical medication is a mainstay of dermatologic therapy. Many topical preparations (or vehicles) exist, including ointments, creams, lotions, gels, solutions, and foams. Vehicle type not only influences bioavailability of the prepared medication but also has a notable impact on adherence and subsequent efficacy of the topical therapy.

Medication adherence is especially challenging in dermatology, as topical medications play a central role in treatment. Compliance with the medication regimen is paramount in treatment efficacy.¹ In dermatology, adherence with oral medications is higher than it is for topical medications²; various factors contribute to this difference. Compliance may decline with topical treatment due to time-consuming application, misunderstanding about the disease or the treatment regimen, frequency of administration, dissatisfaction with efficacy or appearance, and other variables.³

Other factors have been found to be important to topical medication adherence; younger age, female gender, marriage, employment, nonsmoking, nondrinking, and higher cognitive ability were associated with higher topical medication adherence.⁴ Our study focused on one factor: identification of demographic-specific preferences that might have implications on adherence within the studied demographic groups.

It is known that individual preferences exist when patients are choosing a topical preparation. However, a PubMed search of articles indexed for MEDLINE using the terms topical, vehicle, preparation, adherence, and preference revealed few studies that examined the preference for topical vehicle by age, gender, or ethnicity.

Existing studies have examined preferences for topical preparations based on specific disease states; this literature, albeit limited, demonstrates that preferences for topical product formulations vary among acne, atopic dermatitis, and plaque psoriasis patients.⁵ Other studies focus on specific patient populations or medications. For example, one study found that preference for corticosteroid vehicles among psoriasis patients was highly variable and choice of vehicle was critical to adherence.⁶ Another study highlighted differences in vehicle choice between younger and older age groups with psoriasis.⁷

Given the limited data overall, it was our goal to determine if any patterns of preference existed by age, gender, or ethnicity, regardless of disease state or indication for topical product. Importantly, over-the-counter products—cosmetic or otherwise—were not differentiated from prescribed topical medications. Our survey elucidated significant differences in preference by age, gender, and ethnicity.

Notable Findings
Regarding age, patients younger than 40 years preferred lotion, patients aged 40 to 60 years preferred cream, and patients older than 60 years preferred cream. Analysis based on gender showed that females preferred cream, and males preferred lotion and ointment. Analysis based on ethnicity most notably demonstrated a strong preference for ointment in black patients while showing preference for cream in white patients.

Potential Biases and Pitfalls
Limitations of this study included the small Hispanic/Latino and Asian/Pacific Islander populations surveyed, possible misunderstanding of the survey by respondents, and the potential for surveys being filled out twice by the same patient. Future surveys could be conducted over a longer period to increase the total sample size and to better characterize less-represented populations, such as Hispanic and Asian patients. To avoid repeat participation, the first question of the survey asked patients to indicate if they had previously completed the survey and instructed patients who had to return the repeat survey to the front desk.

To limit other errors, our survey included concise accessible descriptions of each preparation along with clear representative photographs and examples of common brands. Still, it is possible that some mistakes could have been made while patients filled out the survey based on comprehension deficits, oversight, or other reasons. It also is possible that preference might vary individually depending on the indication of the topical product—cosmetic or therapeutic—or even by anatomic site of application. Neither of these considerations was assessed specifically in our survey.

Conclusion

Our hope is that this study helps practitioners better anticipate topical preferences among patients with the ultimate goal of increasing medication adherence and patient outcomes. Nevertheless, although these general trends can provide helpful guidance, we acknowledge that individual preferences vary, and care should always be patient centered.

Acknowledgment
We thank An-Lin Cheng, PhD (Kansas City, Missouri), for assistance with the statistical analysis.

Topical medication is a mainstay in the treatment of dermatologic conditions. Adherence to medication regimens can be challenging in patients requiring long-term topical treatment, and nonadherence is multifactorial. A major modifiable contributing factor is patient dissatisfaction with the vehicle used. Medications often have options for different topical preparations. Therefore, it is important to consider patient preference when prescribing topical treatments to maximize adherence, ensure patient satisfaction, and optimize outcomes.

We hypothesized that notable differences exist among demographic groups regarding preference for topical vehicles. Little research has been conducted to delineate trends. This study aimed to identify variations in preference for creams, lotions, and ointments by age, gender, and ethnicity.

Methods

Data were collected through surveys distributed to all patients seen at the Truman Medical Center University Health Dermatology Clinic in Kansas City, Missouri, between September 2018 and June 2019. The study was approved by the University of Missouri Kansas City institutional review board. An estimated response rate of 95% was achieved. Each patient was informed that the survey was voluntary and anonymous, and declining to complete the survey had no effect on the care provided. Each patient completed only 1 survey and returned it to a collection box before departing from clinic.

In the survey, patients provided demographic information, including age, gender, and ethnicity. Age groups included patients younger than 40 years, 40 to 60 years, and older than 60 years. Gender groups included male and female. Ethnicity included white, black, Hispanic/Latino, and Asian/Pacific Islander or other. Patients then chose 1 of 3 options for topical vehicle preference: cream, lotion, or ointment. Each of these options was accompanied by a brief description of the vehicle, a photograph, and examples of common commercial products to aid in decision-making. The expected values were calculated based on a probability distribution under the assumption that variables have no association. Therefore, the discrepancy between the expected value and the observed value was used to describe the significance of the association between variables. 

Data were analyzed using χ² tests with the aid of a statistician. P<.05 was considered statistically significant.

Results

A total of 404 surveys were collected and recorded. Data showed statistically significant trends in each demographic parameter.

Age
First, we analyzed differences in preference based on age (Table 1). Of 404 patients, 163 were younger than 40 years, 171 were aged 40 to 60 years, and 70 were older than 60 years. Patients younger than 40 years preferred lotion (68 vs 46.0 expected). Patients aged 40 to 60 years showed preference for cream (83 vs 76.6 expected) and ointment (56 vs 46.1 expected). Patients older than 60 years preferred cream (41 vs 31.4 expected). These findings were statistically significant (P<.0001).

Comment

Topical medication is a mainstay of dermatologic therapy. Many topical preparations (or vehicles) exist, including ointments, creams, lotions, gels, solutions, and foams. Vehicle type not only influences bioavailability of the prepared medication but also has a notable impact on adherence and subsequent efficacy of the topical therapy.

Medication adherence is especially challenging in dermatology, as topical medications play a central role in treatment. Compliance with the medication regimen is paramount in treatment efficacy.¹ In dermatology, adherence with oral medications is higher than it is for topical medications²; various factors contribute to this difference. Compliance may decline with topical treatment due to time-consuming application, misunderstanding about the disease or the treatment regimen, frequency of administration, dissatisfaction with efficacy or appearance, and other variables.³

Other factors have been found to be important to topical medication adherence; younger age, female gender, marriage, employment, nonsmoking, nondrinking, and higher cognitive ability were associated with higher topical medication adherence.⁴ Our study focused on one factor: identification of demographic-specific preferences that might have implications on adherence within the studied demographic groups.

It is known that individual preferences exist when patients are choosing a topical preparation. However, a PubMed search of articles indexed for MEDLINE using the terms topical, vehicle, preparation, adherence, and preference revealed few studies that examined the preference for topical vehicle by age, gender, or ethnicity.

Existing studies have examined preferences for topical preparations based on specific disease states; this literature, albeit limited, demonstrates that preferences for topical product formulations vary among acne, atopic dermatitis, and plaque psoriasis patients.⁵ Other studies focus on specific patient populations or medications. For example, one study found that preference for corticosteroid vehicles among psoriasis patients was highly variable and choice of vehicle was critical to adherence.⁶ Another study highlighted differences in vehicle choice between younger and older age groups with psoriasis.⁷

Given the limited data overall, it was our goal to determine if any patterns of preference existed by age, gender, or ethnicity, regardless of disease state or indication for topical product. Importantly, over-the-counter products—cosmetic or otherwise—were not differentiated from prescribed topical medications. Our survey elucidated significant differences in preference by age, gender, and ethnicity.

Notable Findings
Regarding age, patients younger than 40 years preferred lotion, patients aged 40 to 60 years preferred cream, and patients older than 60 years preferred cream. Analysis based on gender showed that females preferred cream, and males preferred lotion and ointment. Analysis based on ethnicity most notably demonstrated a strong preference for ointment in black patients while showing preference for cream in white patients.

Potential Biases and Pitfalls
Limitations of this study included the small Hispanic/Latino and Asian/Pacific Islander populations surveyed, possible misunderstanding of the survey by respondents, and the potential for surveys being filled out twice by the same patient. Future surveys could be conducted over a longer period to increase the total sample size and to better characterize less-represented populations, such as Hispanic and Asian patients. To avoid repeat participation, the first question of the survey asked patients to indicate if they had previously completed the survey and instructed patients who had to return the repeat survey to the front desk.

To limit other errors, our survey included concise accessible descriptions of each preparation along with clear representative photographs and examples of common brands. Still, it is possible that some mistakes could have been made while patients filled out the survey based on comprehension deficits, oversight, or other reasons. It also is possible that preference might vary individually depending on the indication of the topical product—cosmetic or therapeutic—or even by anatomic site of application. Neither of these considerations was assessed specifically in our survey.

Conclusion

Our hope is that this study helps practitioners better anticipate topical preferences among patients with the ultimate goal of increasing medication adherence and patient outcomes. Nevertheless, although these general trends can provide helpful guidance, we acknowledge that individual preferences vary, and care should always be patient centered.

Acknowledgment
We thank An-Lin Cheng, PhD (Kansas City, Missouri), for assistance with the statistical analysis.

Topical medication is a mainstay in the treatment of dermatologic conditions. Adherence to medication regimens can be challenging in patients requiring long-term topical treatment, and nonadherence is multifactorial. A major modifiable contributing factor is patient dissatisfaction with the vehicle used. Medications often have options for different topical preparations. Therefore, it is important to consider patient preference when prescribing topical treatments to maximize adherence, ensure patient satisfaction, and optimize outcomes.

We hypothesized that notable differences exist among demographic groups regarding preference for topical vehicles. Little research has been conducted to delineate trends. This study aimed to identify variations in preference for creams, lotions, and ointments by age, gender, and ethnicity.

Methods

Data were collected through surveys distributed to all patients seen at the Truman Medical Center University Health Dermatology Clinic in Kansas City, Missouri, between September 2018 and June 2019. The study was approved by the University of Missouri Kansas City institutional review board. An estimated response rate of 95% was achieved. Each patient was informed that the survey was voluntary and anonymous, and declining to complete the survey had no effect on the care provided. Each patient completed only 1 survey and returned it to a collection box before departing from clinic.

In the survey, patients provided demographic information, including age, gender, and ethnicity. Age groups included patients younger than 40 years, 40 to 60 years, and older than 60 years. Gender groups included male and female. Ethnicity included white, black, Hispanic/Latino, and Asian/Pacific Islander or other. Patients then chose 1 of 3 options for topical vehicle preference: cream, lotion, or ointment. Each of these options was accompanied by a brief description of the vehicle, a photograph, and examples of common commercial products to aid in decision-making. The expected values were calculated based on a probability distribution under the assumption that variables have no association. Therefore, the discrepancy between the expected value and the observed value was used to describe the significance of the association between variables. 

Data were analyzed using χ² tests with the aid of a statistician. P<.05 was considered statistically significant.

Results

A total of 404 surveys were collected and recorded. Data showed statistically significant trends in each demographic parameter.

Age
First, we analyzed differences in preference based on age (Table 1). Of 404 patients, 163 were younger than 40 years, 171 were aged 40 to 60 years, and 70 were older than 60 years. Patients younger than 40 years preferred lotion (68 vs 46.0 expected). Patients aged 40 to 60 years showed preference for cream (83 vs 76.6 expected) and ointment (56 vs 46.1 expected). Patients older than 60 years preferred cream (41 vs 31.4 expected). These findings were statistically significant (P<.0001).

Comment

Topical medication is a mainstay of dermatologic therapy. Many topical preparations (or vehicles) exist, including ointments, creams, lotions, gels, solutions, and foams. Vehicle type not only influences bioavailability of the prepared medication but also has a notable impact on adherence and subsequent efficacy of the topical therapy.

Medication adherence is especially challenging in dermatology, as topical medications play a central role in treatment. Compliance with the medication regimen is paramount in treatment efficacy.¹ In dermatology, adherence with oral medications is higher than it is for topical medications²; various factors contribute to this difference. Compliance may decline with topical treatment due to time-consuming application, misunderstanding about the disease or the treatment regimen, frequency of administration, dissatisfaction with efficacy or appearance, and other variables.³

Other factors have been found to be important to topical medication adherence; younger age, female gender, marriage, employment, nonsmoking, nondrinking, and higher cognitive ability were associated with higher topical medication adherence.⁴ Our study focused on one factor: identification of demographic-specific preferences that might have implications on adherence within the studied demographic groups.

It is known that individual preferences exist when patients are choosing a topical preparation. However, a PubMed search of articles indexed for MEDLINE using the terms topical, vehicle, preparation, adherence, and preference revealed few studies that examined the preference for topical vehicle by age, gender, or ethnicity.

Existing studies have examined preferences for topical preparations based on specific disease states; this literature, albeit limited, demonstrates that preferences for topical product formulations vary among acne, atopic dermatitis, and plaque psoriasis patients.⁵ Other studies focus on specific patient populations or medications. For example, one study found that preference for corticosteroid vehicles among psoriasis patients was highly variable and choice of vehicle was critical to adherence.⁶ Another study highlighted differences in vehicle choice between younger and older age groups with psoriasis.⁷

Given the limited data overall, it was our goal to determine if any patterns of preference existed by age, gender, or ethnicity, regardless of disease state or indication for topical product. Importantly, over-the-counter products—cosmetic or otherwise—were not differentiated from prescribed topical medications. Our survey elucidated significant differences in preference by age, gender, and ethnicity.

Notable Findings
Regarding age, patients younger than 40 years preferred lotion, patients aged 40 to 60 years preferred cream, and patients older than 60 years preferred cream. Analysis based on gender showed that females preferred cream, and males preferred lotion and ointment. Analysis based on ethnicity most notably demonstrated a strong preference for ointment in black patients while showing preference for cream in white patients.

Potential Biases and Pitfalls
Limitations of this study included the small Hispanic/Latino and Asian/Pacific Islander populations surveyed, possible misunderstanding of the survey by respondents, and the potential for surveys being filled out twice by the same patient. Future surveys could be conducted over a longer period to increase the total sample size and to better characterize less-represented populations, such as Hispanic and Asian patients. To avoid repeat participation, the first question of the survey asked patients to indicate if they had previously completed the survey and instructed patients who had to return the repeat survey to the front desk.

To limit other errors, our survey included concise accessible descriptions of each preparation along with clear representative photographs and examples of common brands. Still, it is possible that some mistakes could have been made while patients filled out the survey based on comprehension deficits, oversight, or other reasons. It also is possible that preference might vary individually depending on the indication of the topical product—cosmetic or therapeutic—or even by anatomic site of application. Neither of these considerations was assessed specifically in our survey.

Conclusion

Our hope is that this study helps practitioners better anticipate topical preferences among patients with the ultimate goal of increasing medication adherence and patient outcomes. Nevertheless, although these general trends can provide helpful guidance, we acknowledge that individual preferences vary, and care should always be patient centered.

Acknowledgment
We thank An-Lin Cheng, PhD (Kansas City, Missouri), for assistance with the statistical analysis.

Acne vulgaris (acne) is the most common dermatologic condition in black patients.^1,2 However, among outpatient visits, racial disparities exist in both the likelihood of seeing a dermatologist and being treated.³ Black patients are less likely to visit a dermatologist or receive any acne medication. Acne in black skin is frequently associated with postinflammatory hyperpigmentation (PIH), an important consideration in treatment choice and maintenance.

There is a paucity of clinical studies that specifically evaluate acne treatment in this patient population. An 8-week, vehicle-controlled study with tretinoin cream 0.025% in 27 black patients with acne reported notable decreases in papules, pustules, and hyperpigmented macules in 83% of patients treated with tretinoin compared to only 13% receiving vehicle.⁴ However, irritation and inflammation were problematic. An open-label study of adapalene gel 0.1% in 65 black South Africans also demonstrated significant improvement in inflammatory and noninflammatory lesions and PIH (P<.01), with seemingly better tolerability.^5,6 A meta-analysis of 5 randomized studies from the United States and Europe (N=655) compared the efficacy and safety of adapalene gel 0.1% in black (n=46) and white patients.⁷ There was no significant difference in percentage reduction in comedonal (44%) or total (42%) lesion counts. The percentage reduction in inflammatory lesion counts (53%) was significantly greater in black patients (P=.012). Tolerability also was better; black patients experienced significantly less erythema and scaling (P<.001 and P=.026, respectively), though erythema can be underestimated in darker skin tones because of the masking effects of melanin.^5,7 Dryness was more common, though a smaller percentage of black patients reported moderate or severe dryness compared to white patients (7% vs 18%).⁷

Black patients also are less likely to receive combination therapy, and again clinical data are limited.³ A more recent subgroup analysis evaluated the safety and efficacy of adapalene 0.1%–benzoyl peroxide 2.5% gel in black patients with moderate acne from 3 studies (n=238 out of a total of 3855 patients).⁸ Similar results were obtained as in the overall study populations, with 64.3% and 48.5% reductions in inflammatory and noninflammatory lesion counts, respectively, at week 12. The most common treatment-related adverse event (AE) in both treatment groups was dry skin (11.3%).⁸

Extensive clinical data in a predominantly white population have shown that topical retinoids (eg, tretinoin, adapalene, tazarotene) are highly effective in treating acne, and they are recommended as the cornerstone of topical therapy.⁹ However, there is a common perception that they are primarily effective in comedonal acne¹⁰ and that their use is associated with notable cutaneous irritation.^11,12 Several attempts have been made to alleviate the tolerability issue using novel delivery systems. A new lotion formulation of tretinoin recently was developed and leveraged polymeric emulsion technology with the aim to improve both efficacy and tolerability of tretinoin. Herein, we performed a post hoc analysis of 2 large phase 3 clinical studies¹³ in patients with moderate or severe acne treated with tretinoin lotion 0.05% to evaluate its safety and tolerability in a black population.

METHODS

Study Design

We conducted a post hoc analysis of 2 identical multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical studies¹³ in black patients with moderate or severe acne. Protocols received approval from the appropriate institutional review board for each center before patient enrollment, and the studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice as well as in compliance with local regulatory requirements. All patients were informed of the study details and provided written consent before entering the studies.

Patients were enrolled with an evaluator global severity score (EGSS) of 3 (moderate) or 4 (severe). Participants were randomized (1:1) to receive tretinoin lotion 0.05% or vehicle applied to the face once daily for 12 weeks.

Study Population

Eligible patients for the post hoc analysis included male and female patients with black skin who were 9 years and older and presented with 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 noninflammatory lesions (open and closed comedones), and 2 or fewer nodules. A washout period of up to 1 month was required for patients who previously used prescription and over-the-counter acne treatments, and a washout period of 6 months was required for systemic retinoids.

Safety Evaluation

Cutaneous safety (erythema and scaling) and tolerability (itching, burning, and stinging) were evaluated on a 4-point scale (0=none; 3=severe). Severity of hypopigmentation and hyperpigmentation also was assessed using this 4-point scale. The investigator assessed erythema and scaling at the time of each study visit. Reports of itching, burning, and stinging were solicited from participants and recorded as an average score of their symptoms during the period since the prior visit.

Adverse events were evaluated throughout and summarized by treatment group, severity, and relationship to study medication.

Statistical Analysis

The safety analysis set comprised all randomized patients who were presumed to have used the study drug at least once and who provided at least 1 postbaseline evaluation. All AEs occurring during the studies were recorded and coded using the Medical Dictionary for Regulatory Activities version 18.0. Treatment group comparisons were made by tabulating the frequency of participants reporting 1 or more AEs during the study.

Cutaneous safety (scaling, erythema, hypopigmentation, and hyperpigmentation) and tolerability (itching, burning, and stinging) scores were presented by treatment group with descriptive statistics at baseline and weeks 4, 8, and 12. Frequencies and percentages for each outcome category were included in the statistics.

RESULTS

Baseline Characteristics

A total of 308 patients were included in the post hoc analysis. Overall, 257 (83.4%) patients completed the studies, including 138 (83.6%) patients receiving tretinoin lotion 0.05% and 119 (83.2%) receiving vehicle (Figure 1). Completion rates were similar in the female and male subgroups (83.3% and 83.8%, respectively). The most common reasons for study discontinuations were lost to follow-up (n=32; 10.4%) or participant request (n=13; 4.2%) and were similar irrespective of treatment or sex. There were no study discontinuations due to AEs.

Demographic data (Table) were similar across the 2 treatment arms. The mean age (standard deviation [SD]) of the participants was 22.1 (8.35) years (range, 9–58 years). Participants were predominantly female (209/308 [67.9%]) and tended to be a little older than the males (mean age, 23.6 vs 18.8 years).

At baseline, the mean score (SD) for scaling, erythema, itching, burning, and stinging in those participants that were subsequently treated with tretinoin lotion 0.05% was 0.2 (0.42), 0.4 (0.68), 0.3 (0.60), 0.1 (0.28), and 0.1 (0.32), respectively (where 1=mild)(Figure 2). There were no differences in mean baseline scores between active and vehicle treatment groups for hyperpigmentation (0.8 each) and hypopigmentation (0.1 each) in the active and vehicle treatment groups. Mean baseline scores were slightly higher in the female participants (0.9) compared to male participants (0.6). Baseline moderate or severe hyperpigmentation was reported in 23.2% and 3.2% of participants, respectively, who were subsequently treated with tretinoin lotion 0.05%, which also was more commonly reported in female participants (33/105 [31.5%]) than male participants (8/50 [16.0%]).

Safety

Treatment-Related AEs
More participants treated with tretinoin lotion 0.05% reported treatment-emergent AEs (TEAEs) compared to vehicle (35 vs 18). The majority of participants reporting TEAEs were female (24 of 35). There were 2 (1.3%) serious AEs with tretinoin lotion 0.05% (both female), and 1 female participant (0.6%) discontinued the study drug because of a TEAE (eTable).

Overall, there were 12 (7.7%) treatment-related AEs; all were mild (n=10) or moderate (n=2). Treatment-related AEs reported by more than 1% of participants treated with tretinoin lotion 0.05% included application-site pain (n=4; 2.6%), dryness (n=4; 2.6%), irritation (n=2; 1.3%), exfoliation (n=2; 1.3%), or erythema (n=2; 1.3%). The majority of treatment-related AEs (10/12) were reported in the female subgroup. Although application-site pain (3.4%) and dryness (3.8%) were more commonly reported in the white population (unpublished data, Ortho Dermatologics) in the 2 studies, differences between the 2 racial groups were not significant.

Cutaneous Safety and Tolerability
Erythema and scaling were recorded by the investigator. Mild to moderate erythema was noted in 31% of participants at baseline, with 21% reporting mild to moderate scaling. Both improved over the study period following treatment with tretinoin lotion 0.05%, with 79% of participants having no erythema and 88% having no scaling by week 12. Mean scores for erythema and scaling remained less than 0.5 throughout the study (1=mild). There were slight transient increases in the mean baseline score for scaling (from 0.2 to 0.3) at week 4 in the active treatment group. By week 12, mean scores were half those reported at baseline (Figure 2).

Severity of itching, burning, and stinging was reported by participants. Overall, 23% reported mild to moderate itching at baseline. Only 7 participants (5%) reported any itching by week 12 in the tretinoin lotion 0.05% group. Reports of burning and stinging were both rare and mild at baseline. Mean scores for itching, burning, and stinging at baseline for those participants who were subsequently treated with tretinoin lotion 0.05% were 0.3, 0.1, and 0.1, respectively (1=mild). Itching severity reduced progressively with treatment. There were slight transient increases in mean scores for burning (from 0.1 to 0.2) and stinging (from 0.1 to 0.2) at week 4, returning to baseline levels or below by week 12.

Hyperpigmentation and Hypopigmentation
There was a progressive improvement in baseline hyperpigmentation severity in participants treated with tretinoin lotion 0.05%; mean scores reduced from 0.8 at baseline to 0.6 by week 12 (Figure 3), with a similar improvement in both sexes (Figure 4). Moderate to severe hyperpigmentation was reported in 24 (17.3%) participants by week 12 compared to 41 (26.4%) at baseline; the majority (n=21) were female at week 12. Moderate to severe hyperpigmentation was reported in 24 (19.7%) participants treated with vehicle at week 12.

COMMENT

Topical retinoids (eg, tretinoin, adapalene, tazarotene) are recommended as the cornerstone of topical acne treatment, with safety and efficacy well documented in large pivotal trials.¹⁴ However, data in black patients are lacking. Acne is the most common dermatologic condition in these patients, and yet investigation into this important population is limited to small study populations or subgroup analyses.

Tretinoin lotion 0.05% is a novel topical treatment for moderate to severe acne that leverages polymeric emulsion technology. The development rationale was to provide a tretinoin formulation with improved efficacy and tolerability, features that could be especially suited to black patients with acne.

In our post hoc analysis of black patients with acne, tretinoin lotion 0.05% generally was considered safe and well tolerated. The most commonly reported treatment-related AEs were of low incidence and included application-site reactions and skin-related events attributed to the known properties of tretinoin. Most noteworthy was the extremely low irritation potential of this novel tretinoin formulation. Treatment-related AEs generally were mild, and interestingly, the majority occurred in female patients. The incidence of the most common treatment-related AEs—application-site dryness (2.6%) and application-site pain (2.6%)—was lower than that reported in the white populations in the 2 studies (3.8% and 3.4%, respectively).(unpublished data, Ortho Dermatologics), though the differences were not significant (P=.625 and P=.799).

Approximately one-quarter of participants had mild to moderate erythema, scaling, itching, and stinging at baseline. All of these cutaneous symptoms improved with treatment. There were slight transient increases in scaling and stinging at week 4, with stinging more noticeable in the female population. There were no noticeable changes in mild to moderate burning during the study.

Postinflammatory hyperpigmentation is an important consideration in black patients with acne. It can arise from either acne-induced inflammation or injury. It can be of greater concern to the patient than the acne itself and often is the main reason black patients seek a dermatologist consultation. In a survey of adult female acne, nonwhite women experienced substantially more PIH than white women. In addition, clearance of PIH was most important for these nonwhite women (42% vs 8% for white women), whereas lesion clearance was the most important aspect for white women (58% vs 32% for nonwhite women).¹⁵ Erring on the side of increased tolerability is appropriate in black patients with acne, given that any irritant reactions can lead to pigmentary alterations—hyperpigmentation or hypopigmentation—that can cause considerable patient anxiety. The psychologic impact of PIH can be devastating, and an ideal acne treatment in these patients would be one that is effective against both PIH and acne. Tretinoin cream 0.1% monotherapy has been shown to be effective in reducing PIH.¹⁶ Postinflammatory hyperpigmentation lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens. Although facial PIH lesions in the 24 tretinoin-treated patients were significantly lighter after 40 weeks of treatment compared to vehicle in this study (P<.001), overall improvement was first noted after 4 weeks (P=.009). Normal skin also was minimally lightened by tretinoin; however, exuberant local skin reactions, including peeling, developed in 50% of patients. Mild to moderate PIH was present in the majority of tretinoin-treated patients at baseline in our post hoc analysis, severe in 3.2% of cases, and both more common and severe in females. Mean scores reduced over the 12-week study period, from 0.6 to 0.4 in male patients and 0.9 to 0.7 in female patients. Hypopigmentation was rare and mild at baseline and did not increase over the course of the study. A pilot study with a cream formulation of tazarotene in patients with acne from darker racial groups showed the retinoid to be effective in treating PIH following 18 weeks of once-daily application.¹⁷ Further longer-term studies on treating PIH with tretinoin lotion 0.05% are warranted given its tolerability profile.

CONCLUSION

This novel tretinoin lotion 0.05% formulation is a safe and well-tolerated topical treatment for moderate to severe comedonal and inflammatory acne in black patients. Tretinoin lotion 0.05% does not appear to induce PIH and may afford an effective, well-tolerated, dual-treatment option.



Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for medical writing support. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

Acne vulgaris (acne) is the most common dermatologic condition in black patients.^1,2 However, among outpatient visits, racial disparities exist in both the likelihood of seeing a dermatologist and being treated.³ Black patients are less likely to visit a dermatologist or receive any acne medication. Acne in black skin is frequently associated with postinflammatory hyperpigmentation (PIH), an important consideration in treatment choice and maintenance.

There is a paucity of clinical studies that specifically evaluate acne treatment in this patient population. An 8-week, vehicle-controlled study with tretinoin cream 0.025% in 27 black patients with acne reported notable decreases in papules, pustules, and hyperpigmented macules in 83% of patients treated with tretinoin compared to only 13% receiving vehicle.⁴ However, irritation and inflammation were problematic. An open-label study of adapalene gel 0.1% in 65 black South Africans also demonstrated significant improvement in inflammatory and noninflammatory lesions and PIH (P<.01), with seemingly better tolerability.^5,6 A meta-analysis of 5 randomized studies from the United States and Europe (N=655) compared the efficacy and safety of adapalene gel 0.1% in black (n=46) and white patients.⁷ There was no significant difference in percentage reduction in comedonal (44%) or total (42%) lesion counts. The percentage reduction in inflammatory lesion counts (53%) was significantly greater in black patients (P=.012). Tolerability also was better; black patients experienced significantly less erythema and scaling (P<.001 and P=.026, respectively), though erythema can be underestimated in darker skin tones because of the masking effects of melanin.^5,7 Dryness was more common, though a smaller percentage of black patients reported moderate or severe dryness compared to white patients (7% vs 18%).⁷

Black patients also are less likely to receive combination therapy, and again clinical data are limited.³ A more recent subgroup analysis evaluated the safety and efficacy of adapalene 0.1%–benzoyl peroxide 2.5% gel in black patients with moderate acne from 3 studies (n=238 out of a total of 3855 patients).⁸ Similar results were obtained as in the overall study populations, with 64.3% and 48.5% reductions in inflammatory and noninflammatory lesion counts, respectively, at week 12. The most common treatment-related adverse event (AE) in both treatment groups was dry skin (11.3%).⁸

Extensive clinical data in a predominantly white population have shown that topical retinoids (eg, tretinoin, adapalene, tazarotene) are highly effective in treating acne, and they are recommended as the cornerstone of topical therapy.⁹ However, there is a common perception that they are primarily effective in comedonal acne¹⁰ and that their use is associated with notable cutaneous irritation.^11,12 Several attempts have been made to alleviate the tolerability issue using novel delivery systems. A new lotion formulation of tretinoin recently was developed and leveraged polymeric emulsion technology with the aim to improve both efficacy and tolerability of tretinoin. Herein, we performed a post hoc analysis of 2 large phase 3 clinical studies¹³ in patients with moderate or severe acne treated with tretinoin lotion 0.05% to evaluate its safety and tolerability in a black population.

METHODS

Study Design

We conducted a post hoc analysis of 2 identical multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical studies¹³ in black patients with moderate or severe acne. Protocols received approval from the appropriate institutional review board for each center before patient enrollment, and the studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice as well as in compliance with local regulatory requirements. All patients were informed of the study details and provided written consent before entering the studies.

Patients were enrolled with an evaluator global severity score (EGSS) of 3 (moderate) or 4 (severe). Participants were randomized (1:1) to receive tretinoin lotion 0.05% or vehicle applied to the face once daily for 12 weeks.

Study Population

Eligible patients for the post hoc analysis included male and female patients with black skin who were 9 years and older and presented with 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 noninflammatory lesions (open and closed comedones), and 2 or fewer nodules. A washout period of up to 1 month was required for patients who previously used prescription and over-the-counter acne treatments, and a washout period of 6 months was required for systemic retinoids.

Safety Evaluation

Cutaneous safety (erythema and scaling) and tolerability (itching, burning, and stinging) were evaluated on a 4-point scale (0=none; 3=severe). Severity of hypopigmentation and hyperpigmentation also was assessed using this 4-point scale. The investigator assessed erythema and scaling at the time of each study visit. Reports of itching, burning, and stinging were solicited from participants and recorded as an average score of their symptoms during the period since the prior visit.

Adverse events were evaluated throughout and summarized by treatment group, severity, and relationship to study medication.

Statistical Analysis

The safety analysis set comprised all randomized patients who were presumed to have used the study drug at least once and who provided at least 1 postbaseline evaluation. All AEs occurring during the studies were recorded and coded using the Medical Dictionary for Regulatory Activities version 18.0. Treatment group comparisons were made by tabulating the frequency of participants reporting 1 or more AEs during the study.

Cutaneous safety (scaling, erythema, hypopigmentation, and hyperpigmentation) and tolerability (itching, burning, and stinging) scores were presented by treatment group with descriptive statistics at baseline and weeks 4, 8, and 12. Frequencies and percentages for each outcome category were included in the statistics.

RESULTS

Baseline Characteristics

A total of 308 patients were included in the post hoc analysis. Overall, 257 (83.4%) patients completed the studies, including 138 (83.6%) patients receiving tretinoin lotion 0.05% and 119 (83.2%) receiving vehicle (Figure 1). Completion rates were similar in the female and male subgroups (83.3% and 83.8%, respectively). The most common reasons for study discontinuations were lost to follow-up (n=32; 10.4%) or participant request (n=13; 4.2%) and were similar irrespective of treatment or sex. There were no study discontinuations due to AEs.

Demographic data (Table) were similar across the 2 treatment arms. The mean age (standard deviation [SD]) of the participants was 22.1 (8.35) years (range, 9–58 years). Participants were predominantly female (209/308 [67.9%]) and tended to be a little older than the males (mean age, 23.6 vs 18.8 years).

At baseline, the mean score (SD) for scaling, erythema, itching, burning, and stinging in those participants that were subsequently treated with tretinoin lotion 0.05% was 0.2 (0.42), 0.4 (0.68), 0.3 (0.60), 0.1 (0.28), and 0.1 (0.32), respectively (where 1=mild)(Figure 2). There were no differences in mean baseline scores between active and vehicle treatment groups for hyperpigmentation (0.8 each) and hypopigmentation (0.1 each) in the active and vehicle treatment groups. Mean baseline scores were slightly higher in the female participants (0.9) compared to male participants (0.6). Baseline moderate or severe hyperpigmentation was reported in 23.2% and 3.2% of participants, respectively, who were subsequently treated with tretinoin lotion 0.05%, which also was more commonly reported in female participants (33/105 [31.5%]) than male participants (8/50 [16.0%]).

Safety

Treatment-Related AEs
More participants treated with tretinoin lotion 0.05% reported treatment-emergent AEs (TEAEs) compared to vehicle (35 vs 18). The majority of participants reporting TEAEs were female (24 of 35). There were 2 (1.3%) serious AEs with tretinoin lotion 0.05% (both female), and 1 female participant (0.6%) discontinued the study drug because of a TEAE (eTable).

Overall, there were 12 (7.7%) treatment-related AEs; all were mild (n=10) or moderate (n=2). Treatment-related AEs reported by more than 1% of participants treated with tretinoin lotion 0.05% included application-site pain (n=4; 2.6%), dryness (n=4; 2.6%), irritation (n=2; 1.3%), exfoliation (n=2; 1.3%), or erythema (n=2; 1.3%). The majority of treatment-related AEs (10/12) were reported in the female subgroup. Although application-site pain (3.4%) and dryness (3.8%) were more commonly reported in the white population (unpublished data, Ortho Dermatologics) in the 2 studies, differences between the 2 racial groups were not significant.

Cutaneous Safety and Tolerability
Erythema and scaling were recorded by the investigator. Mild to moderate erythema was noted in 31% of participants at baseline, with 21% reporting mild to moderate scaling. Both improved over the study period following treatment with tretinoin lotion 0.05%, with 79% of participants having no erythema and 88% having no scaling by week 12. Mean scores for erythema and scaling remained less than 0.5 throughout the study (1=mild). There were slight transient increases in the mean baseline score for scaling (from 0.2 to 0.3) at week 4 in the active treatment group. By week 12, mean scores were half those reported at baseline (Figure 2).

Severity of itching, burning, and stinging was reported by participants. Overall, 23% reported mild to moderate itching at baseline. Only 7 participants (5%) reported any itching by week 12 in the tretinoin lotion 0.05% group. Reports of burning and stinging were both rare and mild at baseline. Mean scores for itching, burning, and stinging at baseline for those participants who were subsequently treated with tretinoin lotion 0.05% were 0.3, 0.1, and 0.1, respectively (1=mild). Itching severity reduced progressively with treatment. There were slight transient increases in mean scores for burning (from 0.1 to 0.2) and stinging (from 0.1 to 0.2) at week 4, returning to baseline levels or below by week 12.

Hyperpigmentation and Hypopigmentation
There was a progressive improvement in baseline hyperpigmentation severity in participants treated with tretinoin lotion 0.05%; mean scores reduced from 0.8 at baseline to 0.6 by week 12 (Figure 3), with a similar improvement in both sexes (Figure 4). Moderate to severe hyperpigmentation was reported in 24 (17.3%) participants by week 12 compared to 41 (26.4%) at baseline; the majority (n=21) were female at week 12. Moderate to severe hyperpigmentation was reported in 24 (19.7%) participants treated with vehicle at week 12.

COMMENT

Topical retinoids (eg, tretinoin, adapalene, tazarotene) are recommended as the cornerstone of topical acne treatment, with safety and efficacy well documented in large pivotal trials.¹⁴ However, data in black patients are lacking. Acne is the most common dermatologic condition in these patients, and yet investigation into this important population is limited to small study populations or subgroup analyses.

Tretinoin lotion 0.05% is a novel topical treatment for moderate to severe acne that leverages polymeric emulsion technology. The development rationale was to provide a tretinoin formulation with improved efficacy and tolerability, features that could be especially suited to black patients with acne.

In our post hoc analysis of black patients with acne, tretinoin lotion 0.05% generally was considered safe and well tolerated. The most commonly reported treatment-related AEs were of low incidence and included application-site reactions and skin-related events attributed to the known properties of tretinoin. Most noteworthy was the extremely low irritation potential of this novel tretinoin formulation. Treatment-related AEs generally were mild, and interestingly, the majority occurred in female patients. The incidence of the most common treatment-related AEs—application-site dryness (2.6%) and application-site pain (2.6%)—was lower than that reported in the white populations in the 2 studies (3.8% and 3.4%, respectively).(unpublished data, Ortho Dermatologics), though the differences were not significant (P=.625 and P=.799).

Approximately one-quarter of participants had mild to moderate erythema, scaling, itching, and stinging at baseline. All of these cutaneous symptoms improved with treatment. There were slight transient increases in scaling and stinging at week 4, with stinging more noticeable in the female population. There were no noticeable changes in mild to moderate burning during the study.

Postinflammatory hyperpigmentation is an important consideration in black patients with acne. It can arise from either acne-induced inflammation or injury. It can be of greater concern to the patient than the acne itself and often is the main reason black patients seek a dermatologist consultation. In a survey of adult female acne, nonwhite women experienced substantially more PIH than white women. In addition, clearance of PIH was most important for these nonwhite women (42% vs 8% for white women), whereas lesion clearance was the most important aspect for white women (58% vs 32% for nonwhite women).¹⁵ Erring on the side of increased tolerability is appropriate in black patients with acne, given that any irritant reactions can lead to pigmentary alterations—hyperpigmentation or hypopigmentation—that can cause considerable patient anxiety. The psychologic impact of PIH can be devastating, and an ideal acne treatment in these patients would be one that is effective against both PIH and acne. Tretinoin cream 0.1% monotherapy has been shown to be effective in reducing PIH.¹⁶ Postinflammatory hyperpigmentation lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens. Although facial PIH lesions in the 24 tretinoin-treated patients were significantly lighter after 40 weeks of treatment compared to vehicle in this study (P<.001), overall improvement was first noted after 4 weeks (P=.009). Normal skin also was minimally lightened by tretinoin; however, exuberant local skin reactions, including peeling, developed in 50% of patients. Mild to moderate PIH was present in the majority of tretinoin-treated patients at baseline in our post hoc analysis, severe in 3.2% of cases, and both more common and severe in females. Mean scores reduced over the 12-week study period, from 0.6 to 0.4 in male patients and 0.9 to 0.7 in female patients. Hypopigmentation was rare and mild at baseline and did not increase over the course of the study. A pilot study with a cream formulation of tazarotene in patients with acne from darker racial groups showed the retinoid to be effective in treating PIH following 18 weeks of once-daily application.¹⁷ Further longer-term studies on treating PIH with tretinoin lotion 0.05% are warranted given its tolerability profile.

CONCLUSION

This novel tretinoin lotion 0.05% formulation is a safe and well-tolerated topical treatment for moderate to severe comedonal and inflammatory acne in black patients. Tretinoin lotion 0.05% does not appear to induce PIH and may afford an effective, well-tolerated, dual-treatment option.



Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for medical writing support. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

Acne vulgaris (acne) is the most common dermatologic condition in black patients.^1,2 However, among outpatient visits, racial disparities exist in both the likelihood of seeing a dermatologist and being treated.³ Black patients are less likely to visit a dermatologist or receive any acne medication. Acne in black skin is frequently associated with postinflammatory hyperpigmentation (PIH), an important consideration in treatment choice and maintenance.

There is a paucity of clinical studies that specifically evaluate acne treatment in this patient population. An 8-week, vehicle-controlled study with tretinoin cream 0.025% in 27 black patients with acne reported notable decreases in papules, pustules, and hyperpigmented macules in 83% of patients treated with tretinoin compared to only 13% receiving vehicle.⁴ However, irritation and inflammation were problematic. An open-label study of adapalene gel 0.1% in 65 black South Africans also demonstrated significant improvement in inflammatory and noninflammatory lesions and PIH (P<.01), with seemingly better tolerability.^5,6 A meta-analysis of 5 randomized studies from the United States and Europe (N=655) compared the efficacy and safety of adapalene gel 0.1% in black (n=46) and white patients.⁷ There was no significant difference in percentage reduction in comedonal (44%) or total (42%) lesion counts. The percentage reduction in inflammatory lesion counts (53%) was significantly greater in black patients (P=.012). Tolerability also was better; black patients experienced significantly less erythema and scaling (P<.001 and P=.026, respectively), though erythema can be underestimated in darker skin tones because of the masking effects of melanin.^5,7 Dryness was more common, though a smaller percentage of black patients reported moderate or severe dryness compared to white patients (7% vs 18%).⁷

Black patients also are less likely to receive combination therapy, and again clinical data are limited.³ A more recent subgroup analysis evaluated the safety and efficacy of adapalene 0.1%–benzoyl peroxide 2.5% gel in black patients with moderate acne from 3 studies (n=238 out of a total of 3855 patients).⁸ Similar results were obtained as in the overall study populations, with 64.3% and 48.5% reductions in inflammatory and noninflammatory lesion counts, respectively, at week 12. The most common treatment-related adverse event (AE) in both treatment groups was dry skin (11.3%).⁸

Extensive clinical data in a predominantly white population have shown that topical retinoids (eg, tretinoin, adapalene, tazarotene) are highly effective in treating acne, and they are recommended as the cornerstone of topical therapy.⁹ However, there is a common perception that they are primarily effective in comedonal acne¹⁰ and that their use is associated with notable cutaneous irritation.^11,12 Several attempts have been made to alleviate the tolerability issue using novel delivery systems. A new lotion formulation of tretinoin recently was developed and leveraged polymeric emulsion technology with the aim to improve both efficacy and tolerability of tretinoin. Herein, we performed a post hoc analysis of 2 large phase 3 clinical studies¹³ in patients with moderate or severe acne treated with tretinoin lotion 0.05% to evaluate its safety and tolerability in a black population.

METHODS

Study Design

We conducted a post hoc analysis of 2 identical multicenter, randomized, double-blind, vehicle-controlled, parallel-group clinical studies¹³ in black patients with moderate or severe acne. Protocols received approval from the appropriate institutional review board for each center before patient enrollment, and the studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice as well as in compliance with local regulatory requirements. All patients were informed of the study details and provided written consent before entering the studies.

Patients were enrolled with an evaluator global severity score (EGSS) of 3 (moderate) or 4 (severe). Participants were randomized (1:1) to receive tretinoin lotion 0.05% or vehicle applied to the face once daily for 12 weeks.

Study Population

Eligible patients for the post hoc analysis included male and female patients with black skin who were 9 years and older and presented with 20 to 40 inflammatory lesions (papules, pustules, and nodules), 20 to 100 noninflammatory lesions (open and closed comedones), and 2 or fewer nodules. A washout period of up to 1 month was required for patients who previously used prescription and over-the-counter acne treatments, and a washout period of 6 months was required for systemic retinoids.

Safety Evaluation

Cutaneous safety (erythema and scaling) and tolerability (itching, burning, and stinging) were evaluated on a 4-point scale (0=none; 3=severe). Severity of hypopigmentation and hyperpigmentation also was assessed using this 4-point scale. The investigator assessed erythema and scaling at the time of each study visit. Reports of itching, burning, and stinging were solicited from participants and recorded as an average score of their symptoms during the period since the prior visit.

Adverse events were evaluated throughout and summarized by treatment group, severity, and relationship to study medication.

Statistical Analysis

The safety analysis set comprised all randomized patients who were presumed to have used the study drug at least once and who provided at least 1 postbaseline evaluation. All AEs occurring during the studies were recorded and coded using the Medical Dictionary for Regulatory Activities version 18.0. Treatment group comparisons were made by tabulating the frequency of participants reporting 1 or more AEs during the study.

Cutaneous safety (scaling, erythema, hypopigmentation, and hyperpigmentation) and tolerability (itching, burning, and stinging) scores were presented by treatment group with descriptive statistics at baseline and weeks 4, 8, and 12. Frequencies and percentages for each outcome category were included in the statistics.

RESULTS

Baseline Characteristics

A total of 308 patients were included in the post hoc analysis. Overall, 257 (83.4%) patients completed the studies, including 138 (83.6%) patients receiving tretinoin lotion 0.05% and 119 (83.2%) receiving vehicle (Figure 1). Completion rates were similar in the female and male subgroups (83.3% and 83.8%, respectively). The most common reasons for study discontinuations were lost to follow-up (n=32; 10.4%) or participant request (n=13; 4.2%) and were similar irrespective of treatment or sex. There were no study discontinuations due to AEs.

Demographic data (Table) were similar across the 2 treatment arms. The mean age (standard deviation [SD]) of the participants was 22.1 (8.35) years (range, 9–58 years). Participants were predominantly female (209/308 [67.9%]) and tended to be a little older than the males (mean age, 23.6 vs 18.8 years).

At baseline, the mean score (SD) for scaling, erythema, itching, burning, and stinging in those participants that were subsequently treated with tretinoin lotion 0.05% was 0.2 (0.42), 0.4 (0.68), 0.3 (0.60), 0.1 (0.28), and 0.1 (0.32), respectively (where 1=mild)(Figure 2). There were no differences in mean baseline scores between active and vehicle treatment groups for hyperpigmentation (0.8 each) and hypopigmentation (0.1 each) in the active and vehicle treatment groups. Mean baseline scores were slightly higher in the female participants (0.9) compared to male participants (0.6). Baseline moderate or severe hyperpigmentation was reported in 23.2% and 3.2% of participants, respectively, who were subsequently treated with tretinoin lotion 0.05%, which also was more commonly reported in female participants (33/105 [31.5%]) than male participants (8/50 [16.0%]).

Safety

Treatment-Related AEs
More participants treated with tretinoin lotion 0.05% reported treatment-emergent AEs (TEAEs) compared to vehicle (35 vs 18). The majority of participants reporting TEAEs were female (24 of 35). There were 2 (1.3%) serious AEs with tretinoin lotion 0.05% (both female), and 1 female participant (0.6%) discontinued the study drug because of a TEAE (eTable).

Overall, there were 12 (7.7%) treatment-related AEs; all were mild (n=10) or moderate (n=2). Treatment-related AEs reported by more than 1% of participants treated with tretinoin lotion 0.05% included application-site pain (n=4; 2.6%), dryness (n=4; 2.6%), irritation (n=2; 1.3%), exfoliation (n=2; 1.3%), or erythema (n=2; 1.3%). The majority of treatment-related AEs (10/12) were reported in the female subgroup. Although application-site pain (3.4%) and dryness (3.8%) were more commonly reported in the white population (unpublished data, Ortho Dermatologics) in the 2 studies, differences between the 2 racial groups were not significant.

Cutaneous Safety and Tolerability
Erythema and scaling were recorded by the investigator. Mild to moderate erythema was noted in 31% of participants at baseline, with 21% reporting mild to moderate scaling. Both improved over the study period following treatment with tretinoin lotion 0.05%, with 79% of participants having no erythema and 88% having no scaling by week 12. Mean scores for erythema and scaling remained less than 0.5 throughout the study (1=mild). There were slight transient increases in the mean baseline score for scaling (from 0.2 to 0.3) at week 4 in the active treatment group. By week 12, mean scores were half those reported at baseline (Figure 2).

Severity of itching, burning, and stinging was reported by participants. Overall, 23% reported mild to moderate itching at baseline. Only 7 participants (5%) reported any itching by week 12 in the tretinoin lotion 0.05% group. Reports of burning and stinging were both rare and mild at baseline. Mean scores for itching, burning, and stinging at baseline for those participants who were subsequently treated with tretinoin lotion 0.05% were 0.3, 0.1, and 0.1, respectively (1=mild). Itching severity reduced progressively with treatment. There were slight transient increases in mean scores for burning (from 0.1 to 0.2) and stinging (from 0.1 to 0.2) at week 4, returning to baseline levels or below by week 12.

Hyperpigmentation and Hypopigmentation
There was a progressive improvement in baseline hyperpigmentation severity in participants treated with tretinoin lotion 0.05%; mean scores reduced from 0.8 at baseline to 0.6 by week 12 (Figure 3), with a similar improvement in both sexes (Figure 4). Moderate to severe hyperpigmentation was reported in 24 (17.3%) participants by week 12 compared to 41 (26.4%) at baseline; the majority (n=21) were female at week 12. Moderate to severe hyperpigmentation was reported in 24 (19.7%) participants treated with vehicle at week 12.

COMMENT

Topical retinoids (eg, tretinoin, adapalene, tazarotene) are recommended as the cornerstone of topical acne treatment, with safety and efficacy well documented in large pivotal trials.¹⁴ However, data in black patients are lacking. Acne is the most common dermatologic condition in these patients, and yet investigation into this important population is limited to small study populations or subgroup analyses.

Tretinoin lotion 0.05% is a novel topical treatment for moderate to severe acne that leverages polymeric emulsion technology. The development rationale was to provide a tretinoin formulation with improved efficacy and tolerability, features that could be especially suited to black patients with acne.

In our post hoc analysis of black patients with acne, tretinoin lotion 0.05% generally was considered safe and well tolerated. The most commonly reported treatment-related AEs were of low incidence and included application-site reactions and skin-related events attributed to the known properties of tretinoin. Most noteworthy was the extremely low irritation potential of this novel tretinoin formulation. Treatment-related AEs generally were mild, and interestingly, the majority occurred in female patients. The incidence of the most common treatment-related AEs—application-site dryness (2.6%) and application-site pain (2.6%)—was lower than that reported in the white populations in the 2 studies (3.8% and 3.4%, respectively).(unpublished data, Ortho Dermatologics), though the differences were not significant (P=.625 and P=.799).

Approximately one-quarter of participants had mild to moderate erythema, scaling, itching, and stinging at baseline. All of these cutaneous symptoms improved with treatment. There were slight transient increases in scaling and stinging at week 4, with stinging more noticeable in the female population. There were no noticeable changes in mild to moderate burning during the study.

Postinflammatory hyperpigmentation is an important consideration in black patients with acne. It can arise from either acne-induced inflammation or injury. It can be of greater concern to the patient than the acne itself and often is the main reason black patients seek a dermatologist consultation. In a survey of adult female acne, nonwhite women experienced substantially more PIH than white women. In addition, clearance of PIH was most important for these nonwhite women (42% vs 8% for white women), whereas lesion clearance was the most important aspect for white women (58% vs 32% for nonwhite women).¹⁵ Erring on the side of increased tolerability is appropriate in black patients with acne, given that any irritant reactions can lead to pigmentary alterations—hyperpigmentation or hypopigmentation—that can cause considerable patient anxiety. The psychologic impact of PIH can be devastating, and an ideal acne treatment in these patients would be one that is effective against both PIH and acne. Tretinoin cream 0.1% monotherapy has been shown to be effective in reducing PIH.¹⁶ Postinflammatory hyperpigmentation lesions and normal skin were assessed by clinical and colorimetric evaluations and by analysis of biopsy specimens. Although facial PIH lesions in the 24 tretinoin-treated patients were significantly lighter after 40 weeks of treatment compared to vehicle in this study (P<.001), overall improvement was first noted after 4 weeks (P=.009). Normal skin also was minimally lightened by tretinoin; however, exuberant local skin reactions, including peeling, developed in 50% of patients. Mild to moderate PIH was present in the majority of tretinoin-treated patients at baseline in our post hoc analysis, severe in 3.2% of cases, and both more common and severe in females. Mean scores reduced over the 12-week study period, from 0.6 to 0.4 in male patients and 0.9 to 0.7 in female patients. Hypopigmentation was rare and mild at baseline and did not increase over the course of the study. A pilot study with a cream formulation of tazarotene in patients with acne from darker racial groups showed the retinoid to be effective in treating PIH following 18 weeks of once-daily application.¹⁷ Further longer-term studies on treating PIH with tretinoin lotion 0.05% are warranted given its tolerability profile.

CONCLUSION

This novel tretinoin lotion 0.05% formulation is a safe and well-tolerated topical treatment for moderate to severe comedonal and inflammatory acne in black patients. Tretinoin lotion 0.05% does not appear to induce PIH and may afford an effective, well-tolerated, dual-treatment option.



Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for medical writing support. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

The Pediatric Hospital Medicine Core Competencies were first published in 2010 to help define a specific body of knowledge and measurable skills needed to practice high quality care for hospitalized pediatric patients across all practice settings.¹ Since then, the number of practicing pediatric hospitalists has grown to a conservative estimate of 3,000 physicians and the scope of practice among pediatric hospitalists has matured.² Pediatric hospitalists are increasingly leading or participating in organizational and national efforts that emphasize interprofessional collaboration and the delivery of high value care to hospitalized children and their caregivers—including innovative and family-centered care models, patient safety and quality improvement initiatives, and research and educational enterprises.^3-8 In response to these changes, the American Board of Medical Specialties designated Pediatric Hospital Medicine (PHM) as a pediatric subspecialty in 2016.

The field of PHM in the United States continues to be supported by three core societies—Society of Hospital Medicine (SHM), American Academy of Pediatrics (AAP), and Academic Pediatric Association (APA). Together, these societies serve as tri-sponsors of the annual Pediatric Hospital Medicine national conference, which now welcomes over 1,200 attendees from the United States and abroad.⁹ Each society also individually sponsors a variety of professional development and continuing medical education activities specific to PHM.

In addition, pediatric hospitalists often serve a pivotal role in teaching learners (medical students, residents, and other health profession students), physician colleagues, and other healthcare professionals on the hospital wards and via institutional educational programs. Nearly 50 institutions in the United States offer graduate medical education training in PHM.¹⁰ The PHM Fellowship Directors Council has developed a standardized curricular framework and entrustable professional activities, which reflect the tenets of competency-based medical education, for use in PHM training programs.^11-13

These changes in the practice environment of pediatric hospitalists, as well as the changing landscape of graduate and continuing medical education in PHM, have informed this revision of The PHM Core Competencies. The purpose of this article is to describe the methodology of the review and revision process.

Revision

The PHM Core Competencies: 2020 Revision provide a framework for graduate and continuing medical education that reflects the current roles and expectations for all pediatric hospitalists in the United States. The acuity and complexity of hospitalized children, the availability of pediatric subspecialty care and other resources, and the institutional orientation towards pediatric populations vary across community, tertiary, and children’s hospital settings. In order to unify the practice of PHM across these environments, The PHM Core Competencies: 2020 Revision address the fundamental and most common components of PHM which are encountered by the majority of practicing pediatric hospitalists, as opposed to an extensive review of all aspects of the field.

The compendium includes 66 chapters on both clinical and nonclinical topics, divided into four sections—Common Clinical Diagnoses and Conditions, Core Skills, Specialized Services, and Healthcare Systems: Supporting and Advancing Child Health (Table 1). Within each chapter is an introductory paragraph and learning objectives in three domains of educational outcomes—cognitive (knowledge), psychomotor (skills), and affective (attitudes)—as well as systems organization and improvement, to reflect the emphasis of PHM practice on improving healthcare systems. The objectives encompass a range of observable behaviors and other attributes, from foundational skills such as taking a history and performing a physical exam to more advanced actions such as participating in the development of care models to support the health of complex patient populations. Implicit in these objectives is the expectation that pediatric hospitalists build on experiences in medical school and residency training to attain a level of competency at the advanced levels of a developmental continuum, such as proficient, expert, or master.¹⁴

The objectives also balance specificity to the topic with a timeless quality, allowing for flexibility both as new information emerges and when applied to various educational activities and learner groups. Each chapter can stand alone, and thus themes recur if one reads the compendium in its entirety. However, in order to reflect related content among the chapters, the appendix contains a list of associated chapters (Chapter Links) for further exploration. In addition, a short reference list is provided in each chapter to reflect the literature and best practices at the time of publication.

Finally, The PHM Core Competencies: 2020 Revision reflect the status of children as a vulnerable population. Care for hospitalized children requires attention to many elements unique to the pediatric population. These include age-based differences in development, behavior, physiology, and prevalence of clinical conditions, the impact of acute and chronic disease states on child development, the use of medications and other medical interventions with limited investigative guidance, and the role of caregivers in decision-making and care delivery. Heightened awareness of these factors is required in the hospital setting, where diagnoses and interventions often include the use of high-risk modalities and require coordination of care across multiple providers.

Project Initiation

Revision of The PHM Core Competencies: 2020 Revision began in early 2017 following SHM’s work on The Core Competencies in Hospital Medicine 2017 Revision.¹⁵ The Executive Committee of the SHM Pediatrics Special Interest Group (SIG) supported the initiation of the revision. The 3 editors from the original compendium created an initial plan for the project that included a proposed timeline, processes for engagement of previously involved experts and new talent, and performance of a needs assessment to guide content selection. The Figure highlights these and other important steps in the revision process.

Editor and Associate Editor Selection

The above editors reviewed best practice examples of roles and responsibilities for editor and associate editor positions from relevant, leading societies and journals. From this review, the editors created an editorial structure specifically for The PHM Core Competencies: 2020 Revision. A new position of Contributing Editor was created to address the need for dedicated attention to the community site perspective and ensure review of all content, within and across chapters, by a pediatric hospitalist who is dedicated to this environment. Solicitation for additional editors and associate editors occurred via the SHM Pediatrics SIG to the wider SHM membership. The criteria for selection included active engagement in regional or national activities related to the growth and operations of PHM, strong organizational and leadership skills, including the ability to manage tasks and foster creativity, among others. In addition, a deliberate effort was made to recruit a diverse editorial cohort, considering geographic location, primary work environment, organizational affiliations, content expertise, time in practice, gender, and other factors.

Chapter Topic Selection

The editors conducted a two-pronged needs assessment related to optimal content for inclusion in The PHM Core Competencies: 2020 Revision. First, the editors reviewed content from conferences, textbooks, and handbooks specific to the field of PHM, including the conference programs for the most recent 5 years of both the annual PHM national conference and annual meetings of PHM’s 3 core societies in the United States—SHM, AAP, and APA. Second, the editors conducted a needs assessment survey with several stakeholder groups, including SHM’s Pediatrics and Medicine-Pediatrics SIGs, AAP Section on Hospital Medicine and its subcommittees, APA Hospital Medicine SIG, PHM Fellowship Directors Council, and PHM Division Directors, with encouragement to pass the survey link to others in the PHM community interested in providing input (Appendix Figure). The solicitation asked for comment on existing chapters and suggestions for new chapters. For any new chapter, respondents were asked to note the intended purpose of the chapter and the anticipated value that chapter would bring to our profession and the children and the caregivers served by pediatric hospitalists.

The entire editorial board then reviewed all of the needs assessment data and considered potential changes (additions or deletions) based on emerging trends in pediatric healthcare, the frequency, relevance, and value of the item across all environments in which pediatric hospitalists function, and the value to or impact on hospitalized children and caregivers. Almost all survey ratings and comments were either incorporated into an existing chapter or used to create a new chapter. There was a paucity of comments related to the deletion of chapters, and thus no chapters were entirely excluded. However, there were several comments supporting the exclusion of the suprapubic bladder tap procedure, and thus related content was eliminated from the relevant section in Core Skills. Of the 66 chapters in this revision, the needs assessment data directly informed the creation of 12 new chapters, as well as adjustments and/or additions to the titles of 7 chapters and the content of 29 chapters. In addition, the title of the Specialized Clinical Services section was changed to Specialized Services to represent that both clinical and nonclinical competencies reside in this section devoted to comprehensive management of these unique patient populations commonly encountered by pediatric hospitalists. Many of these changes are highlighted in Table 2.

Author selection

Authors from the initial work were invited to participate again as author of their given chapter. Subsequently, authors were identified for new chapters and chapters for which previous authors were no longer able to be engaged. Authors with content expertise were found by reviewing content from conferences, textbooks, and handbooks specific to the field of PHM. Any content expert who was not identified as a pediatric hospitalist was paired with a pediatric hospitalist as coauthor. In addition, as with the editorial board, a deliberate effort was made to recruit a diverse author cohort, considering geographic location, primary work environment, time in practice, gender, and other factors.

The editorial board held numerous conference calls to review potential authors, and the SHM Pediatrics SIG was directly engaged to ensure authorship opportunities were extended broadly. This vetting process resulted in a robust author list and included members of all three of PHM’s sponsoring societies in the United States. Once participation was confirmed, authors received an “author packet” detailing the process with the proposed timeline, resources related to writing learning objectives, the past chapter (if applicable), assigned associate editor, and other helpful resources.

Internal and External Review Process

After all chapters were drafted, the editorial board conducted a rigorous, internal review process. Each chapter was reviewed by at least one associate editor and two editors, with a focus on content, scope, and a standard approach to phrasing and formatting. In addition, the contributing editor reviewed all the chapters to ensure the community hospitalist perspective was adequately represented.

Thirty-two agencies and societies were solicited for external review, including both those involved in review of the previous edition and new stakeholder groups. External reviewers were first contacted to ascertain their interest in participating in the review process, and if interested, were provided with information on the review process. Robust feedback was received from the APA Hospital Medicine SIG, SHM Pediatrics and Medicine-Pediatrics SIGs, Association of Pediatric Program Directors Curriculum Committee, and 20 AAP committees, councils, and sections.

The feedback from the external reviewers and subsequent edits for each chapter were reviewed by at least one associate editor, two editors, and the contributing editor. Authors were engaged to address any salient changes recommended. As the final steps in the review process, the SHM Board of Directors approved the compendium and the APA provided their endorsement.

This second edition of The PHM Core Competencies: 2020 Revision addresses the knowledge, skills, attitudes, and systems organization and improvement objectives that define the field of pediatric hospital medicine and the leadership roles of pediatric hospitalists. This compendium reflects the recent changes in the practice and educational environments of pediatric hospitalists and can inform education, training, and career development for pediatric hospitalists across all environments in which comprehensive care is rendered for the hospitalized child. Future work at the local and national level can lead to development of associated curricula, conference content, and other training materials.

Acknowledgments

We wish to humbly and respectfully acknowledge the work of the authors, editors, and reviewers involved in the creation of the first edition, as well as this revision, of The PHM Core Competencies. In addition, we are grateful for the input of all pediatric hospitalists and other stakeholders who informed this compendium via contributions to the needs assessment survey, conference proceedings, publications, and other works. Finally, we acknowledge the support and work of SHM project coordinator, Nyla Nicholson, the SHM Pediatrics SIG, and the SHM Board of Directors.

Disclosures

SHM provided administrative support for project coordination (N. Nicholson). No author, editor, or other involved member received any compensation for efforts related to this work. There are no reported conflicts of interest.

The Pediatric Hospital Medicine Core Competencies were first published in 2010 to help define a specific body of knowledge and measurable skills needed to practice high quality care for hospitalized pediatric patients across all practice settings.¹ Since then, the number of practicing pediatric hospitalists has grown to a conservative estimate of 3,000 physicians and the scope of practice among pediatric hospitalists has matured.² Pediatric hospitalists are increasingly leading or participating in organizational and national efforts that emphasize interprofessional collaboration and the delivery of high value care to hospitalized children and their caregivers—including innovative and family-centered care models, patient safety and quality improvement initiatives, and research and educational enterprises.^3-8 In response to these changes, the American Board of Medical Specialties designated Pediatric Hospital Medicine (PHM) as a pediatric subspecialty in 2016.

The field of PHM in the United States continues to be supported by three core societies—Society of Hospital Medicine (SHM), American Academy of Pediatrics (AAP), and Academic Pediatric Association (APA). Together, these societies serve as tri-sponsors of the annual Pediatric Hospital Medicine national conference, which now welcomes over 1,200 attendees from the United States and abroad.⁹ Each society also individually sponsors a variety of professional development and continuing medical education activities specific to PHM.

In addition, pediatric hospitalists often serve a pivotal role in teaching learners (medical students, residents, and other health profession students), physician colleagues, and other healthcare professionals on the hospital wards and via institutional educational programs. Nearly 50 institutions in the United States offer graduate medical education training in PHM.¹⁰ The PHM Fellowship Directors Council has developed a standardized curricular framework and entrustable professional activities, which reflect the tenets of competency-based medical education, for use in PHM training programs.^11-13

These changes in the practice environment of pediatric hospitalists, as well as the changing landscape of graduate and continuing medical education in PHM, have informed this revision of The PHM Core Competencies. The purpose of this article is to describe the methodology of the review and revision process.

Revision

The PHM Core Competencies: 2020 Revision provide a framework for graduate and continuing medical education that reflects the current roles and expectations for all pediatric hospitalists in the United States. The acuity and complexity of hospitalized children, the availability of pediatric subspecialty care and other resources, and the institutional orientation towards pediatric populations vary across community, tertiary, and children’s hospital settings. In order to unify the practice of PHM across these environments, The PHM Core Competencies: 2020 Revision address the fundamental and most common components of PHM which are encountered by the majority of practicing pediatric hospitalists, as opposed to an extensive review of all aspects of the field.

The compendium includes 66 chapters on both clinical and nonclinical topics, divided into four sections—Common Clinical Diagnoses and Conditions, Core Skills, Specialized Services, and Healthcare Systems: Supporting and Advancing Child Health (Table 1). Within each chapter is an introductory paragraph and learning objectives in three domains of educational outcomes—cognitive (knowledge), psychomotor (skills), and affective (attitudes)—as well as systems organization and improvement, to reflect the emphasis of PHM practice on improving healthcare systems. The objectives encompass a range of observable behaviors and other attributes, from foundational skills such as taking a history and performing a physical exam to more advanced actions such as participating in the development of care models to support the health of complex patient populations. Implicit in these objectives is the expectation that pediatric hospitalists build on experiences in medical school and residency training to attain a level of competency at the advanced levels of a developmental continuum, such as proficient, expert, or master.¹⁴

The objectives also balance specificity to the topic with a timeless quality, allowing for flexibility both as new information emerges and when applied to various educational activities and learner groups. Each chapter can stand alone, and thus themes recur if one reads the compendium in its entirety. However, in order to reflect related content among the chapters, the appendix contains a list of associated chapters (Chapter Links) for further exploration. In addition, a short reference list is provided in each chapter to reflect the literature and best practices at the time of publication.

Finally, The PHM Core Competencies: 2020 Revision reflect the status of children as a vulnerable population. Care for hospitalized children requires attention to many elements unique to the pediatric population. These include age-based differences in development, behavior, physiology, and prevalence of clinical conditions, the impact of acute and chronic disease states on child development, the use of medications and other medical interventions with limited investigative guidance, and the role of caregivers in decision-making and care delivery. Heightened awareness of these factors is required in the hospital setting, where diagnoses and interventions often include the use of high-risk modalities and require coordination of care across multiple providers.

Project Initiation

Revision of The PHM Core Competencies: 2020 Revision began in early 2017 following SHM’s work on The Core Competencies in Hospital Medicine 2017 Revision.¹⁵ The Executive Committee of the SHM Pediatrics Special Interest Group (SIG) supported the initiation of the revision. The 3 editors from the original compendium created an initial plan for the project that included a proposed timeline, processes for engagement of previously involved experts and new talent, and performance of a needs assessment to guide content selection. The Figure highlights these and other important steps in the revision process.

Editor and Associate Editor Selection

The above editors reviewed best practice examples of roles and responsibilities for editor and associate editor positions from relevant, leading societies and journals. From this review, the editors created an editorial structure specifically for The PHM Core Competencies: 2020 Revision. A new position of Contributing Editor was created to address the need for dedicated attention to the community site perspective and ensure review of all content, within and across chapters, by a pediatric hospitalist who is dedicated to this environment. Solicitation for additional editors and associate editors occurred via the SHM Pediatrics SIG to the wider SHM membership. The criteria for selection included active engagement in regional or national activities related to the growth and operations of PHM, strong organizational and leadership skills, including the ability to manage tasks and foster creativity, among others. In addition, a deliberate effort was made to recruit a diverse editorial cohort, considering geographic location, primary work environment, organizational affiliations, content expertise, time in practice, gender, and other factors.

Chapter Topic Selection

The editors conducted a two-pronged needs assessment related to optimal content for inclusion in The PHM Core Competencies: 2020 Revision. First, the editors reviewed content from conferences, textbooks, and handbooks specific to the field of PHM, including the conference programs for the most recent 5 years of both the annual PHM national conference and annual meetings of PHM’s 3 core societies in the United States—SHM, AAP, and APA. Second, the editors conducted a needs assessment survey with several stakeholder groups, including SHM’s Pediatrics and Medicine-Pediatrics SIGs, AAP Section on Hospital Medicine and its subcommittees, APA Hospital Medicine SIG, PHM Fellowship Directors Council, and PHM Division Directors, with encouragement to pass the survey link to others in the PHM community interested in providing input (Appendix Figure). The solicitation asked for comment on existing chapters and suggestions for new chapters. For any new chapter, respondents were asked to note the intended purpose of the chapter and the anticipated value that chapter would bring to our profession and the children and the caregivers served by pediatric hospitalists.

The entire editorial board then reviewed all of the needs assessment data and considered potential changes (additions or deletions) based on emerging trends in pediatric healthcare, the frequency, relevance, and value of the item across all environments in which pediatric hospitalists function, and the value to or impact on hospitalized children and caregivers. Almost all survey ratings and comments were either incorporated into an existing chapter or used to create a new chapter. There was a paucity of comments related to the deletion of chapters, and thus no chapters were entirely excluded. However, there were several comments supporting the exclusion of the suprapubic bladder tap procedure, and thus related content was eliminated from the relevant section in Core Skills. Of the 66 chapters in this revision, the needs assessment data directly informed the creation of 12 new chapters, as well as adjustments and/or additions to the titles of 7 chapters and the content of 29 chapters. In addition, the title of the Specialized Clinical Services section was changed to Specialized Services to represent that both clinical and nonclinical competencies reside in this section devoted to comprehensive management of these unique patient populations commonly encountered by pediatric hospitalists. Many of these changes are highlighted in Table 2.

Author selection

Authors from the initial work were invited to participate again as author of their given chapter. Subsequently, authors were identified for new chapters and chapters for which previous authors were no longer able to be engaged. Authors with content expertise were found by reviewing content from conferences, textbooks, and handbooks specific to the field of PHM. Any content expert who was not identified as a pediatric hospitalist was paired with a pediatric hospitalist as coauthor. In addition, as with the editorial board, a deliberate effort was made to recruit a diverse author cohort, considering geographic location, primary work environment, time in practice, gender, and other factors.

The editorial board held numerous conference calls to review potential authors, and the SHM Pediatrics SIG was directly engaged to ensure authorship opportunities were extended broadly. This vetting process resulted in a robust author list and included members of all three of PHM’s sponsoring societies in the United States. Once participation was confirmed, authors received an “author packet” detailing the process with the proposed timeline, resources related to writing learning objectives, the past chapter (if applicable), assigned associate editor, and other helpful resources.

Internal and External Review Process

After all chapters were drafted, the editorial board conducted a rigorous, internal review process. Each chapter was reviewed by at least one associate editor and two editors, with a focus on content, scope, and a standard approach to phrasing and formatting. In addition, the contributing editor reviewed all the chapters to ensure the community hospitalist perspective was adequately represented.

Thirty-two agencies and societies were solicited for external review, including both those involved in review of the previous edition and new stakeholder groups. External reviewers were first contacted to ascertain their interest in participating in the review process, and if interested, were provided with information on the review process. Robust feedback was received from the APA Hospital Medicine SIG, SHM Pediatrics and Medicine-Pediatrics SIGs, Association of Pediatric Program Directors Curriculum Committee, and 20 AAP committees, councils, and sections.

The feedback from the external reviewers and subsequent edits for each chapter were reviewed by at least one associate editor, two editors, and the contributing editor. Authors were engaged to address any salient changes recommended. As the final steps in the review process, the SHM Board of Directors approved the compendium and the APA provided their endorsement.

This second edition of The PHM Core Competencies: 2020 Revision addresses the knowledge, skills, attitudes, and systems organization and improvement objectives that define the field of pediatric hospital medicine and the leadership roles of pediatric hospitalists. This compendium reflects the recent changes in the practice and educational environments of pediatric hospitalists and can inform education, training, and career development for pediatric hospitalists across all environments in which comprehensive care is rendered for the hospitalized child. Future work at the local and national level can lead to development of associated curricula, conference content, and other training materials.

Acknowledgments

We wish to humbly and respectfully acknowledge the work of the authors, editors, and reviewers involved in the creation of the first edition, as well as this revision, of The PHM Core Competencies. In addition, we are grateful for the input of all pediatric hospitalists and other stakeholders who informed this compendium via contributions to the needs assessment survey, conference proceedings, publications, and other works. Finally, we acknowledge the support and work of SHM project coordinator, Nyla Nicholson, the SHM Pediatrics SIG, and the SHM Board of Directors.

Disclosures

SHM provided administrative support for project coordination (N. Nicholson). No author, editor, or other involved member received any compensation for efforts related to this work. There are no reported conflicts of interest.

The Pediatric Hospital Medicine Core Competencies were first published in 2010 to help define a specific body of knowledge and measurable skills needed to practice high quality care for hospitalized pediatric patients across all practice settings.¹ Since then, the number of practicing pediatric hospitalists has grown to a conservative estimate of 3,000 physicians and the scope of practice among pediatric hospitalists has matured.² Pediatric hospitalists are increasingly leading or participating in organizational and national efforts that emphasize interprofessional collaboration and the delivery of high value care to hospitalized children and their caregivers—including innovative and family-centered care models, patient safety and quality improvement initiatives, and research and educational enterprises.^3-8 In response to these changes, the American Board of Medical Specialties designated Pediatric Hospital Medicine (PHM) as a pediatric subspecialty in 2016.

The field of PHM in the United States continues to be supported by three core societies—Society of Hospital Medicine (SHM), American Academy of Pediatrics (AAP), and Academic Pediatric Association (APA). Together, these societies serve as tri-sponsors of the annual Pediatric Hospital Medicine national conference, which now welcomes over 1,200 attendees from the United States and abroad.⁹ Each society also individually sponsors a variety of professional development and continuing medical education activities specific to PHM.

In addition, pediatric hospitalists often serve a pivotal role in teaching learners (medical students, residents, and other health profession students), physician colleagues, and other healthcare professionals on the hospital wards and via institutional educational programs. Nearly 50 institutions in the United States offer graduate medical education training in PHM.¹⁰ The PHM Fellowship Directors Council has developed a standardized curricular framework and entrustable professional activities, which reflect the tenets of competency-based medical education, for use in PHM training programs.^11-13

These changes in the practice environment of pediatric hospitalists, as well as the changing landscape of graduate and continuing medical education in PHM, have informed this revision of The PHM Core Competencies. The purpose of this article is to describe the methodology of the review and revision process.

Revision

The PHM Core Competencies: 2020 Revision provide a framework for graduate and continuing medical education that reflects the current roles and expectations for all pediatric hospitalists in the United States. The acuity and complexity of hospitalized children, the availability of pediatric subspecialty care and other resources, and the institutional orientation towards pediatric populations vary across community, tertiary, and children’s hospital settings. In order to unify the practice of PHM across these environments, The PHM Core Competencies: 2020 Revision address the fundamental and most common components of PHM which are encountered by the majority of practicing pediatric hospitalists, as opposed to an extensive review of all aspects of the field.

The compendium includes 66 chapters on both clinical and nonclinical topics, divided into four sections—Common Clinical Diagnoses and Conditions, Core Skills, Specialized Services, and Healthcare Systems: Supporting and Advancing Child Health (Table 1). Within each chapter is an introductory paragraph and learning objectives in three domains of educational outcomes—cognitive (knowledge), psychomotor (skills), and affective (attitudes)—as well as systems organization and improvement, to reflect the emphasis of PHM practice on improving healthcare systems. The objectives encompass a range of observable behaviors and other attributes, from foundational skills such as taking a history and performing a physical exam to more advanced actions such as participating in the development of care models to support the health of complex patient populations. Implicit in these objectives is the expectation that pediatric hospitalists build on experiences in medical school and residency training to attain a level of competency at the advanced levels of a developmental continuum, such as proficient, expert, or master.¹⁴

The objectives also balance specificity to the topic with a timeless quality, allowing for flexibility both as new information emerges and when applied to various educational activities and learner groups. Each chapter can stand alone, and thus themes recur if one reads the compendium in its entirety. However, in order to reflect related content among the chapters, the appendix contains a list of associated chapters (Chapter Links) for further exploration. In addition, a short reference list is provided in each chapter to reflect the literature and best practices at the time of publication.

Finally, The PHM Core Competencies: 2020 Revision reflect the status of children as a vulnerable population. Care for hospitalized children requires attention to many elements unique to the pediatric population. These include age-based differences in development, behavior, physiology, and prevalence of clinical conditions, the impact of acute and chronic disease states on child development, the use of medications and other medical interventions with limited investigative guidance, and the role of caregivers in decision-making and care delivery. Heightened awareness of these factors is required in the hospital setting, where diagnoses and interventions often include the use of high-risk modalities and require coordination of care across multiple providers.

Project Initiation

Revision of The PHM Core Competencies: 2020 Revision began in early 2017 following SHM’s work on The Core Competencies in Hospital Medicine 2017 Revision.¹⁵ The Executive Committee of the SHM Pediatrics Special Interest Group (SIG) supported the initiation of the revision. The 3 editors from the original compendium created an initial plan for the project that included a proposed timeline, processes for engagement of previously involved experts and new talent, and performance of a needs assessment to guide content selection. The Figure highlights these and other important steps in the revision process.

Editor and Associate Editor Selection

The above editors reviewed best practice examples of roles and responsibilities for editor and associate editor positions from relevant, leading societies and journals. From this review, the editors created an editorial structure specifically for The PHM Core Competencies: 2020 Revision. A new position of Contributing Editor was created to address the need for dedicated attention to the community site perspective and ensure review of all content, within and across chapters, by a pediatric hospitalist who is dedicated to this environment. Solicitation for additional editors and associate editors occurred via the SHM Pediatrics SIG to the wider SHM membership. The criteria for selection included active engagement in regional or national activities related to the growth and operations of PHM, strong organizational and leadership skills, including the ability to manage tasks and foster creativity, among others. In addition, a deliberate effort was made to recruit a diverse editorial cohort, considering geographic location, primary work environment, organizational affiliations, content expertise, time in practice, gender, and other factors.

Chapter Topic Selection

The editors conducted a two-pronged needs assessment related to optimal content for inclusion in The PHM Core Competencies: 2020 Revision. First, the editors reviewed content from conferences, textbooks, and handbooks specific to the field of PHM, including the conference programs for the most recent 5 years of both the annual PHM national conference and annual meetings of PHM’s 3 core societies in the United States—SHM, AAP, and APA. Second, the editors conducted a needs assessment survey with several stakeholder groups, including SHM’s Pediatrics and Medicine-Pediatrics SIGs, AAP Section on Hospital Medicine and its subcommittees, APA Hospital Medicine SIG, PHM Fellowship Directors Council, and PHM Division Directors, with encouragement to pass the survey link to others in the PHM community interested in providing input (Appendix Figure). The solicitation asked for comment on existing chapters and suggestions for new chapters. For any new chapter, respondents were asked to note the intended purpose of the chapter and the anticipated value that chapter would bring to our profession and the children and the caregivers served by pediatric hospitalists.

The entire editorial board then reviewed all of the needs assessment data and considered potential changes (additions or deletions) based on emerging trends in pediatric healthcare, the frequency, relevance, and value of the item across all environments in which pediatric hospitalists function, and the value to or impact on hospitalized children and caregivers. Almost all survey ratings and comments were either incorporated into an existing chapter or used to create a new chapter. There was a paucity of comments related to the deletion of chapters, and thus no chapters were entirely excluded. However, there were several comments supporting the exclusion of the suprapubic bladder tap procedure, and thus related content was eliminated from the relevant section in Core Skills. Of the 66 chapters in this revision, the needs assessment data directly informed the creation of 12 new chapters, as well as adjustments and/or additions to the titles of 7 chapters and the content of 29 chapters. In addition, the title of the Specialized Clinical Services section was changed to Specialized Services to represent that both clinical and nonclinical competencies reside in this section devoted to comprehensive management of these unique patient populations commonly encountered by pediatric hospitalists. Many of these changes are highlighted in Table 2.

Author selection

Authors from the initial work were invited to participate again as author of their given chapter. Subsequently, authors were identified for new chapters and chapters for which previous authors were no longer able to be engaged. Authors with content expertise were found by reviewing content from conferences, textbooks, and handbooks specific to the field of PHM. Any content expert who was not identified as a pediatric hospitalist was paired with a pediatric hospitalist as coauthor. In addition, as with the editorial board, a deliberate effort was made to recruit a diverse author cohort, considering geographic location, primary work environment, time in practice, gender, and other factors.

The editorial board held numerous conference calls to review potential authors, and the SHM Pediatrics SIG was directly engaged to ensure authorship opportunities were extended broadly. This vetting process resulted in a robust author list and included members of all three of PHM’s sponsoring societies in the United States. Once participation was confirmed, authors received an “author packet” detailing the process with the proposed timeline, resources related to writing learning objectives, the past chapter (if applicable), assigned associate editor, and other helpful resources.

Internal and External Review Process

After all chapters were drafted, the editorial board conducted a rigorous, internal review process. Each chapter was reviewed by at least one associate editor and two editors, with a focus on content, scope, and a standard approach to phrasing and formatting. In addition, the contributing editor reviewed all the chapters to ensure the community hospitalist perspective was adequately represented.

Thirty-two agencies and societies were solicited for external review, including both those involved in review of the previous edition and new stakeholder groups. External reviewers were first contacted to ascertain their interest in participating in the review process, and if interested, were provided with information on the review process. Robust feedback was received from the APA Hospital Medicine SIG, SHM Pediatrics and Medicine-Pediatrics SIGs, Association of Pediatric Program Directors Curriculum Committee, and 20 AAP committees, councils, and sections.

The feedback from the external reviewers and subsequent edits for each chapter were reviewed by at least one associate editor, two editors, and the contributing editor. Authors were engaged to address any salient changes recommended. As the final steps in the review process, the SHM Board of Directors approved the compendium and the APA provided their endorsement.

This second edition of The PHM Core Competencies: 2020 Revision addresses the knowledge, skills, attitudes, and systems organization and improvement objectives that define the field of pediatric hospital medicine and the leadership roles of pediatric hospitalists. This compendium reflects the recent changes in the practice and educational environments of pediatric hospitalists and can inform education, training, and career development for pediatric hospitalists across all environments in which comprehensive care is rendered for the hospitalized child. Future work at the local and national level can lead to development of associated curricula, conference content, and other training materials.

Acknowledgments

We wish to humbly and respectfully acknowledge the work of the authors, editors, and reviewers involved in the creation of the first edition, as well as this revision, of The PHM Core Competencies. In addition, we are grateful for the input of all pediatric hospitalists and other stakeholders who informed this compendium via contributions to the needs assessment survey, conference proceedings, publications, and other works. Finally, we acknowledge the support and work of SHM project coordinator, Nyla Nicholson, the SHM Pediatrics SIG, and the SHM Board of Directors.

Disclosures

SHM provided administrative support for project coordination (N. Nicholson). No author, editor, or other involved member received any compensation for efforts related to this work. There are no reported conflicts of interest.

Mycosis fungoides (MF), the most common variant of cutaneous T-cell lymphoma, is a non-Hodgkin lymphoma of T-cell origin that primarily develops in the skin and has a chronic relapsing course. Early-stage MF (stages IA–IIA) is defined as papules, patches, or plaques with limited (if any) lymph node and blood involvement and no visceral involvement.¹ Early-stage MF has a favorable prognosis, and first-line treatments are skin-directed therapies including topical corticosteroids (CSs), topical chemotherapy (nitrogen mustard or carmustine), topical retinoids, topical imiquimod, local radiation, or phototherapy.² Topical CSs are effective in treating early-stage MF and have been widely used for this indication for several decades; however, there are very little data in the literature on topical CS use in MF.³ Superpotent topical CSs have been shown to have a high overall response rate in early-stage MF³; however, cutaneous side effects associated with long-term topical use include cutaneous atrophy, striae formation, skin fragility, and irritation.

The US Food and Drug Administration (FDA) approved bexarotene gel and mechlorethamine gel for topical treatment of cutaneous lesions in patients with stage IA and IB MF in 2000 and 2013, respectively. Although each may be effective in achieving complete or partial response in MF, both agents are associated with cutaneous side effects, mainly irritation and frequent contact hypersensitivity reactions, respectively.^4,5 Additionally, their high prices and limited availability are other major drawbacks of treatment.

At our institution, high-potency topical CSs, specifically once or twice daily clobetasol propionate cream 0.05% prescribed as monotherapy for at least several months, remain the mainstay of treatment in patients with limited patches, papules, and plaques covering less than 10% of the skin surface (stage IA). In this study, we aimed to assess the risk of cutaneous side effects in patients with early-stage MF who were treated with long-term, high-potency topical CSs.

Methods

This prospective observational cohort study included patients with early-stage MF who were seen at the Cutaneous Lymphoma Clinic at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, and were started on a superpotent (class I) topical CS (clobetasol propionate cream 0.05%) as monotherapy for MF from July 2016 to July 2017. The diagnosis of MF had to be supported by clinical findings and histopathologic features. All patients were Fitzpatrick skin types I, II, or III. Eligible patients were evaluated for development of CS-induced cutaneous AEs by physical examination and clinical photography of the treated lesions performed at baseline and as part of routine follow-up visits (usually scheduled every 2 to 6 months) at the MSKCC Cutaneous Lymphoma Clinic. Patients’ skin was evaluated clinically for MF activity, atrophy, telangiectasia, purpura, hypopigmentation, and stretch marks (striae). Use of the topical CS was self-reported and also was documented at follow-up visits. Treatment response was defined as follows: complete clinical response (CCR) if the treated lesions resolved completely compared to initial photography; minimal active disease (MAD) if resolution of the vast majority (≥75%) of lesions was seen; and partial response (PR) if some of the lesions resolved (<75%). We analyzed the treatment response rates and adverse effects (AEs). Results were summarized using descriptive statistics.

Results

We identified 13 patients who were started on topical clobetasol propionate as monotherapy for early-stage MF during the study period. Our cohort included 6 males and 7 females aged 36 to 76 years (median age, 61 years). All but 1 participant were diagnosed with stage IA MF (12/13 [92.3%]); of those, 9 (75.0%) had patch-stage disease and 3 (25.0%) presented with plaques. One (7.7%) participant presented with hyperpigmented patches and plaques that involved a little more than 10% of the skin surface (stage IB), and involvement of the hair follicles was noted on histology (folliculotropic MF). All prior treatments were stopped when participants started the superpotent topical CS: 6 (46.2%) participants had been treated with lower-potency topical agents and 1 (7.7%) participant was getting psoralen plus UVA therapy, while the other 6 (46.2%) participants were receiving no therapy for MF prior to starting the study. All participants were prescribed clobetasol propionate cream 0.05% once or twice daily as monotherapy and were instructed to apply it to the MF lesions only, avoiding skin folds and the face. One participant was lost to follow-up, and another stopped using the clobetasol propionate cream after 1.5 months due to local irritation associated with treatment. At their follow-up visits, the other 11 participants were advised to continue with once-daily treatment with clobetasol propionate or were tapered to once every other day, twice weekly, or once weekly depending on their response to treatment and AEs (Table). Participants were advised not to use more than 50 g of clobetasol propionate cream weekly.

All participants responded to the clobetasol propionate cream, and improvement was noted in the treated lesions; however, progression of disease (from stage IA to stage IB) occurred in 1 (8.3%) participant, and phototherapy was added with good response. The participants in our cohort were followed for 4 to 17 months (median, 11.5 months). At the last follow-up visit, all 12 participants showed treatment response: 4 (33.3%) had CCR, 5 (41.7%) had MAD; and 3 (25.0%) had PR. In one participant with a history of partial response to bexarotene gel 1%, daily clobetasol propionate cream 0.05% initially was used alone for 9 months and was later combined with bexarotene gel once weekly, resulting in MAD.

In 7 (58.3%) participants, no AEs to topical clobetasol propionate were recorded. Four (33.3%) participants developed local hypopigmentation at the application site, and 2 (16.7%) developed cutaneous atrophy with local fine wrinkling of the skin (Figure 1); none of the participants developed stretch marks (striae), telangiectases, or skin fragility. One (8.3%) participant developed a petechial rash at the clobetasol propionate application site that resolved once treatment was discontinued and did not recur after restarting clobetasol propionate twice weekly.

Comment

Topical CSs are the most commonly prescribed agents, either as monotherapy or in combination with other agents, in the treatment of numerous dermatologic conditions, including cutaneous T-cell lymphoma and MF. Cutaneous and systemic AEs have been associated with topical CS use. Local AEs are encountered more frequently and include cutaneous atrophy, striae, telangiectasia, purpura, skin fragility, hypopigmentation, hyperpigmentation, acneform eruptions, and hypertrichosis.⁶ Factors other than potency of the topical CS agent may affect the development of skin atrophy, including anatomic location, duration of therapy, vehicle, and method and frequency of application.⁷ The potential for systemic AEs due to percutaneous absorption of high-potency CSs, specifically Cushing syndrome and pathologic adrenal suppression, has been a long-standing concern and led the FDA to recommend limiting the use of superpotent CSs to 50 g weekly for 2 or 4 consecutive weeks.⁸ However, if using an excess of 50 g weekly is avoided, superpotent topical CSs may be safe to use consecutively for months, perhaps even years, without causing systemic effects.⁹

The effects of topical CSs in MF include induction of apoptosis; inhibition of lymphocyte binding to the endothelium; and downregulation of transcription factors with decreased cytokines, adhesion molecules, and production of growth factors.² For patients with limited early-stage MF patches and thin plaques, topical CSs often control the disease for many years and frequently are the only form of therapy required. Intralesional steroids can be effective in treating thicker lesions, such as plaques or tumors.¹⁰ In an uncontrolled study, Zackheim et al¹¹ prospectively evaluated the effectiveness and safety of twice-daily use of mainly high-potency topical CSs in 79 patients with MF stages IA to IB and observed an overall response rate of 94%. None of the patients were using systemic agents while being treated with topical CSs. Adverse effects were rare: 2 (2.5%) patients experienced temporary minor irritation from the topical CS, 1 (1.3%) patient developed localized skin atrophy under the breast that resolved several months after she stopped treatment, and 1 (1.3%) patient developed stretch marks on the thighs.¹¹ Zackheim¹² later reported treatment of approximately 200 patients with class I topical CSs, and overall response rates were over 90% in stage T1 and over 80% in stage T2 patients. Response to topical CS was reported to be evident within 3 months and often much sooner. Side effects were most likely related to the more prolonged treatment periods. Irritant dermatitis or purpura developed in approximately 10% to 20% of patients, and purpura was seen at the sites of treatment as well as at distant sites. Only a small number of patients developed cutaneous atrophy and striae, which were reversible.¹² Successful use of intralesional steroids for treatment-resistant MF was reported in 4 patients who tolerated treatment well without any side effects other than local hypopigmentation in a single patient.¹³

At MSKCC, the first line of treatment in localized (stage IA) MF in light-skinned individuals most frequently is class I topical CSs, usually clobetasol propionate cream 0.05%. Patients are instructed to apply the cream twice daily on active MF lesions uninterruptedly until completely clear and to avoid using it on the face and in skin folds (axillary, inguinal, and abdominal). Patients are instructed to observe themselves for possible cutaneous AEs related to treatment and to stop or taper treatment if any AEs are noticed. In patients with darker skin, we may recommend other modalities such as narrowband UVB phototherapy for even limited MF disease because of the risk for uneven/hypopigmentation with superpotent CSs.

The current study offers a real-life observation of topical high-potency CSs for treatment of early-stage MF and the associated cutaneous AEs. Local hypopigmentation was identified in 4 participants (33.3%), local skin atrophy was seen in 2 participants (16.7%), and local purpura and irritation were seen in 1 participant each (8.3%). All patients responded to therapy and 75.0% (9/12) achieved CCR or showed only MAD at their last follow-up visit. The limitations of our study were the small number of patients included and the relatively short follow-up period.

In MF patients, patches can present as fine wrinkling of the skin resembling atrophy, which can make it difficult to differentiate active MF from CS-induced atrophy in patients treated with topical CSs (Figure 1) and may have caused us to overestimate the occurrence of this AE. Corticosteroid-induced skin atrophy has been studied mainly in normal skin and to a lesser extent in pathological skin in psoriasis and atopic dermatitis. Some of these studies reported that CS-induced atrophy is reversible, and skin thickness can return to normal after topical application of CS is stopped.⁷

When hypopigmentation is seen around MF lesions, it is a confirmation that the patient is compliant with the therapy. From our experience, local hypopigmentation due to topical CSs is reversible (Figure 2). In some cases, MF patients have applied topical clobetasol propionate to lesional and surrounding skin, and hypopigmentation can be lessened with more careful limited application. In most cases, after discontinuation or tapering of the therapy, the skin returns to its normal color.

Conclusion

Patients with early-stage MF should be treated with skin-directed therapies, and the choice between different therapeutic options is made based on the physician’s experience with the treatment, patient characteristics, location and morphology of the MF lesions, and the AE profile of the treatment. Based on our experience, superpotent topical CSs are readily available and easily applied, have minor side effects, and remain the mainstay of therapy in patients with stage IA disease. Patients with MF on superpotent topical CS therapy should be monitored periodically and instructed how to identify cutaneous AEs related to treatment.

Mycosis fungoides (MF), the most common variant of cutaneous T-cell lymphoma, is a non-Hodgkin lymphoma of T-cell origin that primarily develops in the skin and has a chronic relapsing course. Early-stage MF (stages IA–IIA) is defined as papules, patches, or plaques with limited (if any) lymph node and blood involvement and no visceral involvement.¹ Early-stage MF has a favorable prognosis, and first-line treatments are skin-directed therapies including topical corticosteroids (CSs), topical chemotherapy (nitrogen mustard or carmustine), topical retinoids, topical imiquimod, local radiation, or phototherapy.² Topical CSs are effective in treating early-stage MF and have been widely used for this indication for several decades; however, there are very little data in the literature on topical CS use in MF.³ Superpotent topical CSs have been shown to have a high overall response rate in early-stage MF³; however, cutaneous side effects associated with long-term topical use include cutaneous atrophy, striae formation, skin fragility, and irritation.

The US Food and Drug Administration (FDA) approved bexarotene gel and mechlorethamine gel for topical treatment of cutaneous lesions in patients with stage IA and IB MF in 2000 and 2013, respectively. Although each may be effective in achieving complete or partial response in MF, both agents are associated with cutaneous side effects, mainly irritation and frequent contact hypersensitivity reactions, respectively.^4,5 Additionally, their high prices and limited availability are other major drawbacks of treatment.

At our institution, high-potency topical CSs, specifically once or twice daily clobetasol propionate cream 0.05% prescribed as monotherapy for at least several months, remain the mainstay of treatment in patients with limited patches, papules, and plaques covering less than 10% of the skin surface (stage IA). In this study, we aimed to assess the risk of cutaneous side effects in patients with early-stage MF who were treated with long-term, high-potency topical CSs.

Methods

This prospective observational cohort study included patients with early-stage MF who were seen at the Cutaneous Lymphoma Clinic at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, and were started on a superpotent (class I) topical CS (clobetasol propionate cream 0.05%) as monotherapy for MF from July 2016 to July 2017. The diagnosis of MF had to be supported by clinical findings and histopathologic features. All patients were Fitzpatrick skin types I, II, or III. Eligible patients were evaluated for development of CS-induced cutaneous AEs by physical examination and clinical photography of the treated lesions performed at baseline and as part of routine follow-up visits (usually scheduled every 2 to 6 months) at the MSKCC Cutaneous Lymphoma Clinic. Patients’ skin was evaluated clinically for MF activity, atrophy, telangiectasia, purpura, hypopigmentation, and stretch marks (striae). Use of the topical CS was self-reported and also was documented at follow-up visits. Treatment response was defined as follows: complete clinical response (CCR) if the treated lesions resolved completely compared to initial photography; minimal active disease (MAD) if resolution of the vast majority (≥75%) of lesions was seen; and partial response (PR) if some of the lesions resolved (<75%). We analyzed the treatment response rates and adverse effects (AEs). Results were summarized using descriptive statistics.

Results

We identified 13 patients who were started on topical clobetasol propionate as monotherapy for early-stage MF during the study period. Our cohort included 6 males and 7 females aged 36 to 76 years (median age, 61 years). All but 1 participant were diagnosed with stage IA MF (12/13 [92.3%]); of those, 9 (75.0%) had patch-stage disease and 3 (25.0%) presented with plaques. One (7.7%) participant presented with hyperpigmented patches and plaques that involved a little more than 10% of the skin surface (stage IB), and involvement of the hair follicles was noted on histology (folliculotropic MF). All prior treatments were stopped when participants started the superpotent topical CS: 6 (46.2%) participants had been treated with lower-potency topical agents and 1 (7.7%) participant was getting psoralen plus UVA therapy, while the other 6 (46.2%) participants were receiving no therapy for MF prior to starting the study. All participants were prescribed clobetasol propionate cream 0.05% once or twice daily as monotherapy and were instructed to apply it to the MF lesions only, avoiding skin folds and the face. One participant was lost to follow-up, and another stopped using the clobetasol propionate cream after 1.5 months due to local irritation associated with treatment. At their follow-up visits, the other 11 participants were advised to continue with once-daily treatment with clobetasol propionate or were tapered to once every other day, twice weekly, or once weekly depending on their response to treatment and AEs (Table). Participants were advised not to use more than 50 g of clobetasol propionate cream weekly.

All participants responded to the clobetasol propionate cream, and improvement was noted in the treated lesions; however, progression of disease (from stage IA to stage IB) occurred in 1 (8.3%) participant, and phototherapy was added with good response. The participants in our cohort were followed for 4 to 17 months (median, 11.5 months). At the last follow-up visit, all 12 participants showed treatment response: 4 (33.3%) had CCR, 5 (41.7%) had MAD; and 3 (25.0%) had PR. In one participant with a history of partial response to bexarotene gel 1%, daily clobetasol propionate cream 0.05% initially was used alone for 9 months and was later combined with bexarotene gel once weekly, resulting in MAD.

In 7 (58.3%) participants, no AEs to topical clobetasol propionate were recorded. Four (33.3%) participants developed local hypopigmentation at the application site, and 2 (16.7%) developed cutaneous atrophy with local fine wrinkling of the skin (Figure 1); none of the participants developed stretch marks (striae), telangiectases, or skin fragility. One (8.3%) participant developed a petechial rash at the clobetasol propionate application site that resolved once treatment was discontinued and did not recur after restarting clobetasol propionate twice weekly.

Comment

Topical CSs are the most commonly prescribed agents, either as monotherapy or in combination with other agents, in the treatment of numerous dermatologic conditions, including cutaneous T-cell lymphoma and MF. Cutaneous and systemic AEs have been associated with topical CS use. Local AEs are encountered more frequently and include cutaneous atrophy, striae, telangiectasia, purpura, skin fragility, hypopigmentation, hyperpigmentation, acneform eruptions, and hypertrichosis.⁶ Factors other than potency of the topical CS agent may affect the development of skin atrophy, including anatomic location, duration of therapy, vehicle, and method and frequency of application.⁷ The potential for systemic AEs due to percutaneous absorption of high-potency CSs, specifically Cushing syndrome and pathologic adrenal suppression, has been a long-standing concern and led the FDA to recommend limiting the use of superpotent CSs to 50 g weekly for 2 or 4 consecutive weeks.⁸ However, if using an excess of 50 g weekly is avoided, superpotent topical CSs may be safe to use consecutively for months, perhaps even years, without causing systemic effects.⁹

The effects of topical CSs in MF include induction of apoptosis; inhibition of lymphocyte binding to the endothelium; and downregulation of transcription factors with decreased cytokines, adhesion molecules, and production of growth factors.² For patients with limited early-stage MF patches and thin plaques, topical CSs often control the disease for many years and frequently are the only form of therapy required. Intralesional steroids can be effective in treating thicker lesions, such as plaques or tumors.¹⁰ In an uncontrolled study, Zackheim et al¹¹ prospectively evaluated the effectiveness and safety of twice-daily use of mainly high-potency topical CSs in 79 patients with MF stages IA to IB and observed an overall response rate of 94%. None of the patients were using systemic agents while being treated with topical CSs. Adverse effects were rare: 2 (2.5%) patients experienced temporary minor irritation from the topical CS, 1 (1.3%) patient developed localized skin atrophy under the breast that resolved several months after she stopped treatment, and 1 (1.3%) patient developed stretch marks on the thighs.¹¹ Zackheim¹² later reported treatment of approximately 200 patients with class I topical CSs, and overall response rates were over 90% in stage T1 and over 80% in stage T2 patients. Response to topical CS was reported to be evident within 3 months and often much sooner. Side effects were most likely related to the more prolonged treatment periods. Irritant dermatitis or purpura developed in approximately 10% to 20% of patients, and purpura was seen at the sites of treatment as well as at distant sites. Only a small number of patients developed cutaneous atrophy and striae, which were reversible.¹² Successful use of intralesional steroids for treatment-resistant MF was reported in 4 patients who tolerated treatment well without any side effects other than local hypopigmentation in a single patient.¹³

At MSKCC, the first line of treatment in localized (stage IA) MF in light-skinned individuals most frequently is class I topical CSs, usually clobetasol propionate cream 0.05%. Patients are instructed to apply the cream twice daily on active MF lesions uninterruptedly until completely clear and to avoid using it on the face and in skin folds (axillary, inguinal, and abdominal). Patients are instructed to observe themselves for possible cutaneous AEs related to treatment and to stop or taper treatment if any AEs are noticed. In patients with darker skin, we may recommend other modalities such as narrowband UVB phototherapy for even limited MF disease because of the risk for uneven/hypopigmentation with superpotent CSs.

The current study offers a real-life observation of topical high-potency CSs for treatment of early-stage MF and the associated cutaneous AEs. Local hypopigmentation was identified in 4 participants (33.3%), local skin atrophy was seen in 2 participants (16.7%), and local purpura and irritation were seen in 1 participant each (8.3%). All patients responded to therapy and 75.0% (9/12) achieved CCR or showed only MAD at their last follow-up visit. The limitations of our study were the small number of patients included and the relatively short follow-up period.

In MF patients, patches can present as fine wrinkling of the skin resembling atrophy, which can make it difficult to differentiate active MF from CS-induced atrophy in patients treated with topical CSs (Figure 1) and may have caused us to overestimate the occurrence of this AE. Corticosteroid-induced skin atrophy has been studied mainly in normal skin and to a lesser extent in pathological skin in psoriasis and atopic dermatitis. Some of these studies reported that CS-induced atrophy is reversible, and skin thickness can return to normal after topical application of CS is stopped.⁷

When hypopigmentation is seen around MF lesions, it is a confirmation that the patient is compliant with the therapy. From our experience, local hypopigmentation due to topical CSs is reversible (Figure 2). In some cases, MF patients have applied topical clobetasol propionate to lesional and surrounding skin, and hypopigmentation can be lessened with more careful limited application. In most cases, after discontinuation or tapering of the therapy, the skin returns to its normal color.

Conclusion

Patients with early-stage MF should be treated with skin-directed therapies, and the choice between different therapeutic options is made based on the physician’s experience with the treatment, patient characteristics, location and morphology of the MF lesions, and the AE profile of the treatment. Based on our experience, superpotent topical CSs are readily available and easily applied, have minor side effects, and remain the mainstay of therapy in patients with stage IA disease. Patients with MF on superpotent topical CS therapy should be monitored periodically and instructed how to identify cutaneous AEs related to treatment.

Mycosis fungoides (MF), the most common variant of cutaneous T-cell lymphoma, is a non-Hodgkin lymphoma of T-cell origin that primarily develops in the skin and has a chronic relapsing course. Early-stage MF (stages IA–IIA) is defined as papules, patches, or plaques with limited (if any) lymph node and blood involvement and no visceral involvement.¹ Early-stage MF has a favorable prognosis, and first-line treatments are skin-directed therapies including topical corticosteroids (CSs), topical chemotherapy (nitrogen mustard or carmustine), topical retinoids, topical imiquimod, local radiation, or phototherapy.² Topical CSs are effective in treating early-stage MF and have been widely used for this indication for several decades; however, there are very little data in the literature on topical CS use in MF.³ Superpotent topical CSs have been shown to have a high overall response rate in early-stage MF³; however, cutaneous side effects associated with long-term topical use include cutaneous atrophy, striae formation, skin fragility, and irritation.

The US Food and Drug Administration (FDA) approved bexarotene gel and mechlorethamine gel for topical treatment of cutaneous lesions in patients with stage IA and IB MF in 2000 and 2013, respectively. Although each may be effective in achieving complete or partial response in MF, both agents are associated with cutaneous side effects, mainly irritation and frequent contact hypersensitivity reactions, respectively.^4,5 Additionally, their high prices and limited availability are other major drawbacks of treatment.

At our institution, high-potency topical CSs, specifically once or twice daily clobetasol propionate cream 0.05% prescribed as monotherapy for at least several months, remain the mainstay of treatment in patients with limited patches, papules, and plaques covering less than 10% of the skin surface (stage IA). In this study, we aimed to assess the risk of cutaneous side effects in patients with early-stage MF who were treated with long-term, high-potency topical CSs.

Methods

This prospective observational cohort study included patients with early-stage MF who were seen at the Cutaneous Lymphoma Clinic at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, and were started on a superpotent (class I) topical CS (clobetasol propionate cream 0.05%) as monotherapy for MF from July 2016 to July 2017. The diagnosis of MF had to be supported by clinical findings and histopathologic features. All patients were Fitzpatrick skin types I, II, or III. Eligible patients were evaluated for development of CS-induced cutaneous AEs by physical examination and clinical photography of the treated lesions performed at baseline and as part of routine follow-up visits (usually scheduled every 2 to 6 months) at the MSKCC Cutaneous Lymphoma Clinic. Patients’ skin was evaluated clinically for MF activity, atrophy, telangiectasia, purpura, hypopigmentation, and stretch marks (striae). Use of the topical CS was self-reported and also was documented at follow-up visits. Treatment response was defined as follows: complete clinical response (CCR) if the treated lesions resolved completely compared to initial photography; minimal active disease (MAD) if resolution of the vast majority (≥75%) of lesions was seen; and partial response (PR) if some of the lesions resolved (<75%). We analyzed the treatment response rates and adverse effects (AEs). Results were summarized using descriptive statistics.

Results

We identified 13 patients who were started on topical clobetasol propionate as monotherapy for early-stage MF during the study period. Our cohort included 6 males and 7 females aged 36 to 76 years (median age, 61 years). All but 1 participant were diagnosed with stage IA MF (12/13 [92.3%]); of those, 9 (75.0%) had patch-stage disease and 3 (25.0%) presented with plaques. One (7.7%) participant presented with hyperpigmented patches and plaques that involved a little more than 10% of the skin surface (stage IB), and involvement of the hair follicles was noted on histology (folliculotropic MF). All prior treatments were stopped when participants started the superpotent topical CS: 6 (46.2%) participants had been treated with lower-potency topical agents and 1 (7.7%) participant was getting psoralen plus UVA therapy, while the other 6 (46.2%) participants were receiving no therapy for MF prior to starting the study. All participants were prescribed clobetasol propionate cream 0.05% once or twice daily as monotherapy and were instructed to apply it to the MF lesions only, avoiding skin folds and the face. One participant was lost to follow-up, and another stopped using the clobetasol propionate cream after 1.5 months due to local irritation associated with treatment. At their follow-up visits, the other 11 participants were advised to continue with once-daily treatment with clobetasol propionate or were tapered to once every other day, twice weekly, or once weekly depending on their response to treatment and AEs (Table). Participants were advised not to use more than 50 g of clobetasol propionate cream weekly.

All participants responded to the clobetasol propionate cream, and improvement was noted in the treated lesions; however, progression of disease (from stage IA to stage IB) occurred in 1 (8.3%) participant, and phototherapy was added with good response. The participants in our cohort were followed for 4 to 17 months (median, 11.5 months). At the last follow-up visit, all 12 participants showed treatment response: 4 (33.3%) had CCR, 5 (41.7%) had MAD; and 3 (25.0%) had PR. In one participant with a history of partial response to bexarotene gel 1%, daily clobetasol propionate cream 0.05% initially was used alone for 9 months and was later combined with bexarotene gel once weekly, resulting in MAD.

In 7 (58.3%) participants, no AEs to topical clobetasol propionate were recorded. Four (33.3%) participants developed local hypopigmentation at the application site, and 2 (16.7%) developed cutaneous atrophy with local fine wrinkling of the skin (Figure 1); none of the participants developed stretch marks (striae), telangiectases, or skin fragility. One (8.3%) participant developed a petechial rash at the clobetasol propionate application site that resolved once treatment was discontinued and did not recur after restarting clobetasol propionate twice weekly.

Comment

Topical CSs are the most commonly prescribed agents, either as monotherapy or in combination with other agents, in the treatment of numerous dermatologic conditions, including cutaneous T-cell lymphoma and MF. Cutaneous and systemic AEs have been associated with topical CS use. Local AEs are encountered more frequently and include cutaneous atrophy, striae, telangiectasia, purpura, skin fragility, hypopigmentation, hyperpigmentation, acneform eruptions, and hypertrichosis.⁶ Factors other than potency of the topical CS agent may affect the development of skin atrophy, including anatomic location, duration of therapy, vehicle, and method and frequency of application.⁷ The potential for systemic AEs due to percutaneous absorption of high-potency CSs, specifically Cushing syndrome and pathologic adrenal suppression, has been a long-standing concern and led the FDA to recommend limiting the use of superpotent CSs to 50 g weekly for 2 or 4 consecutive weeks.⁸ However, if using an excess of 50 g weekly is avoided, superpotent topical CSs may be safe to use consecutively for months, perhaps even years, without causing systemic effects.⁹

The effects of topical CSs in MF include induction of apoptosis; inhibition of lymphocyte binding to the endothelium; and downregulation of transcription factors with decreased cytokines, adhesion molecules, and production of growth factors.² For patients with limited early-stage MF patches and thin plaques, topical CSs often control the disease for many years and frequently are the only form of therapy required. Intralesional steroids can be effective in treating thicker lesions, such as plaques or tumors.¹⁰ In an uncontrolled study, Zackheim et al¹¹ prospectively evaluated the effectiveness and safety of twice-daily use of mainly high-potency topical CSs in 79 patients with MF stages IA to IB and observed an overall response rate of 94%. None of the patients were using systemic agents while being treated with topical CSs. Adverse effects were rare: 2 (2.5%) patients experienced temporary minor irritation from the topical CS, 1 (1.3%) patient developed localized skin atrophy under the breast that resolved several months after she stopped treatment, and 1 (1.3%) patient developed stretch marks on the thighs.¹¹ Zackheim¹² later reported treatment of approximately 200 patients with class I topical CSs, and overall response rates were over 90% in stage T1 and over 80% in stage T2 patients. Response to topical CS was reported to be evident within 3 months and often much sooner. Side effects were most likely related to the more prolonged treatment periods. Irritant dermatitis or purpura developed in approximately 10% to 20% of patients, and purpura was seen at the sites of treatment as well as at distant sites. Only a small number of patients developed cutaneous atrophy and striae, which were reversible.¹² Successful use of intralesional steroids for treatment-resistant MF was reported in 4 patients who tolerated treatment well without any side effects other than local hypopigmentation in a single patient.¹³

At MSKCC, the first line of treatment in localized (stage IA) MF in light-skinned individuals most frequently is class I topical CSs, usually clobetasol propionate cream 0.05%. Patients are instructed to apply the cream twice daily on active MF lesions uninterruptedly until completely clear and to avoid using it on the face and in skin folds (axillary, inguinal, and abdominal). Patients are instructed to observe themselves for possible cutaneous AEs related to treatment and to stop or taper treatment if any AEs are noticed. In patients with darker skin, we may recommend other modalities such as narrowband UVB phototherapy for even limited MF disease because of the risk for uneven/hypopigmentation with superpotent CSs.

The current study offers a real-life observation of topical high-potency CSs for treatment of early-stage MF and the associated cutaneous AEs. Local hypopigmentation was identified in 4 participants (33.3%), local skin atrophy was seen in 2 participants (16.7%), and local purpura and irritation were seen in 1 participant each (8.3%). All patients responded to therapy and 75.0% (9/12) achieved CCR or showed only MAD at their last follow-up visit. The limitations of our study were the small number of patients included and the relatively short follow-up period.

In MF patients, patches can present as fine wrinkling of the skin resembling atrophy, which can make it difficult to differentiate active MF from CS-induced atrophy in patients treated with topical CSs (Figure 1) and may have caused us to overestimate the occurrence of this AE. Corticosteroid-induced skin atrophy has been studied mainly in normal skin and to a lesser extent in pathological skin in psoriasis and atopic dermatitis. Some of these studies reported that CS-induced atrophy is reversible, and skin thickness can return to normal after topical application of CS is stopped.⁷

When hypopigmentation is seen around MF lesions, it is a confirmation that the patient is compliant with the therapy. From our experience, local hypopigmentation due to topical CSs is reversible (Figure 2). In some cases, MF patients have applied topical clobetasol propionate to lesional and surrounding skin, and hypopigmentation can be lessened with more careful limited application. In most cases, after discontinuation or tapering of the therapy, the skin returns to its normal color.

Conclusion

Patients with early-stage MF should be treated with skin-directed therapies, and the choice between different therapeutic options is made based on the physician’s experience with the treatment, patient characteristics, location and morphology of the MF lesions, and the AE profile of the treatment. Based on our experience, superpotent topical CSs are readily available and easily applied, have minor side effects, and remain the mainstay of therapy in patients with stage IA disease. Patients with MF on superpotent topical CS therapy should be monitored periodically and instructed how to identify cutaneous AEs related to treatment.

Population studies show high prevalence of chronic hepatitis C virus (HCV) infection among veterans, especially Vietnam War era veterans.^1,2 The development of safe and efficacious direct-acting antiviral (DAA) medications to treat HCV infection made the majority of those infected eligible for treatment. However, the large number of veterans needing DAA treatment stressed the resources of the US Department of Veterans Affairs (VA) health care system. This occurred while Congress was focused on reducing wait times for veterans receiving care at the VA.

Congress passed the Veterans Access, Choice, and Accountability Act on August 7, 2014, leading to the creation of the Veterans Choice Program. Legislators felt there were inappropriate delays in care at the VA, and the Choice program was meant to address this problem and provide an “apples-to-apples comparison [of the VA] with non-VA hospitals.”³

Congress acknowledged the importance of curing HCV in the veteran population and allocated $1.5 billion for fiscal year (FY) 2016 for DAAs. The VA Central Office (VACO) carefully monitored these resources. The first policy memorandum from VACO for HCV care, issued on May 21, 2015, recommended that the sickest patients who will benefit from the treatment “receive priority over those who are less ill.”^4,5 Those who met criteria for advanced liver disease were prioritized for treatment at the VA, while those who did not meet criteria were given the option of receiving treatment through Choice, or waiting for a change in policy.6 Over time, revisions to the guidelines relaxed the criteria for VA treatment eligibility, and on February 24, 2016, all restrictions on HCV treatment at the VA were lifted.^7,8

The aim of this study was to provide a comparison of VA and non-VA care, specifically to determine whether care provided through Choice was timelier and more cost effective than care provided by the VA, and whether there was a quality difference. The high prevalence among veterans, wellestablished standards of care, and finite treatment course with clear indicators of success and failure makes HCV treatment an ideal disease with which to make this comparison.

Methods

We retrospectively analyzed the VA electronic health records of all veterans seen in the VA Loma Linda Healthcare System (VALLHCS) Hepatology clinic for chronic HCV infection during FY 2016 who were referred to Choice for HCV treatment. One hundred veterans met these criteria, encompassing the Choice population; 71 were seen at least once by a non-VA (Choice) health care provider (HCP) and 61 completed a treatment regimen through Choice. Treatment completion was defined as cessation of medication after the planned duration of therapy, or early termination of medication without resumption by that HCP. The Choice population was matched to an equal number of veterans who received HCV treatment from VALLHCS HCPs.

Data collected included age, gender, HCV genotype, determinants of liver fibrosis, and treatment success (defined as sustained virologic response at 12 weeks after the last dose of medication [SVR12]). Determinants of liver fibrosis included documented cirrhosis or complications of cirrhosis, Fibrosis-4 score (Fib-4), and platelet count.

Treatment failures were categorized as nonresponse (defined as detectable HCV viral load at the end of treatment), relapse (defined as an undetectable HCV viral load at the end of treatment with a subsequent positive test), and early termination (defined as a failure to complete the planned treatment regimen). Documented patient nonadherence, medical comorbidities that affected the treatment protocol, mental health diagnoses, and active social issues (defined as active or history of heavy alcohol use, active or history of illicit drug use, lack of social support, and homelessness) were noted.

Timeliness of delivery of care was measured in days. For the VA group, the wait time was defined as the date the consult for HCV treatment was placed to the date of the initial appointment with the HCV treatment provider. For the Choice group, the wait time was defined as the date the referral to the Choice program was made to the date of the initial appointment with the Choice HCP. Treatment regimens were evaluated for appropriateness based on guidelines from VACO and the American Association for the Study of Liver Diseases.^9-11

Tests performed by Choice providers were evaluated for whether they were relevant to HCV care and whether similar data already were available from VALLHCS. Tests that were not indicated were identified as unnecessary costs incurred by the Choice program, as were tests that had to be repeated at the VA because of a lack of documentation from the Choice provider. All medications given inappropriately were considered added costs. Medicare reimbursement rates for the most applicable Current Procedural Terminology (CPT) code and VA national contract pricing for medications were used for calculations. This study was approved by the VALLHCS institutional review board.

Statistical Analysis

IBM (Armonk, NY) Statistical Package for Social Sciences software was used to evaluate for differences in Fib-4, platelet count, prevalence of cirrhosis, prevalence of medical comorbidities, prevalence of mental health comorbidities, prevalence of the social issues defined in the Methods section, time from referral to time of appointment date, and SVR12 rate between the VA and Choice groups.

Exclusions

There were 15 veterans in the VA group who had a wait time of > 100 days. Of these, 5 (33%) were initially Choice referrals, but due to negative interactions with the Choice provider, the veterans returned to VALLHCS for care. Two of the 15 (13%) did not keep appointments and were lost to follow up. Six of the 15 (40%) had medical comorbidities that required more immediate attention, so HCV treatment initiation was deliberately moved back. The final 2 veterans scheduled their appointments unusually far apart, artificially increasing their wait time. Given that these were unique situations and some of the veterans received care from both Choice and VA providers, a decision was made to exclude these individuals from the study.

It has been shown that platelet count correlates with degree of liver fibrosis, a concept that is the basis for the Fib-4 scoring system.12 Studies have shown that platelet count is a survival predictor in those with cirrhosis, and thrombocytopenia is a negative predictor of HCV treatment success using peginterferon and ribavirin^13,14 Therefore, the VA memorandum automatically assigned the sickest individuals to the VA for HCV treatment. The goal of this study was to compare the impact of factors other than stage of fibrosis on HCV treatment success, which is why the 12 veterans with platelet count < 100,000 in the VA group were excluded. There were no veterans with platelet count < 100,000 in the Choice group.

When comparing SVR12 rates between the VA and Choice groups, every veteran treated at VALLHCS in FY 2016 was included, increasing the number in the VA group from 100 to 320 and therefore the power of this comparison.

Results

A summary of the statistical analysis can be found in Table 1. The genotype distribution was consistent with epidemiological studies, including those specific to veterans.^15,16 There were statistically significant differences (P < .001) in mean Fib-4 and mean platelet count. The VA group had a higher Fib-4 and lower platelet count. Seventy-four percent of the VA population was defined as cirrhotic, while only 3% of the Choice population met similar criteria (P < .001). The VA and Choice groups were similar in terms of age, gender, and genotype distribution (Table 2).

The VA group was found to have a higher prevalence of comorbidities that affected HCV treatment. These conditions included but were not limited to: chronic kidney disease that precluded the use of certain medications, any condition that required medication with a known interaction with DAAs (ie, proton pump inhibitors, statins, and amiodarone), and cirrhosis if it impacted the treatment regimen. The difference in the prevalence of mental health comorbidities was not significant (P = .39), but there was a higher prevalence of social issues among the VA group (P = .002).

The mean wait time from referral to appointment was 28.6 days for the VA group and 42.3 days for the Choice group (P < .001), indicating that a Choice referral took longer to complete than a referral within the VA for HCV treatment. Thirty of the 71 (42%) veterans seen by a Choice provider accrued extraneous cost, with a mean additional cost of $8,561.40 per veteran. In the Choice group, 61 veterans completed a treatment regimen with the Choice HCP. Fifty-five veterans completed treatment and had available SVR12 data (6 were lost to follow up without SVR12 testing) and 50 (91%) had confirmed SVR12. The charts of the 5 treatment failures were reviewed to discern the cause for failure. Two cases involved early termination of therapy, 3 involved relapse and 2 failed to comply with medication instructions. There was 1 case of the Choice HCP not addressing simultaneous use of ledipasvir and a proton pump inhibitor, potentially causing an interaction, and 1 case where both the VA and Choice providers failed to recognize indicators of cirrhosis, which impacted the regimen used.

In the VALLHCS group, records of 320 veterans who completed treatment and had SVR12 testing were reviewed. While the Choice memorandum was active, veterans selected to be treated at VALLHCS had advanced liver fibrosis or cirrhosis, medical and mental health comorbidities that increased the risk of treatment complications or were considered to have difficulty adhering to the medication regimen. For this group, 296 (93%) had confirmed SVR12. Eighteen of the 24 (75%) treatment failures were complicated by nonadherence, including all 13 cases of early termination. One patient died from complications of decompensated cirrhosis before completing treatment, and 1 did not receive HCV medications during a hospital admission due to poor coordination of care between the VA inpatient and outpatient pharmacy services, leading to multiple missed doses.

The difference in SVR12 rates (ie, treatment failure rates), between the VA and Choice groups was not statistically significant (P = .61). None of the specific reasons for treatment failure had a statistically significant difference between groups. A treatment failure analysis is shown in Table 3, and Table 4 indicates the breakdown of treatment regimens.

Discussion

The Veterans Health Administration (VHA) is the largest integrated health care system in the US, consisting of 152 medical centers and > 1,700 sites of care. The VA has the potential to meet the health care needs of 21.6 million veterans. About 9 million veterans are enrolled in the VA system and 5.9 million received health care through VHA.17 However, every medical service cannot realistically be made available at every facility, and some veterans have difficulty gaining access to VHA care; distance and wait times have been well-publicized issues that need further exploration.^18,19 The Choice program is an attempt to meet gaps in VA coverage using non-VA HCPs.

HCV infection is a specific diagnosis with national treatment guidelines and wellstudied treatments; it can be cured, with an evidence- based definition of cure. The VACO policy memorandum to refer less sick veterans to Choice while treating sicker veterans at the VA provided the opportunity to directly compare the quality of the 2 programs. The SVR12 rates of VALLHCS and Choice providers were comparable to the national average at the time, and while the difference in SVR12 rate was not significant, VALLHCS treated a significantly higher number of patients with cirrhosis because of the referral criteria^.20

The significant difference in medical comorbidities between the VA and Choice groups was not surprising, partly because of the referral criteria. Cirrhosis can impact the treatment regimen, especially in regard to use of ribavirin. Since the presence of mental health comorbidities did not affect selection into the Choice group, it makes sense that there was no significant difference in prevalence between the groups.

VACO allowed veterans with HCV treatment plans that VA HCPs felt were too complicated for the Choice program to be treated by VHA HCPs.⁹ VALLHCS exercised this right for veterans at risk for nonadherence, because in HCV treatment, nonadherence leads to treatment failure and development of drug resistant virus strains. Therefore, veterans who would have difficulty traveling to VALLHCS to pick up medications, those who lacked means of communication (such as those who were homeless), and those who had active substance abuse were treated at the VA, where closer monitoring and immediate access to a wide range of services was possible. Studies have confirmed the impact of these types of issues on HCV treatment adherence and success. ²¹ This explains the higher prevalence of social issues in the VA group.

For an internal referral for HCV treatment at VALLHCS, the hepatology provider submits a consult request to the HCV treatment provider, who works in the same office, making direct communication simple. The main administrative limiting factor to minimizing wait times is the number of HCPs, which is dependent on hiring allowances.

When a veteran is referred to Choice, the VA provider places a consult for non-VA care, which the VA Office of Community Care processes by compiling relevant documents and sending the package to Triwest Healthcare Alliance, a private insurance processor contracted with the VA. Triwest selects the Choice provider, often without any input from the VA, and arranges the veteran’s initial appointment.²² Geographic distance to the veteran’s address is the main selection criteria for Triwest. Documents sent between the Choice and VA HCPs go through the Office of Community Care and Triwest. This significantly increases the potential for delays and failed communication. Triwest had a comprehensive list of providers deemed to be qualified to treat HCV within the geographic catchment of VALLHCS. This list was reviewed, and all veterans referred to Choice had HCPs near their home address; therefore, availability of Choice HCPs was not an issue.

The VA can provide guidance on management of the veteran in the form of bundle packages containing a list of services for which the Choice provider is authorized to provide, and ones the Choice provider is not authorized to provide. Some Choice HCPs ordered tests that were not authorized for HCV treatment such as esophagogastroduodenoscopy, colonoscopy, and liver biopsy. In all, 17 of 71 (24%) veterans seen by Choice HCPs had tests performed or ordered that VA HCPs would not have obtained for the purpose of HCV treatment (Table 5).

In order to prevent veterans from receiving unnecessary tests, a VALLHCS hepatologist asked to be notified by VA administrators overseeing Choice referrals whenever a secondary authorization request (SAR) was submitted by a Choice HCP. This strategy is not standard VA practice, therefore at many VA sites these requested tests would have been performed by the Choice HCP, which is why SARs were factored into cost analysis.

SVR12 test results that were drawn too early and had to be repeated at VALLHCS were a cost unique to the Choice program. Duplicate tests, particularly imaging studies and blood work, were extraneous costs. The largest extraneous costs were treatment regimens prescribed by Choice HCPs that did not follow standard of care and required VA provider intervention. Thirty of the 71 (42%) veterans seen by a Choice provider accrued a mean $8,561.40 in extra costs. As a result, the Choice program cost VHA $250,000 more to provide care for 30 veterans (enough to pay for a physician’s annual salary).

Some inappropriate treatment regimens were the result of Choice HCP error, such as 1 case in which a veteran was inadvertently switched from ledipasvir/sofosbuvir to ombitasvir/ paritaprevir/ritonavir/dasabuvir after week 4. The veteran had to start therapy over but still achieved SVR12. Other cases saw veterans receive regimens for which they had clear contraindications, such as creatinine clearance < 30 mL/min/1.73m2 for sofosbuvir or a positive resistance panel for specific medications. Eleven of 62 (18%) veterans who were started on HCV treatment by a Choice HCP received a regimen not consistent with VA guidelines—an alarming result.

Follow up for veterans referred to Choice was extremely labor intensive, and assessment of personnel requirements in a Choice-based VA system must take this into consideration. The Choice HCP has no obligation to communicate with the VA HCP. At the time of chart review, 57 of 71 (80%) Choice veterans had inadequate documentation to make a confident assessment of the treatment outcome. Multiple calls to the offices of the Choice HCP were needed to acquire records, and veterans had to be tracked down for additional tests. Veterans often would complete treatment and stop following up with the Choice provider before SVR12 confirmation. The VA hepatology provider reviewing Choice referrals served as clinician, case manager, and clerk in order to get veterans to an appropriate end point in their hepatitis C treatment, with mostly unmeasured hours of work.

Limitations

The study population size was limited by the number of veterans able to complete treatment through Choice. The parameters in the VACO policy memos automatically selected the VA and Choice groups but made them clinically distinct populations. New treatment medications were released during the study period, which impacted management strategy. Occasionally, VA and non- VA HCPs preferred different treatment regimens, leading to variation in the distribution of regimens used despite similar genotype distribution (Tables 2 and 4). In addition, a retrospective study is at risk for recall bias. A prospective study randomizing veterans to the Choice and VA groups is an important future endeavor. Comparing veteran satisfaction for Choice and VA services is also crucial.

Conclusions

This study demonstrates that the VA was able to provide more cost-effective and more timely care for HCV treatment to a relatively sicker population with no reduction in treatment success when compared with non-VA HCPs through the Choice program. While the Choice program can help veterans receive services they may otherwise not have access to and reduce travel time, the current system introduces inefficiencies that delay care and decrease cost-effectiveness. The Choice HCP selection process is based on proximity rather than quality, which may place the veteran at risk for receiving substandard care. Large-scale quality of care studies that compare efficiency measures, clinical outcomes, patient demographics, travel distance, cost efficacy and patient satisfaction for veterans receiving similar services at a VA facility and through Choice should be performed to ensure that veterans receive the best care available.

Population studies show high prevalence of chronic hepatitis C virus (HCV) infection among veterans, especially Vietnam War era veterans.^1,2 The development of safe and efficacious direct-acting antiviral (DAA) medications to treat HCV infection made the majority of those infected eligible for treatment. However, the large number of veterans needing DAA treatment stressed the resources of the US Department of Veterans Affairs (VA) health care system. This occurred while Congress was focused on reducing wait times for veterans receiving care at the VA.

Congress passed the Veterans Access, Choice, and Accountability Act on August 7, 2014, leading to the creation of the Veterans Choice Program. Legislators felt there were inappropriate delays in care at the VA, and the Choice program was meant to address this problem and provide an “apples-to-apples comparison [of the VA] with non-VA hospitals.”³

Congress acknowledged the importance of curing HCV in the veteran population and allocated $1.5 billion for fiscal year (FY) 2016 for DAAs. The VA Central Office (VACO) carefully monitored these resources. The first policy memorandum from VACO for HCV care, issued on May 21, 2015, recommended that the sickest patients who will benefit from the treatment “receive priority over those who are less ill.”^4,5 Those who met criteria for advanced liver disease were prioritized for treatment at the VA, while those who did not meet criteria were given the option of receiving treatment through Choice, or waiting for a change in policy.6 Over time, revisions to the guidelines relaxed the criteria for VA treatment eligibility, and on February 24, 2016, all restrictions on HCV treatment at the VA were lifted.^7,8

The aim of this study was to provide a comparison of VA and non-VA care, specifically to determine whether care provided through Choice was timelier and more cost effective than care provided by the VA, and whether there was a quality difference. The high prevalence among veterans, wellestablished standards of care, and finite treatment course with clear indicators of success and failure makes HCV treatment an ideal disease with which to make this comparison.

Methods

We retrospectively analyzed the VA electronic health records of all veterans seen in the VA Loma Linda Healthcare System (VALLHCS) Hepatology clinic for chronic HCV infection during FY 2016 who were referred to Choice for HCV treatment. One hundred veterans met these criteria, encompassing the Choice population; 71 were seen at least once by a non-VA (Choice) health care provider (HCP) and 61 completed a treatment regimen through Choice. Treatment completion was defined as cessation of medication after the planned duration of therapy, or early termination of medication without resumption by that HCP. The Choice population was matched to an equal number of veterans who received HCV treatment from VALLHCS HCPs.

Data collected included age, gender, HCV genotype, determinants of liver fibrosis, and treatment success (defined as sustained virologic response at 12 weeks after the last dose of medication [SVR12]). Determinants of liver fibrosis included documented cirrhosis or complications of cirrhosis, Fibrosis-4 score (Fib-4), and platelet count.

Treatment failures were categorized as nonresponse (defined as detectable HCV viral load at the end of treatment), relapse (defined as an undetectable HCV viral load at the end of treatment with a subsequent positive test), and early termination (defined as a failure to complete the planned treatment regimen). Documented patient nonadherence, medical comorbidities that affected the treatment protocol, mental health diagnoses, and active social issues (defined as active or history of heavy alcohol use, active or history of illicit drug use, lack of social support, and homelessness) were noted.

Timeliness of delivery of care was measured in days. For the VA group, the wait time was defined as the date the consult for HCV treatment was placed to the date of the initial appointment with the HCV treatment provider. For the Choice group, the wait time was defined as the date the referral to the Choice program was made to the date of the initial appointment with the Choice HCP. Treatment regimens were evaluated for appropriateness based on guidelines from VACO and the American Association for the Study of Liver Diseases.^9-11

Tests performed by Choice providers were evaluated for whether they were relevant to HCV care and whether similar data already were available from VALLHCS. Tests that were not indicated were identified as unnecessary costs incurred by the Choice program, as were tests that had to be repeated at the VA because of a lack of documentation from the Choice provider. All medications given inappropriately were considered added costs. Medicare reimbursement rates for the most applicable Current Procedural Terminology (CPT) code and VA national contract pricing for medications were used for calculations. This study was approved by the VALLHCS institutional review board.

Statistical Analysis

IBM (Armonk, NY) Statistical Package for Social Sciences software was used to evaluate for differences in Fib-4, platelet count, prevalence of cirrhosis, prevalence of medical comorbidities, prevalence of mental health comorbidities, prevalence of the social issues defined in the Methods section, time from referral to time of appointment date, and SVR12 rate between the VA and Choice groups.

Exclusions

There were 15 veterans in the VA group who had a wait time of > 100 days. Of these, 5 (33%) were initially Choice referrals, but due to negative interactions with the Choice provider, the veterans returned to VALLHCS for care. Two of the 15 (13%) did not keep appointments and were lost to follow up. Six of the 15 (40%) had medical comorbidities that required more immediate attention, so HCV treatment initiation was deliberately moved back. The final 2 veterans scheduled their appointments unusually far apart, artificially increasing their wait time. Given that these were unique situations and some of the veterans received care from both Choice and VA providers, a decision was made to exclude these individuals from the study.

It has been shown that platelet count correlates with degree of liver fibrosis, a concept that is the basis for the Fib-4 scoring system.12 Studies have shown that platelet count is a survival predictor in those with cirrhosis, and thrombocytopenia is a negative predictor of HCV treatment success using peginterferon and ribavirin^13,14 Therefore, the VA memorandum automatically assigned the sickest individuals to the VA for HCV treatment. The goal of this study was to compare the impact of factors other than stage of fibrosis on HCV treatment success, which is why the 12 veterans with platelet count < 100,000 in the VA group were excluded. There were no veterans with platelet count < 100,000 in the Choice group.

When comparing SVR12 rates between the VA and Choice groups, every veteran treated at VALLHCS in FY 2016 was included, increasing the number in the VA group from 100 to 320 and therefore the power of this comparison.

Results

A summary of the statistical analysis can be found in Table 1. The genotype distribution was consistent with epidemiological studies, including those specific to veterans.^15,16 There were statistically significant differences (P < .001) in mean Fib-4 and mean platelet count. The VA group had a higher Fib-4 and lower platelet count. Seventy-four percent of the VA population was defined as cirrhotic, while only 3% of the Choice population met similar criteria (P < .001). The VA and Choice groups were similar in terms of age, gender, and genotype distribution (Table 2).

The VA group was found to have a higher prevalence of comorbidities that affected HCV treatment. These conditions included but were not limited to: chronic kidney disease that precluded the use of certain medications, any condition that required medication with a known interaction with DAAs (ie, proton pump inhibitors, statins, and amiodarone), and cirrhosis if it impacted the treatment regimen. The difference in the prevalence of mental health comorbidities was not significant (P = .39), but there was a higher prevalence of social issues among the VA group (P = .002).

The mean wait time from referral to appointment was 28.6 days for the VA group and 42.3 days for the Choice group (P < .001), indicating that a Choice referral took longer to complete than a referral within the VA for HCV treatment. Thirty of the 71 (42%) veterans seen by a Choice provider accrued extraneous cost, with a mean additional cost of $8,561.40 per veteran. In the Choice group, 61 veterans completed a treatment regimen with the Choice HCP. Fifty-five veterans completed treatment and had available SVR12 data (6 were lost to follow up without SVR12 testing) and 50 (91%) had confirmed SVR12. The charts of the 5 treatment failures were reviewed to discern the cause for failure. Two cases involved early termination of therapy, 3 involved relapse and 2 failed to comply with medication instructions. There was 1 case of the Choice HCP not addressing simultaneous use of ledipasvir and a proton pump inhibitor, potentially causing an interaction, and 1 case where both the VA and Choice providers failed to recognize indicators of cirrhosis, which impacted the regimen used.

In the VALLHCS group, records of 320 veterans who completed treatment and had SVR12 testing were reviewed. While the Choice memorandum was active, veterans selected to be treated at VALLHCS had advanced liver fibrosis or cirrhosis, medical and mental health comorbidities that increased the risk of treatment complications or were considered to have difficulty adhering to the medication regimen. For this group, 296 (93%) had confirmed SVR12. Eighteen of the 24 (75%) treatment failures were complicated by nonadherence, including all 13 cases of early termination. One patient died from complications of decompensated cirrhosis before completing treatment, and 1 did not receive HCV medications during a hospital admission due to poor coordination of care between the VA inpatient and outpatient pharmacy services, leading to multiple missed doses.

The difference in SVR12 rates (ie, treatment failure rates), between the VA and Choice groups was not statistically significant (P = .61). None of the specific reasons for treatment failure had a statistically significant difference between groups. A treatment failure analysis is shown in Table 3, and Table 4 indicates the breakdown of treatment regimens.

Discussion

The Veterans Health Administration (VHA) is the largest integrated health care system in the US, consisting of 152 medical centers and > 1,700 sites of care. The VA has the potential to meet the health care needs of 21.6 million veterans. About 9 million veterans are enrolled in the VA system and 5.9 million received health care through VHA.17 However, every medical service cannot realistically be made available at every facility, and some veterans have difficulty gaining access to VHA care; distance and wait times have been well-publicized issues that need further exploration.^18,19 The Choice program is an attempt to meet gaps in VA coverage using non-VA HCPs.

HCV infection is a specific diagnosis with national treatment guidelines and wellstudied treatments; it can be cured, with an evidence- based definition of cure. The VACO policy memorandum to refer less sick veterans to Choice while treating sicker veterans at the VA provided the opportunity to directly compare the quality of the 2 programs. The SVR12 rates of VALLHCS and Choice providers were comparable to the national average at the time, and while the difference in SVR12 rate was not significant, VALLHCS treated a significantly higher number of patients with cirrhosis because of the referral criteria^.20

The significant difference in medical comorbidities between the VA and Choice groups was not surprising, partly because of the referral criteria. Cirrhosis can impact the treatment regimen, especially in regard to use of ribavirin. Since the presence of mental health comorbidities did not affect selection into the Choice group, it makes sense that there was no significant difference in prevalence between the groups.

VACO allowed veterans with HCV treatment plans that VA HCPs felt were too complicated for the Choice program to be treated by VHA HCPs.⁹ VALLHCS exercised this right for veterans at risk for nonadherence, because in HCV treatment, nonadherence leads to treatment failure and development of drug resistant virus strains. Therefore, veterans who would have difficulty traveling to VALLHCS to pick up medications, those who lacked means of communication (such as those who were homeless), and those who had active substance abuse were treated at the VA, where closer monitoring and immediate access to a wide range of services was possible. Studies have confirmed the impact of these types of issues on HCV treatment adherence and success. ²¹ This explains the higher prevalence of social issues in the VA group.

For an internal referral for HCV treatment at VALLHCS, the hepatology provider submits a consult request to the HCV treatment provider, who works in the same office, making direct communication simple. The main administrative limiting factor to minimizing wait times is the number of HCPs, which is dependent on hiring allowances.

When a veteran is referred to Choice, the VA provider places a consult for non-VA care, which the VA Office of Community Care processes by compiling relevant documents and sending the package to Triwest Healthcare Alliance, a private insurance processor contracted with the VA. Triwest selects the Choice provider, often without any input from the VA, and arranges the veteran’s initial appointment.²² Geographic distance to the veteran’s address is the main selection criteria for Triwest. Documents sent between the Choice and VA HCPs go through the Office of Community Care and Triwest. This significantly increases the potential for delays and failed communication. Triwest had a comprehensive list of providers deemed to be qualified to treat HCV within the geographic catchment of VALLHCS. This list was reviewed, and all veterans referred to Choice had HCPs near their home address; therefore, availability of Choice HCPs was not an issue.

The VA can provide guidance on management of the veteran in the form of bundle packages containing a list of services for which the Choice provider is authorized to provide, and ones the Choice provider is not authorized to provide. Some Choice HCPs ordered tests that were not authorized for HCV treatment such as esophagogastroduodenoscopy, colonoscopy, and liver biopsy. In all, 17 of 71 (24%) veterans seen by Choice HCPs had tests performed or ordered that VA HCPs would not have obtained for the purpose of HCV treatment (Table 5).

In order to prevent veterans from receiving unnecessary tests, a VALLHCS hepatologist asked to be notified by VA administrators overseeing Choice referrals whenever a secondary authorization request (SAR) was submitted by a Choice HCP. This strategy is not standard VA practice, therefore at many VA sites these requested tests would have been performed by the Choice HCP, which is why SARs were factored into cost analysis.

SVR12 test results that were drawn too early and had to be repeated at VALLHCS were a cost unique to the Choice program. Duplicate tests, particularly imaging studies and blood work, were extraneous costs. The largest extraneous costs were treatment regimens prescribed by Choice HCPs that did not follow standard of care and required VA provider intervention. Thirty of the 71 (42%) veterans seen by a Choice provider accrued a mean $8,561.40 in extra costs. As a result, the Choice program cost VHA $250,000 more to provide care for 30 veterans (enough to pay for a physician’s annual salary).

Some inappropriate treatment regimens were the result of Choice HCP error, such as 1 case in which a veteran was inadvertently switched from ledipasvir/sofosbuvir to ombitasvir/ paritaprevir/ritonavir/dasabuvir after week 4. The veteran had to start therapy over but still achieved SVR12. Other cases saw veterans receive regimens for which they had clear contraindications, such as creatinine clearance < 30 mL/min/1.73m2 for sofosbuvir or a positive resistance panel for specific medications. Eleven of 62 (18%) veterans who were started on HCV treatment by a Choice HCP received a regimen not consistent with VA guidelines—an alarming result.

Follow up for veterans referred to Choice was extremely labor intensive, and assessment of personnel requirements in a Choice-based VA system must take this into consideration. The Choice HCP has no obligation to communicate with the VA HCP. At the time of chart review, 57 of 71 (80%) Choice veterans had inadequate documentation to make a confident assessment of the treatment outcome. Multiple calls to the offices of the Choice HCP were needed to acquire records, and veterans had to be tracked down for additional tests. Veterans often would complete treatment and stop following up with the Choice provider before SVR12 confirmation. The VA hepatology provider reviewing Choice referrals served as clinician, case manager, and clerk in order to get veterans to an appropriate end point in their hepatitis C treatment, with mostly unmeasured hours of work.

Limitations

The study population size was limited by the number of veterans able to complete treatment through Choice. The parameters in the VACO policy memos automatically selected the VA and Choice groups but made them clinically distinct populations. New treatment medications were released during the study period, which impacted management strategy. Occasionally, VA and non- VA HCPs preferred different treatment regimens, leading to variation in the distribution of regimens used despite similar genotype distribution (Tables 2 and 4). In addition, a retrospective study is at risk for recall bias. A prospective study randomizing veterans to the Choice and VA groups is an important future endeavor. Comparing veteran satisfaction for Choice and VA services is also crucial.

Conclusions

This study demonstrates that the VA was able to provide more cost-effective and more timely care for HCV treatment to a relatively sicker population with no reduction in treatment success when compared with non-VA HCPs through the Choice program. While the Choice program can help veterans receive services they may otherwise not have access to and reduce travel time, the current system introduces inefficiencies that delay care and decrease cost-effectiveness. The Choice HCP selection process is based on proximity rather than quality, which may place the veteran at risk for receiving substandard care. Large-scale quality of care studies that compare efficiency measures, clinical outcomes, patient demographics, travel distance, cost efficacy and patient satisfaction for veterans receiving similar services at a VA facility and through Choice should be performed to ensure that veterans receive the best care available.

Population studies show high prevalence of chronic hepatitis C virus (HCV) infection among veterans, especially Vietnam War era veterans.^1,2 The development of safe and efficacious direct-acting antiviral (DAA) medications to treat HCV infection made the majority of those infected eligible for treatment. However, the large number of veterans needing DAA treatment stressed the resources of the US Department of Veterans Affairs (VA) health care system. This occurred while Congress was focused on reducing wait times for veterans receiving care at the VA.

Congress passed the Veterans Access, Choice, and Accountability Act on August 7, 2014, leading to the creation of the Veterans Choice Program. Legislators felt there were inappropriate delays in care at the VA, and the Choice program was meant to address this problem and provide an “apples-to-apples comparison [of the VA] with non-VA hospitals.”³

Congress acknowledged the importance of curing HCV in the veteran population and allocated $1.5 billion for fiscal year (FY) 2016 for DAAs. The VA Central Office (VACO) carefully monitored these resources. The first policy memorandum from VACO for HCV care, issued on May 21, 2015, recommended that the sickest patients who will benefit from the treatment “receive priority over those who are less ill.”^4,5 Those who met criteria for advanced liver disease were prioritized for treatment at the VA, while those who did not meet criteria were given the option of receiving treatment through Choice, or waiting for a change in policy.6 Over time, revisions to the guidelines relaxed the criteria for VA treatment eligibility, and on February 24, 2016, all restrictions on HCV treatment at the VA were lifted.^7,8

The aim of this study was to provide a comparison of VA and non-VA care, specifically to determine whether care provided through Choice was timelier and more cost effective than care provided by the VA, and whether there was a quality difference. The high prevalence among veterans, wellestablished standards of care, and finite treatment course with clear indicators of success and failure makes HCV treatment an ideal disease with which to make this comparison.

Methods

We retrospectively analyzed the VA electronic health records of all veterans seen in the VA Loma Linda Healthcare System (VALLHCS) Hepatology clinic for chronic HCV infection during FY 2016 who were referred to Choice for HCV treatment. One hundred veterans met these criteria, encompassing the Choice population; 71 were seen at least once by a non-VA (Choice) health care provider (HCP) and 61 completed a treatment regimen through Choice. Treatment completion was defined as cessation of medication after the planned duration of therapy, or early termination of medication without resumption by that HCP. The Choice population was matched to an equal number of veterans who received HCV treatment from VALLHCS HCPs.

Data collected included age, gender, HCV genotype, determinants of liver fibrosis, and treatment success (defined as sustained virologic response at 12 weeks after the last dose of medication [SVR12]). Determinants of liver fibrosis included documented cirrhosis or complications of cirrhosis, Fibrosis-4 score (Fib-4), and platelet count.

Treatment failures were categorized as nonresponse (defined as detectable HCV viral load at the end of treatment), relapse (defined as an undetectable HCV viral load at the end of treatment with a subsequent positive test), and early termination (defined as a failure to complete the planned treatment regimen). Documented patient nonadherence, medical comorbidities that affected the treatment protocol, mental health diagnoses, and active social issues (defined as active or history of heavy alcohol use, active or history of illicit drug use, lack of social support, and homelessness) were noted.

Timeliness of delivery of care was measured in days. For the VA group, the wait time was defined as the date the consult for HCV treatment was placed to the date of the initial appointment with the HCV treatment provider. For the Choice group, the wait time was defined as the date the referral to the Choice program was made to the date of the initial appointment with the Choice HCP. Treatment regimens were evaluated for appropriateness based on guidelines from VACO and the American Association for the Study of Liver Diseases.^9-11

Tests performed by Choice providers were evaluated for whether they were relevant to HCV care and whether similar data already were available from VALLHCS. Tests that were not indicated were identified as unnecessary costs incurred by the Choice program, as were tests that had to be repeated at the VA because of a lack of documentation from the Choice provider. All medications given inappropriately were considered added costs. Medicare reimbursement rates for the most applicable Current Procedural Terminology (CPT) code and VA national contract pricing for medications were used for calculations. This study was approved by the VALLHCS institutional review board.

Statistical Analysis

IBM (Armonk, NY) Statistical Package for Social Sciences software was used to evaluate for differences in Fib-4, platelet count, prevalence of cirrhosis, prevalence of medical comorbidities, prevalence of mental health comorbidities, prevalence of the social issues defined in the Methods section, time from referral to time of appointment date, and SVR12 rate between the VA and Choice groups.

Exclusions

There were 15 veterans in the VA group who had a wait time of > 100 days. Of these, 5 (33%) were initially Choice referrals, but due to negative interactions with the Choice provider, the veterans returned to VALLHCS for care. Two of the 15 (13%) did not keep appointments and were lost to follow up. Six of the 15 (40%) had medical comorbidities that required more immediate attention, so HCV treatment initiation was deliberately moved back. The final 2 veterans scheduled their appointments unusually far apart, artificially increasing their wait time. Given that these were unique situations and some of the veterans received care from both Choice and VA providers, a decision was made to exclude these individuals from the study.

It has been shown that platelet count correlates with degree of liver fibrosis, a concept that is the basis for the Fib-4 scoring system.12 Studies have shown that platelet count is a survival predictor in those with cirrhosis, and thrombocytopenia is a negative predictor of HCV treatment success using peginterferon and ribavirin^13,14 Therefore, the VA memorandum automatically assigned the sickest individuals to the VA for HCV treatment. The goal of this study was to compare the impact of factors other than stage of fibrosis on HCV treatment success, which is why the 12 veterans with platelet count < 100,000 in the VA group were excluded. There were no veterans with platelet count < 100,000 in the Choice group.

When comparing SVR12 rates between the VA and Choice groups, every veteran treated at VALLHCS in FY 2016 was included, increasing the number in the VA group from 100 to 320 and therefore the power of this comparison.

Results

A summary of the statistical analysis can be found in Table 1. The genotype distribution was consistent with epidemiological studies, including those specific to veterans.^15,16 There were statistically significant differences (P < .001) in mean Fib-4 and mean platelet count. The VA group had a higher Fib-4 and lower platelet count. Seventy-four percent of the VA population was defined as cirrhotic, while only 3% of the Choice population met similar criteria (P < .001). The VA and Choice groups were similar in terms of age, gender, and genotype distribution (Table 2).

The VA group was found to have a higher prevalence of comorbidities that affected HCV treatment. These conditions included but were not limited to: chronic kidney disease that precluded the use of certain medications, any condition that required medication with a known interaction with DAAs (ie, proton pump inhibitors, statins, and amiodarone), and cirrhosis if it impacted the treatment regimen. The difference in the prevalence of mental health comorbidities was not significant (P = .39), but there was a higher prevalence of social issues among the VA group (P = .002).

The mean wait time from referral to appointment was 28.6 days for the VA group and 42.3 days for the Choice group (P < .001), indicating that a Choice referral took longer to complete than a referral within the VA for HCV treatment. Thirty of the 71 (42%) veterans seen by a Choice provider accrued extraneous cost, with a mean additional cost of $8,561.40 per veteran. In the Choice group, 61 veterans completed a treatment regimen with the Choice HCP. Fifty-five veterans completed treatment and had available SVR12 data (6 were lost to follow up without SVR12 testing) and 50 (91%) had confirmed SVR12. The charts of the 5 treatment failures were reviewed to discern the cause for failure. Two cases involved early termination of therapy, 3 involved relapse and 2 failed to comply with medication instructions. There was 1 case of the Choice HCP not addressing simultaneous use of ledipasvir and a proton pump inhibitor, potentially causing an interaction, and 1 case where both the VA and Choice providers failed to recognize indicators of cirrhosis, which impacted the regimen used.

In the VALLHCS group, records of 320 veterans who completed treatment and had SVR12 testing were reviewed. While the Choice memorandum was active, veterans selected to be treated at VALLHCS had advanced liver fibrosis or cirrhosis, medical and mental health comorbidities that increased the risk of treatment complications or were considered to have difficulty adhering to the medication regimen. For this group, 296 (93%) had confirmed SVR12. Eighteen of the 24 (75%) treatment failures were complicated by nonadherence, including all 13 cases of early termination. One patient died from complications of decompensated cirrhosis before completing treatment, and 1 did not receive HCV medications during a hospital admission due to poor coordination of care between the VA inpatient and outpatient pharmacy services, leading to multiple missed doses.

The difference in SVR12 rates (ie, treatment failure rates), between the VA and Choice groups was not statistically significant (P = .61). None of the specific reasons for treatment failure had a statistically significant difference between groups. A treatment failure analysis is shown in Table 3, and Table 4 indicates the breakdown of treatment regimens.

Discussion

The Veterans Health Administration (VHA) is the largest integrated health care system in the US, consisting of 152 medical centers and > 1,700 sites of care. The VA has the potential to meet the health care needs of 21.6 million veterans. About 9 million veterans are enrolled in the VA system and 5.9 million received health care through VHA.17 However, every medical service cannot realistically be made available at every facility, and some veterans have difficulty gaining access to VHA care; distance and wait times have been well-publicized issues that need further exploration.^18,19 The Choice program is an attempt to meet gaps in VA coverage using non-VA HCPs.

HCV infection is a specific diagnosis with national treatment guidelines and wellstudied treatments; it can be cured, with an evidence- based definition of cure. The VACO policy memorandum to refer less sick veterans to Choice while treating sicker veterans at the VA provided the opportunity to directly compare the quality of the 2 programs. The SVR12 rates of VALLHCS and Choice providers were comparable to the national average at the time, and while the difference in SVR12 rate was not significant, VALLHCS treated a significantly higher number of patients with cirrhosis because of the referral criteria^.20

The significant difference in medical comorbidities between the VA and Choice groups was not surprising, partly because of the referral criteria. Cirrhosis can impact the treatment regimen, especially in regard to use of ribavirin. Since the presence of mental health comorbidities did not affect selection into the Choice group, it makes sense that there was no significant difference in prevalence between the groups.

VACO allowed veterans with HCV treatment plans that VA HCPs felt were too complicated for the Choice program to be treated by VHA HCPs.⁹ VALLHCS exercised this right for veterans at risk for nonadherence, because in HCV treatment, nonadherence leads to treatment failure and development of drug resistant virus strains. Therefore, veterans who would have difficulty traveling to VALLHCS to pick up medications, those who lacked means of communication (such as those who were homeless), and those who had active substance abuse were treated at the VA, where closer monitoring and immediate access to a wide range of services was possible. Studies have confirmed the impact of these types of issues on HCV treatment adherence and success. ²¹ This explains the higher prevalence of social issues in the VA group.

For an internal referral for HCV treatment at VALLHCS, the hepatology provider submits a consult request to the HCV treatment provider, who works in the same office, making direct communication simple. The main administrative limiting factor to minimizing wait times is the number of HCPs, which is dependent on hiring allowances.

When a veteran is referred to Choice, the VA provider places a consult for non-VA care, which the VA Office of Community Care processes by compiling relevant documents and sending the package to Triwest Healthcare Alliance, a private insurance processor contracted with the VA. Triwest selects the Choice provider, often without any input from the VA, and arranges the veteran’s initial appointment.²² Geographic distance to the veteran’s address is the main selection criteria for Triwest. Documents sent between the Choice and VA HCPs go through the Office of Community Care and Triwest. This significantly increases the potential for delays and failed communication. Triwest had a comprehensive list of providers deemed to be qualified to treat HCV within the geographic catchment of VALLHCS. This list was reviewed, and all veterans referred to Choice had HCPs near their home address; therefore, availability of Choice HCPs was not an issue.

The VA can provide guidance on management of the veteran in the form of bundle packages containing a list of services for which the Choice provider is authorized to provide, and ones the Choice provider is not authorized to provide. Some Choice HCPs ordered tests that were not authorized for HCV treatment such as esophagogastroduodenoscopy, colonoscopy, and liver biopsy. In all, 17 of 71 (24%) veterans seen by Choice HCPs had tests performed or ordered that VA HCPs would not have obtained for the purpose of HCV treatment (Table 5).

In order to prevent veterans from receiving unnecessary tests, a VALLHCS hepatologist asked to be notified by VA administrators overseeing Choice referrals whenever a secondary authorization request (SAR) was submitted by a Choice HCP. This strategy is not standard VA practice, therefore at many VA sites these requested tests would have been performed by the Choice HCP, which is why SARs were factored into cost analysis.

SVR12 test results that were drawn too early and had to be repeated at VALLHCS were a cost unique to the Choice program. Duplicate tests, particularly imaging studies and blood work, were extraneous costs. The largest extraneous costs were treatment regimens prescribed by Choice HCPs that did not follow standard of care and required VA provider intervention. Thirty of the 71 (42%) veterans seen by a Choice provider accrued a mean $8,561.40 in extra costs. As a result, the Choice program cost VHA $250,000 more to provide care for 30 veterans (enough to pay for a physician’s annual salary).

Some inappropriate treatment regimens were the result of Choice HCP error, such as 1 case in which a veteran was inadvertently switched from ledipasvir/sofosbuvir to ombitasvir/ paritaprevir/ritonavir/dasabuvir after week 4. The veteran had to start therapy over but still achieved SVR12. Other cases saw veterans receive regimens for which they had clear contraindications, such as creatinine clearance < 30 mL/min/1.73m2 for sofosbuvir or a positive resistance panel for specific medications. Eleven of 62 (18%) veterans who were started on HCV treatment by a Choice HCP received a regimen not consistent with VA guidelines—an alarming result.

Follow up for veterans referred to Choice was extremely labor intensive, and assessment of personnel requirements in a Choice-based VA system must take this into consideration. The Choice HCP has no obligation to communicate with the VA HCP. At the time of chart review, 57 of 71 (80%) Choice veterans had inadequate documentation to make a confident assessment of the treatment outcome. Multiple calls to the offices of the Choice HCP were needed to acquire records, and veterans had to be tracked down for additional tests. Veterans often would complete treatment and stop following up with the Choice provider before SVR12 confirmation. The VA hepatology provider reviewing Choice referrals served as clinician, case manager, and clerk in order to get veterans to an appropriate end point in their hepatitis C treatment, with mostly unmeasured hours of work.

Limitations

The study population size was limited by the number of veterans able to complete treatment through Choice. The parameters in the VACO policy memos automatically selected the VA and Choice groups but made them clinically distinct populations. New treatment medications were released during the study period, which impacted management strategy. Occasionally, VA and non- VA HCPs preferred different treatment regimens, leading to variation in the distribution of regimens used despite similar genotype distribution (Tables 2 and 4). In addition, a retrospective study is at risk for recall bias. A prospective study randomizing veterans to the Choice and VA groups is an important future endeavor. Comparing veteran satisfaction for Choice and VA services is also crucial.

Conclusions

This study demonstrates that the VA was able to provide more cost-effective and more timely care for HCV treatment to a relatively sicker population with no reduction in treatment success when compared with non-VA HCPs through the Choice program. While the Choice program can help veterans receive services they may otherwise not have access to and reduce travel time, the current system introduces inefficiencies that delay care and decrease cost-effectiveness. The Choice HCP selection process is based on proximity rather than quality, which may place the veteran at risk for receiving substandard care. Large-scale quality of care studies that compare efficiency measures, clinical outcomes, patient demographics, travel distance, cost efficacy and patient satisfaction for veterans receiving similar services at a VA facility and through Choice should be performed to ensure that veterans receive the best care available.

What have you been doing since you left the US Public Health Service?

RADM Boris D. Lushniak, MD, MPH. I retired in 2015 and spent a year at the Uniformed Services University for the Health Sciences in Bethesda, Maryland as the Chair of Preventive Medicine and Biostatistics before I took the opportunity to become the Dean of the School of Public Health at the University of Maryland in College Park. I was very intrigued with that position. It’s a large and young school of public health—just 13 years since its inception. And it functions at both the undergraduate and graduate school levels. We have 2,400 undergraduates in 4 different degree paths. The intriguing part of this is the ability to influence a young person’s educational pathway, and for them to look at all the opportunities in public health, and to focus on a mission, which falls into the mission of the US Public Health Service (PHS) Commissioned Corps: Protect, promote and advance the health and safety of our nation.

It has been a very intriguing transition; I have been the Dean there for 3 years. Who would have predicted that things would change drastically in that time, both at the academic level (ie, moving a school from being a normal college environment to an online environment) and now moving into the realm of preparing for the near future of that university in terms of a potential reopening. It is using all of my public health experiences and putting it at that culmination point, which is my community of 52,000 people—40,000 students at the University in College Park, and 12,000 faculty and staff members.

We are responsible for making sure that the return is as safe as possible. With so many unknowns in the world of COVID-19 and so many unpredictable components, it is quite an undertaking to be able to determine for that community of 52,000 whether it’s time to return, and under what circumstances do we return.

In addition, we’re part of a larger community. The University of Maryland in College Park is in Prince George’s County, which is the epicenter of disease and death in Maryland. The School of Public Health is working closely with county authorities. Some of our students are now contact tracers. It’s been interesting to see our faculty, staff, and students standing up as a volunteer support structure for Public Health.

We have incredible research going on at the school. One of my prime research physicians, Don Milton, MD, DrPH, has been studying the transmission of influenza. Now his work is priming on not just influenza, but also COVID-19. Our hope is to establish a community that will be safe and healthy for everyone, and so it’s been an incredible amount of work.

How would you describe the federal/ local public health cooperation?

RADM Lushniak. First and foremost, we have seen a major issue in terms of state and local response to the COVID-19 pandemic. I have to congratulate the state and the local officials for doing as best as they can under the strained circumstances that they’re in.

The first strained circumstance is that local and state health departments have lost nearly a quarter of their workforce: 50,000 jobs across the country since the recession of 2008. Part of the answer why it’s been such a struggle is that our nation as a whole hasn’t looked at public health and hasn’t looked at prevention as a key component of how our country works. We have seen a lack of support at the state and the local level, the shedding of jobs, and the lack of foresight in terms of saying that prevention works and public health is important for our cities, states, regions, and the nation. We need to reemphasize that in terms of public health.

In the State of Maryland, in general, the counties are doing as best as they can under the circumstances. They certainly started out with trying to do as much testing as possible. Testing is a critical component to this response, and obviously, we have a situation nationwide with the testing still trying to be put online to the extent that it needs to be. We need to be able to test more and more individuals to be able to determine the people who are positive. The curve ball that COVID-19 threw us is that 25 to 50% of individuals who may have a positive test may be asymptomatic. So, this isn’t simple. It’s not a matter of just saying, “Okay, you’re sick. You may then have it.” It may be: “Hey, you’re feeling healthy, you still may have it.”

But just as important as testing is what you do with those individuals who are tested. You need to have health departments turning to these individuals and providing them directions of what needs to be done. If one is COVID-19-positive, one goes into isolation for at least 14 days. And if ill, they need to be connected with a medical care system. That’s an important part of the state and local response is making sure the individuals are properly directed to the right pathway.

In addition, contact tracing is critical. The way we’re going to fight COVID-19 is the ability for us to go out there and determine if you are a positive, who did you come in contact with, and did you potentially spread this to others? You need to direct individuals who may have been in contact with the person who is now COVID- 19-positive, saying “You may have to quarantine yourself, watch out for symptoms, and you have to be really careful in the meantime.”

State and local officials took up the burden of making decisions in terms of communicating the directions given to the population. Is stay at home required? Is it the closure of businesses? Is it the wearing of masks? Certainly, the issue of physical distancing plays a role.

All that was implemented at the state and local level. Under the circumstances, it has been done as well as possible, but that now reflects on the issue of the federal response. And the federal response, I’ll admit, has been less than I had hoped for on several realms.

Number one, coordination and direction from the federal level has been rather piecemeal. State and local officials, I think, were waiting for further directions. What did federal officials think; what did they want us to do? State and local officials want independence to implement things, but what’s the right answer? I think this has been not handled well at the highest levels of the US government.

Secondly, obviously, there was an issue with testing, and the responsibility here lays with the Centers of Disease Control and Prevention (CDC), which had problems from the get-go with setting up their testing caches and getting them out. We’re still catching up from there. Now it’s unfolding that the tie in between the federal government and the private sector and academic centers are at least making some headway on that testing front.

Third, people rely on the federal officials not only for action but also for communication. It really boils down to: Who’s in charge, who’s telling me the information that I need to know, who’s honest with me and telling me what they don’t know, and who has the insight to say, “Here’s how we’re going to find out the things that we don’t know?” Who’s there empathizing with the population?

The reality is there’s been a mismatch between the communication channels for the federal government and getting down not just to the state and locals but, also, to the general population in this country.

How would you characterize the US Public Health Service Response?

RADM Lushniak. I’ll first start off with kudos and congratulations to the Commissioned Corps of the PHS for their response to date. I think the latest numbers that ADM Brett Giroir, MD, Assistant Secretary of Health, told Congress in May, was that at the time more than 3,100 of the 6,100 current officers at the PHS have been deployed over the last several months. The reality is that the Commissioned Corps is out there doing service to our nation and to the world. PHS teams were deployed initially to Japan and the Diamond Princess cruise ship. The Corps been out there internationally.

Nationally, the Corps was at the Javits Center in New York assisting in setting up that medical response. They have been assisting at the military bases initially where some of the individuals who were coming in from China and other places were being held in quarantine. They have been assisting with investigations at nursing homes across the country and meat packing plants where there have been outbreaks occurring. The Commissioned Corps has been out there, so that’s the good news.

The bad news is that the Corps is a small uniformed service. The reality is nobody still is seeing the Corps or knows about the Corps as they’re out there doing their thing. It was very nice that ADM Giroir put a plug in for them in his recent congressional testimony. That’s great that our leadership is out there acknowledging the Corps. But to a large extent, I still have an issue with the Commissioned Corps being an underfunded uniformed service of this country. The Commissioned Corps is the only uniformed service in the world whose only mission is public health. But, lack of support reflects the idea of the lack of importance that public health plays in the minds of policy makers.

To a large extent, we have had no dollars in the Corps recently for training of officers to prepare for this. For 10 years we’ve waited for a Ready Reserve to be set up. The Ready Reserve component was part of the Affordable Care Act. I was in the office of the Surgeon General as we were told to ramp this up. Now 10 years later, in the midst of this COVID-19 pandemic, Congress finally has passed legislation that sets a pathway for a Ready Reserve.

Why is the Ready Reserve important? In essence, we have incredible public health professionals out there in the civilian ranks who would be willing to assist the Commissioned Corps in their mission, either to backfill critical positions where Corps officers are currently stationed and need to be deployed, or as a Ready Reserve that’s ready to deploy itself. All this is happening right now. I hope for better days, and I hope this COVID-19 pandemic will wake our nation up to the need of a Public Health Service Commissioned Corps, a uniformed service, that's out there doing good.

What lessons are we learning about public health in this pandemic?

RADM Lushniak. We’ve just developed a new space force, the 8th uniformed US service. In reality they are talking about tens of thousands of people assigned to it. Excuse me if I’m going to be assertive. I’m a big fan of space exploration. I realize that space is the final frontier and that perhaps we have to be able to defend our country in that regard. But we’re already saying that space is worth investing in. Where is the wisdom that we’re not investing in battling on this planet against emerging threats like COVID-19? And why is it that to this date the Commissioned Corps of the Public Health Service does not have its own budget; does not have a line item anywhere; does not have money directed for training; and, in essence, only serves because its officers are stationed at other agencies who pay for these officers? It’s a personnel system and not really treated as a key and critical uniformed service of this country. That’s point number one in terms of lessons learned and what needs to be done.

In addition, it’s not just the people in uniform who serve at the federal level, civilians serve as well. These civilians work at the CDC, at the US Food and Drug Administration, at the National Institute of Health, at the Indian Health Service, and at many, many other agencies throughout the US government. Within those realms, we need to show support of those federal practitioners who are working very diligently and in a devoted fashion to fight this pandemic as well. Part of it is the moral support to recognize that there are multiple fronts to fighting this pandemic and the federal practitioner who is working out there, is a key component to this.

I don’t want everything to be money, money, money, but the fact is that CDC’s budget has been decreasing over the years. How are we supposed to set up the laboratories, how are we supposed to demand the high level of expertise when, in fact, everything has to be done on a shoestring?

Finally, we notice public health in the midst of a crisis, but public health matters each and every day. The idea that the pandemic certainly brings to light what needs to get done, but without a pandemic, what do we have? We still have cigarette smoking, the number 1 killer in this country. That’s a public health issue. We have cardiovascular diseases as an extreme killer in this country. That’s a public health issue. We have diabetes mellitus that is rampant. We have substance abuse, including the opioid epidemic. Those are public health issues. We have hypertension, we have overweight and obesity. Those are all public health issues that public health battles each and every day without the recognition.

What we need is a major shift in the philosophy of this country to really take the health and wellness of our society as a key component of how you’ll raise that on to a pedestal—the idea that health and wellness is critical to the functioning of this country.

How have recent public health emergencies influenced the Commissioned Corps?

RADM Lushniak. The key feature is that the Public Health Service Commissioned Corps has been growing in its mission over the years. The pre-9/11 Commissioned Corps, was a different life. The post-9/11 world is the first time that the Commissioned Corps really fell into this idea of being America’s public health responders. I think that we ramped it up; we started out strong.

This was shown not only in the World Trade Center and the 9/11 disasters that occurred, but in the anthrax scenario that unfolded shortly afterwards. We saw it further continue in Hurricane Katrina and the multiple hurricane responses.

Then the Ebola response, in my last year of serving in uniform, was another action of both the civilian sector of federal responders as well as the uniformed sector. The beauty of that in terms of what we learned from Ebola was that coordination is key. That was the first time that the PHS worked so closely with the US Department of Defense and our sister services to basically have an international mission unfold with that level of coordination.

We can use those changes that have gone on, the metamorphoses that have happened over the years, as a jumping off point, but they need to be fulfilled with further growth and support of the Commissioned Corps of the US Public Health Service. The numbers are the lowest they’ve been in recent times in terms of active duty officers. That’s not a good thing. As the mission expands, the idea of recruiting and retaining remains a problem. We have to deal with it.

Was your interest in taking the position at the University of Maryland in part to help build the future of public health?

RADM Lushniak. Certainly, I was so excited to be at the University of Maryland College Park exactly for that reason. The undergraduates are coming in from high school and their eyes are wide open. Two things are important at that stage. One is to teach them about the beauty of public health. That it’s a bold and noble mission. As I always tell our students, it’s about the 3 Ps: Promoting health and wellbeing, preventing disease and injury, and prolonging a high quality of life.

When you put all those things together, that’s an incredible mission. I want to tell them at that young age, “Be a part of this, figure out where you fit in.” But it’s not for everyone. I tell my students that one of the major attributes that I need to see in a student is optimism. Public health does not deal well with pessimism. If your character is pessimistic, I actually dissuade you from becoming a public health person because there are a lot of barriers in this incredible bold and noble mission, and optimism needs to be a key feature that keeps us all going.

Next is the realization that there’s so many different public health issues in our world, so many different problems to deal with. I mentioned some of them previously in terms of the public health issues we see each and every day.

Let me talk about one that’s, in particular, shining through in the midst of COVID-19, but also shines through each and every day. That’s the issue of health equity in our communities. A young person, who usually comes in and wants to help their community, needs to realize that part of the battle of public health is to make sure that we deal with the disparities that exist. We must make health equity a key component of our jobs. We are here to serve others.

There’s a saying at the University of Maryland College Park that we’re a “Do good university.” I would say that public health is a do-good profession. It is about compassion, it’s about love, it’s about caring. Those are the types of people that I try to bring into the school, and I try to mentor and support.

What have you been doing since you left the US Public Health Service?

RADM Boris D. Lushniak, MD, MPH. I retired in 2015 and spent a year at the Uniformed Services University for the Health Sciences in Bethesda, Maryland as the Chair of Preventive Medicine and Biostatistics before I took the opportunity to become the Dean of the School of Public Health at the University of Maryland in College Park. I was very intrigued with that position. It’s a large and young school of public health—just 13 years since its inception. And it functions at both the undergraduate and graduate school levels. We have 2,400 undergraduates in 4 different degree paths. The intriguing part of this is the ability to influence a young person’s educational pathway, and for them to look at all the opportunities in public health, and to focus on a mission, which falls into the mission of the US Public Health Service (PHS) Commissioned Corps: Protect, promote and advance the health and safety of our nation.

It has been a very intriguing transition; I have been the Dean there for 3 years. Who would have predicted that things would change drastically in that time, both at the academic level (ie, moving a school from being a normal college environment to an online environment) and now moving into the realm of preparing for the near future of that university in terms of a potential reopening. It is using all of my public health experiences and putting it at that culmination point, which is my community of 52,000 people—40,000 students at the University in College Park, and 12,000 faculty and staff members.

We are responsible for making sure that the return is as safe as possible. With so many unknowns in the world of COVID-19 and so many unpredictable components, it is quite an undertaking to be able to determine for that community of 52,000 whether it’s time to return, and under what circumstances do we return.

In addition, we’re part of a larger community. The University of Maryland in College Park is in Prince George’s County, which is the epicenter of disease and death in Maryland. The School of Public Health is working closely with county authorities. Some of our students are now contact tracers. It’s been interesting to see our faculty, staff, and students standing up as a volunteer support structure for Public Health.

We have incredible research going on at the school. One of my prime research physicians, Don Milton, MD, DrPH, has been studying the transmission of influenza. Now his work is priming on not just influenza, but also COVID-19. Our hope is to establish a community that will be safe and healthy for everyone, and so it’s been an incredible amount of work.

How would you describe the federal/ local public health cooperation?

RADM Lushniak. First and foremost, we have seen a major issue in terms of state and local response to the COVID-19 pandemic. I have to congratulate the state and the local officials for doing as best as they can under the strained circumstances that they’re in.

The first strained circumstance is that local and state health departments have lost nearly a quarter of their workforce: 50,000 jobs across the country since the recession of 2008. Part of the answer why it’s been such a struggle is that our nation as a whole hasn’t looked at public health and hasn’t looked at prevention as a key component of how our country works. We have seen a lack of support at the state and the local level, the shedding of jobs, and the lack of foresight in terms of saying that prevention works and public health is important for our cities, states, regions, and the nation. We need to reemphasize that in terms of public health.

In the State of Maryland, in general, the counties are doing as best as they can under the circumstances. They certainly started out with trying to do as much testing as possible. Testing is a critical component to this response, and obviously, we have a situation nationwide with the testing still trying to be put online to the extent that it needs to be. We need to be able to test more and more individuals to be able to determine the people who are positive. The curve ball that COVID-19 threw us is that 25 to 50% of individuals who may have a positive test may be asymptomatic. So, this isn’t simple. It’s not a matter of just saying, “Okay, you’re sick. You may then have it.” It may be: “Hey, you’re feeling healthy, you still may have it.”

But just as important as testing is what you do with those individuals who are tested. You need to have health departments turning to these individuals and providing them directions of what needs to be done. If one is COVID-19-positive, one goes into isolation for at least 14 days. And if ill, they need to be connected with a medical care system. That’s an important part of the state and local response is making sure the individuals are properly directed to the right pathway.

In addition, contact tracing is critical. The way we’re going to fight COVID-19 is the ability for us to go out there and determine if you are a positive, who did you come in contact with, and did you potentially spread this to others? You need to direct individuals who may have been in contact with the person who is now COVID- 19-positive, saying “You may have to quarantine yourself, watch out for symptoms, and you have to be really careful in the meantime.”

State and local officials took up the burden of making decisions in terms of communicating the directions given to the population. Is stay at home required? Is it the closure of businesses? Is it the wearing of masks? Certainly, the issue of physical distancing plays a role.

All that was implemented at the state and local level. Under the circumstances, it has been done as well as possible, but that now reflects on the issue of the federal response. And the federal response, I’ll admit, has been less than I had hoped for on several realms.

Number one, coordination and direction from the federal level has been rather piecemeal. State and local officials, I think, were waiting for further directions. What did federal officials think; what did they want us to do? State and local officials want independence to implement things, but what’s the right answer? I think this has been not handled well at the highest levels of the US government.

Secondly, obviously, there was an issue with testing, and the responsibility here lays with the Centers of Disease Control and Prevention (CDC), which had problems from the get-go with setting up their testing caches and getting them out. We’re still catching up from there. Now it’s unfolding that the tie in between the federal government and the private sector and academic centers are at least making some headway on that testing front.

Third, people rely on the federal officials not only for action but also for communication. It really boils down to: Who’s in charge, who’s telling me the information that I need to know, who’s honest with me and telling me what they don’t know, and who has the insight to say, “Here’s how we’re going to find out the things that we don’t know?” Who’s there empathizing with the population?

The reality is there’s been a mismatch between the communication channels for the federal government and getting down not just to the state and locals but, also, to the general population in this country.

How would you characterize the US Public Health Service Response?

RADM Lushniak. I’ll first start off with kudos and congratulations to the Commissioned Corps of the PHS for their response to date. I think the latest numbers that ADM Brett Giroir, MD, Assistant Secretary of Health, told Congress in May, was that at the time more than 3,100 of the 6,100 current officers at the PHS have been deployed over the last several months. The reality is that the Commissioned Corps is out there doing service to our nation and to the world. PHS teams were deployed initially to Japan and the Diamond Princess cruise ship. The Corps been out there internationally.

Nationally, the Corps was at the Javits Center in New York assisting in setting up that medical response. They have been assisting at the military bases initially where some of the individuals who were coming in from China and other places were being held in quarantine. They have been assisting with investigations at nursing homes across the country and meat packing plants where there have been outbreaks occurring. The Commissioned Corps has been out there, so that’s the good news.

The bad news is that the Corps is a small uniformed service. The reality is nobody still is seeing the Corps or knows about the Corps as they’re out there doing their thing. It was very nice that ADM Giroir put a plug in for them in his recent congressional testimony. That’s great that our leadership is out there acknowledging the Corps. But to a large extent, I still have an issue with the Commissioned Corps being an underfunded uniformed service of this country. The Commissioned Corps is the only uniformed service in the world whose only mission is public health. But, lack of support reflects the idea of the lack of importance that public health plays in the minds of policy makers.

To a large extent, we have had no dollars in the Corps recently for training of officers to prepare for this. For 10 years we’ve waited for a Ready Reserve to be set up. The Ready Reserve component was part of the Affordable Care Act. I was in the office of the Surgeon General as we were told to ramp this up. Now 10 years later, in the midst of this COVID-19 pandemic, Congress finally has passed legislation that sets a pathway for a Ready Reserve.

Why is the Ready Reserve important? In essence, we have incredible public health professionals out there in the civilian ranks who would be willing to assist the Commissioned Corps in their mission, either to backfill critical positions where Corps officers are currently stationed and need to be deployed, or as a Ready Reserve that’s ready to deploy itself. All this is happening right now. I hope for better days, and I hope this COVID-19 pandemic will wake our nation up to the need of a Public Health Service Commissioned Corps, a uniformed service, that's out there doing good.

What lessons are we learning about public health in this pandemic?

RADM Lushniak. We’ve just developed a new space force, the 8th uniformed US service. In reality they are talking about tens of thousands of people assigned to it. Excuse me if I’m going to be assertive. I’m a big fan of space exploration. I realize that space is the final frontier and that perhaps we have to be able to defend our country in that regard. But we’re already saying that space is worth investing in. Where is the wisdom that we’re not investing in battling on this planet against emerging threats like COVID-19? And why is it that to this date the Commissioned Corps of the Public Health Service does not have its own budget; does not have a line item anywhere; does not have money directed for training; and, in essence, only serves because its officers are stationed at other agencies who pay for these officers? It’s a personnel system and not really treated as a key and critical uniformed service of this country. That’s point number one in terms of lessons learned and what needs to be done.

In addition, it’s not just the people in uniform who serve at the federal level, civilians serve as well. These civilians work at the CDC, at the US Food and Drug Administration, at the National Institute of Health, at the Indian Health Service, and at many, many other agencies throughout the US government. Within those realms, we need to show support of those federal practitioners who are working very diligently and in a devoted fashion to fight this pandemic as well. Part of it is the moral support to recognize that there are multiple fronts to fighting this pandemic and the federal practitioner who is working out there, is a key component to this.

I don’t want everything to be money, money, money, but the fact is that CDC’s budget has been decreasing over the years. How are we supposed to set up the laboratories, how are we supposed to demand the high level of expertise when, in fact, everything has to be done on a shoestring?

Finally, we notice public health in the midst of a crisis, but public health matters each and every day. The idea that the pandemic certainly brings to light what needs to get done, but without a pandemic, what do we have? We still have cigarette smoking, the number 1 killer in this country. That’s a public health issue. We have cardiovascular diseases as an extreme killer in this country. That’s a public health issue. We have diabetes mellitus that is rampant. We have substance abuse, including the opioid epidemic. Those are public health issues. We have hypertension, we have overweight and obesity. Those are all public health issues that public health battles each and every day without the recognition.

What we need is a major shift in the philosophy of this country to really take the health and wellness of our society as a key component of how you’ll raise that on to a pedestal—the idea that health and wellness is critical to the functioning of this country.

How have recent public health emergencies influenced the Commissioned Corps?

RADM Lushniak. The key feature is that the Public Health Service Commissioned Corps has been growing in its mission over the years. The pre-9/11 Commissioned Corps, was a different life. The post-9/11 world is the first time that the Commissioned Corps really fell into this idea of being America’s public health responders. I think that we ramped it up; we started out strong.

This was shown not only in the World Trade Center and the 9/11 disasters that occurred, but in the anthrax scenario that unfolded shortly afterwards. We saw it further continue in Hurricane Katrina and the multiple hurricane responses.

Then the Ebola response, in my last year of serving in uniform, was another action of both the civilian sector of federal responders as well as the uniformed sector. The beauty of that in terms of what we learned from Ebola was that coordination is key. That was the first time that the PHS worked so closely with the US Department of Defense and our sister services to basically have an international mission unfold with that level of coordination.

We can use those changes that have gone on, the metamorphoses that have happened over the years, as a jumping off point, but they need to be fulfilled with further growth and support of the Commissioned Corps of the US Public Health Service. The numbers are the lowest they’ve been in recent times in terms of active duty officers. That’s not a good thing. As the mission expands, the idea of recruiting and retaining remains a problem. We have to deal with it.

Was your interest in taking the position at the University of Maryland in part to help build the future of public health?

RADM Lushniak. Certainly, I was so excited to be at the University of Maryland College Park exactly for that reason. The undergraduates are coming in from high school and their eyes are wide open. Two things are important at that stage. One is to teach them about the beauty of public health. That it’s a bold and noble mission. As I always tell our students, it’s about the 3 Ps: Promoting health and wellbeing, preventing disease and injury, and prolonging a high quality of life.

When you put all those things together, that’s an incredible mission. I want to tell them at that young age, “Be a part of this, figure out where you fit in.” But it’s not for everyone. I tell my students that one of the major attributes that I need to see in a student is optimism. Public health does not deal well with pessimism. If your character is pessimistic, I actually dissuade you from becoming a public health person because there are a lot of barriers in this incredible bold and noble mission, and optimism needs to be a key feature that keeps us all going.

Next is the realization that there’s so many different public health issues in our world, so many different problems to deal with. I mentioned some of them previously in terms of the public health issues we see each and every day.

Let me talk about one that’s, in particular, shining through in the midst of COVID-19, but also shines through each and every day. That’s the issue of health equity in our communities. A young person, who usually comes in and wants to help their community, needs to realize that part of the battle of public health is to make sure that we deal with the disparities that exist. We must make health equity a key component of our jobs. We are here to serve others.

There’s a saying at the University of Maryland College Park that we’re a “Do good university.” I would say that public health is a do-good profession. It is about compassion, it’s about love, it’s about caring. Those are the types of people that I try to bring into the school, and I try to mentor and support.

What have you been doing since you left the US Public Health Service?

RADM Boris D. Lushniak, MD, MPH. I retired in 2015 and spent a year at the Uniformed Services University for the Health Sciences in Bethesda, Maryland as the Chair of Preventive Medicine and Biostatistics before I took the opportunity to become the Dean of the School of Public Health at the University of Maryland in College Park. I was very intrigued with that position. It’s a large and young school of public health—just 13 years since its inception. And it functions at both the undergraduate and graduate school levels. We have 2,400 undergraduates in 4 different degree paths. The intriguing part of this is the ability to influence a young person’s educational pathway, and for them to look at all the opportunities in public health, and to focus on a mission, which falls into the mission of the US Public Health Service (PHS) Commissioned Corps: Protect, promote and advance the health and safety of our nation.

It has been a very intriguing transition; I have been the Dean there for 3 years. Who would have predicted that things would change drastically in that time, both at the academic level (ie, moving a school from being a normal college environment to an online environment) and now moving into the realm of preparing for the near future of that university in terms of a potential reopening. It is using all of my public health experiences and putting it at that culmination point, which is my community of 52,000 people—40,000 students at the University in College Park, and 12,000 faculty and staff members.

We are responsible for making sure that the return is as safe as possible. With so many unknowns in the world of COVID-19 and so many unpredictable components, it is quite an undertaking to be able to determine for that community of 52,000 whether it’s time to return, and under what circumstances do we return.

In addition, we’re part of a larger community. The University of Maryland in College Park is in Prince George’s County, which is the epicenter of disease and death in Maryland. The School of Public Health is working closely with county authorities. Some of our students are now contact tracers. It’s been interesting to see our faculty, staff, and students standing up as a volunteer support structure for Public Health.

We have incredible research going on at the school. One of my prime research physicians, Don Milton, MD, DrPH, has been studying the transmission of influenza. Now his work is priming on not just influenza, but also COVID-19. Our hope is to establish a community that will be safe and healthy for everyone, and so it’s been an incredible amount of work.

How would you describe the federal/ local public health cooperation?

RADM Lushniak. First and foremost, we have seen a major issue in terms of state and local response to the COVID-19 pandemic. I have to congratulate the state and the local officials for doing as best as they can under the strained circumstances that they’re in.

The first strained circumstance is that local and state health departments have lost nearly a quarter of their workforce: 50,000 jobs across the country since the recession of 2008. Part of the answer why it’s been such a struggle is that our nation as a whole hasn’t looked at public health and hasn’t looked at prevention as a key component of how our country works. We have seen a lack of support at the state and the local level, the shedding of jobs, and the lack of foresight in terms of saying that prevention works and public health is important for our cities, states, regions, and the nation. We need to reemphasize that in terms of public health.

In the State of Maryland, in general, the counties are doing as best as they can under the circumstances. They certainly started out with trying to do as much testing as possible. Testing is a critical component to this response, and obviously, we have a situation nationwide with the testing still trying to be put online to the extent that it needs to be. We need to be able to test more and more individuals to be able to determine the people who are positive. The curve ball that COVID-19 threw us is that 25 to 50% of individuals who may have a positive test may be asymptomatic. So, this isn’t simple. It’s not a matter of just saying, “Okay, you’re sick. You may then have it.” It may be: “Hey, you’re feeling healthy, you still may have it.”

But just as important as testing is what you do with those individuals who are tested. You need to have health departments turning to these individuals and providing them directions of what needs to be done. If one is COVID-19-positive, one goes into isolation for at least 14 days. And if ill, they need to be connected with a medical care system. That’s an important part of the state and local response is making sure the individuals are properly directed to the right pathway.

In addition, contact tracing is critical. The way we’re going to fight COVID-19 is the ability for us to go out there and determine if you are a positive, who did you come in contact with, and did you potentially spread this to others? You need to direct individuals who may have been in contact with the person who is now COVID- 19-positive, saying “You may have to quarantine yourself, watch out for symptoms, and you have to be really careful in the meantime.”

State and local officials took up the burden of making decisions in terms of communicating the directions given to the population. Is stay at home required? Is it the closure of businesses? Is it the wearing of masks? Certainly, the issue of physical distancing plays a role.

All that was implemented at the state and local level. Under the circumstances, it has been done as well as possible, but that now reflects on the issue of the federal response. And the federal response, I’ll admit, has been less than I had hoped for on several realms.

Number one, coordination and direction from the federal level has been rather piecemeal. State and local officials, I think, were waiting for further directions. What did federal officials think; what did they want us to do? State and local officials want independence to implement things, but what’s the right answer? I think this has been not handled well at the highest levels of the US government.

Secondly, obviously, there was an issue with testing, and the responsibility here lays with the Centers of Disease Control and Prevention (CDC), which had problems from the get-go with setting up their testing caches and getting them out. We’re still catching up from there. Now it’s unfolding that the tie in between the federal government and the private sector and academic centers are at least making some headway on that testing front.

Third, people rely on the federal officials not only for action but also for communication. It really boils down to: Who’s in charge, who’s telling me the information that I need to know, who’s honest with me and telling me what they don’t know, and who has the insight to say, “Here’s how we’re going to find out the things that we don’t know?” Who’s there empathizing with the population?

The reality is there’s been a mismatch between the communication channels for the federal government and getting down not just to the state and locals but, also, to the general population in this country.

How would you characterize the US Public Health Service Response?

RADM Lushniak. I’ll first start off with kudos and congratulations to the Commissioned Corps of the PHS for their response to date. I think the latest numbers that ADM Brett Giroir, MD, Assistant Secretary of Health, told Congress in May, was that at the time more than 3,100 of the 6,100 current officers at the PHS have been deployed over the last several months. The reality is that the Commissioned Corps is out there doing service to our nation and to the world. PHS teams were deployed initially to Japan and the Diamond Princess cruise ship. The Corps been out there internationally.

Nationally, the Corps was at the Javits Center in New York assisting in setting up that medical response. They have been assisting at the military bases initially where some of the individuals who were coming in from China and other places were being held in quarantine. They have been assisting with investigations at nursing homes across the country and meat packing plants where there have been outbreaks occurring. The Commissioned Corps has been out there, so that’s the good news.

The bad news is that the Corps is a small uniformed service. The reality is nobody still is seeing the Corps or knows about the Corps as they’re out there doing their thing. It was very nice that ADM Giroir put a plug in for them in his recent congressional testimony. That’s great that our leadership is out there acknowledging the Corps. But to a large extent, I still have an issue with the Commissioned Corps being an underfunded uniformed service of this country. The Commissioned Corps is the only uniformed service in the world whose only mission is public health. But, lack of support reflects the idea of the lack of importance that public health plays in the minds of policy makers.

To a large extent, we have had no dollars in the Corps recently for training of officers to prepare for this. For 10 years we’ve waited for a Ready Reserve to be set up. The Ready Reserve component was part of the Affordable Care Act. I was in the office of the Surgeon General as we were told to ramp this up. Now 10 years later, in the midst of this COVID-19 pandemic, Congress finally has passed legislation that sets a pathway for a Ready Reserve.

Why is the Ready Reserve important? In essence, we have incredible public health professionals out there in the civilian ranks who would be willing to assist the Commissioned Corps in their mission, either to backfill critical positions where Corps officers are currently stationed and need to be deployed, or as a Ready Reserve that’s ready to deploy itself. All this is happening right now. I hope for better days, and I hope this COVID-19 pandemic will wake our nation up to the need of a Public Health Service Commissioned Corps, a uniformed service, that's out there doing good.

What lessons are we learning about public health in this pandemic?

RADM Lushniak. We’ve just developed a new space force, the 8th uniformed US service. In reality they are talking about tens of thousands of people assigned to it. Excuse me if I’m going to be assertive. I’m a big fan of space exploration. I realize that space is the final frontier and that perhaps we have to be able to defend our country in that regard. But we’re already saying that space is worth investing in. Where is the wisdom that we’re not investing in battling on this planet against emerging threats like COVID-19? And why is it that to this date the Commissioned Corps of the Public Health Service does not have its own budget; does not have a line item anywhere; does not have money directed for training; and, in essence, only serves because its officers are stationed at other agencies who pay for these officers? It’s a personnel system and not really treated as a key and critical uniformed service of this country. That’s point number one in terms of lessons learned and what needs to be done.

In addition, it’s not just the people in uniform who serve at the federal level, civilians serve as well. These civilians work at the CDC, at the US Food and Drug Administration, at the National Institute of Health, at the Indian Health Service, and at many, many other agencies throughout the US government. Within those realms, we need to show support of those federal practitioners who are working very diligently and in a devoted fashion to fight this pandemic as well. Part of it is the moral support to recognize that there are multiple fronts to fighting this pandemic and the federal practitioner who is working out there, is a key component to this.

I don’t want everything to be money, money, money, but the fact is that CDC’s budget has been decreasing over the years. How are we supposed to set up the laboratories, how are we supposed to demand the high level of expertise when, in fact, everything has to be done on a shoestring?

Finally, we notice public health in the midst of a crisis, but public health matters each and every day. The idea that the pandemic certainly brings to light what needs to get done, but without a pandemic, what do we have? We still have cigarette smoking, the number 1 killer in this country. That’s a public health issue. We have cardiovascular diseases as an extreme killer in this country. That’s a public health issue. We have diabetes mellitus that is rampant. We have substance abuse, including the opioid epidemic. Those are public health issues. We have hypertension, we have overweight and obesity. Those are all public health issues that public health battles each and every day without the recognition.

What we need is a major shift in the philosophy of this country to really take the health and wellness of our society as a key component of how you’ll raise that on to a pedestal—the idea that health and wellness is critical to the functioning of this country.

How have recent public health emergencies influenced the Commissioned Corps?

RADM Lushniak. The key feature is that the Public Health Service Commissioned Corps has been growing in its mission over the years. The pre-9/11 Commissioned Corps, was a different life. The post-9/11 world is the first time that the Commissioned Corps really fell into this idea of being America’s public health responders. I think that we ramped it up; we started out strong.

This was shown not only in the World Trade Center and the 9/11 disasters that occurred, but in the anthrax scenario that unfolded shortly afterwards. We saw it further continue in Hurricane Katrina and the multiple hurricane responses.

Then the Ebola response, in my last year of serving in uniform, was another action of both the civilian sector of federal responders as well as the uniformed sector. The beauty of that in terms of what we learned from Ebola was that coordination is key. That was the first time that the PHS worked so closely with the US Department of Defense and our sister services to basically have an international mission unfold with that level of coordination.

We can use those changes that have gone on, the metamorphoses that have happened over the years, as a jumping off point, but they need to be fulfilled with further growth and support of the Commissioned Corps of the US Public Health Service. The numbers are the lowest they’ve been in recent times in terms of active duty officers. That’s not a good thing. As the mission expands, the idea of recruiting and retaining remains a problem. We have to deal with it.

Was your interest in taking the position at the University of Maryland in part to help build the future of public health?

RADM Lushniak. Certainly, I was so excited to be at the University of Maryland College Park exactly for that reason. The undergraduates are coming in from high school and their eyes are wide open. Two things are important at that stage. One is to teach them about the beauty of public health. That it’s a bold and noble mission. As I always tell our students, it’s about the 3 Ps: Promoting health and wellbeing, preventing disease and injury, and prolonging a high quality of life.

When you put all those things together, that’s an incredible mission. I want to tell them at that young age, “Be a part of this, figure out where you fit in.” But it’s not for everyone. I tell my students that one of the major attributes that I need to see in a student is optimism. Public health does not deal well with pessimism. If your character is pessimistic, I actually dissuade you from becoming a public health person because there are a lot of barriers in this incredible bold and noble mission, and optimism needs to be a key feature that keeps us all going.

Next is the realization that there’s so many different public health issues in our world, so many different problems to deal with. I mentioned some of them previously in terms of the public health issues we see each and every day.

Let me talk about one that’s, in particular, shining through in the midst of COVID-19, but also shines through each and every day. That’s the issue of health equity in our communities. A young person, who usually comes in and wants to help their community, needs to realize that part of the battle of public health is to make sure that we deal with the disparities that exist. We must make health equity a key component of our jobs. We are here to serve others.

There’s a saying at the University of Maryland College Park that we’re a “Do good university.” I would say that public health is a do-good profession. It is about compassion, it’s about love, it’s about caring. Those are the types of people that I try to bring into the school, and I try to mentor and support.

The use of weight-based dosing with trough-based monitoring of vancomycin has been in clinical practice for more than a decade. The American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP) published the first guidelines for vancomycin monitoring in 2009.¹ Although it has been well established that area under the curve (AUC) over the minimal inhibitory concentration (MIC) ratio > 400 mg.h/L is the best predictor of clinical efficacy, obtaining this value in clinical practice was not pragmatic. Therefore, the 2009 guidelines recommended a goal vancomycin trough of 15 to 20 mcg/ml as a surrogate marker for AUC/MIC > 400 mg.hr/L. This has since become a common practice despite little data that support this recommendation.

The efficacy and safety of trough-based monitoring has been evaluated extensively over the past several years and more recent data suggest that there is wide patient variability in AUC with this method and higher trough levels are associated with more nephrotoxicity.^2,3 ASHP, IDSA, SIDP, and the Pediatric Infectious Diseases Society (PIDS) updated the consensus guidelines in 2020.⁴ Trough-based monitoring is no longer recommended. Instead AUC₂₄ monitoring should be implemented with a goal range of 400 to 600 mg.h/L for efficacy and safety. Given concerns for vancomycin penetration into the central nervous system (CNS), many facility protocols utilize higher targets (> 600 mg.h/L) for CNS infections.

Some hospitals have been utilizing AUC-based monitoring for years. There are strategies from tertiary care centers that drive this practice change in the medical literature.^5,6 However, it is important to reproduce these implementation practices in small, rural facilities that may face unique challenges with limited resources and may be slower to implement consensus guidelines.^7,8 As this is a major practice change, it is imperative to evaluate the extent of transition and identify areas of needed improvement.

Accurate therapeutic drug monitoring ensures both the safety and efficacy of vancomycin therapy. Unfortunately, research shows that inappropriate laboratory tests are common in medical facilities.⁹ Drug levels taken inappropriately can lead to delays in therapeutic decision-making, inappropriate dosage adjustments and create a need for repeated drug levels, which increases the overall cost of admission.

Given the multiple affected services needed to make successful practice transitions, it is paramount that facilities evaluate progress during the transition phase. The Agency for Healthcare Research and Quality and the Institute for Healthcare Improvement provide guidance in the Plan-Do-Study-Act Cycle for quality assessment and improvement of new initiatives.^10,11 A gap analysis can be used as a simple tool for evaluating the transition of research into practice and to identify areas of needed improvement.

The Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas made the transition from trough-based monitoring to 2-level AUC-based monitoring on April 1, 2019. The purpose of this study was to evaluate the effectiveness of transition methods used to implement AUC-monitoring for vancomycin treated patients in a small, primary facility. A further goal of the study was to identify areas of needed improvement and education and whether the problems derived from deficiencies in knowledge and ordering (medical and pharmacy services) or execution (nursing and laboratory services).

Methods

VHSO is a 52-bed US Department of Veterans Affairs primary care hospital. The pharmacy and laboratory are staffed 24 hours each day. There is 1 clinical pharmacy specialist (CPS) available for therapeutic drug monitoring consults Monday through Friday between the hours of 7:30 AM and 4:00 PM. No partial full-time equivalent employees were added for this conversion. Pharmacy-driven vancomycin dosing and monitoring is conducted on a collaborative basis, with pharmacy managing the majority of vancomycin treated patients. Night and weekend pharmacy staff provide cross-coverage on vancomycin consultations. Laboratory orders and medication dosage adjustments fall within the CPS scope of practice. Nurses do not perform laboratory draws for therapeutic drug monitoring; this is done solely by phlebotomists. There is no infectious diseases specialist at the facility to champion antibiotic dosing initiatives.

The implementation strategy largely reflected those outlined from tertiary care centers.^5,6 First, key personnel from the laboratory department met to discuss this practice change and to add vancomycin peaks to the ordering menu. A critical value was set at 40 mcg/ml. Vancomycin troughs and random levels already were orderable items. A comment field was added to all laboratory orders for further clarification. Verbiage was added to laboratory reports in the computerized medical record to assist clinicians in determining the appropriateness of the level. This was followed by an educational email to both the nursing and laboratory departments explaining the practice change and included a link to the Pharmacy Joe “Vancomycin Dosing by AUC:MIC Instead of Trough-level” podcast (www.pharmacyjoe.com episode 356).

The pharmacy department received an interactive 30-minute presentation, followed immediately by a group activity to discuss practice problems. This presentation was condensed, recorded, and emailed to all VHSO pharmacists. A shared folder contained pertinent material on AUC monitoring.

Finally, an interactive presentation was set up for hospitalists and a video teleconferencing was conducted for rotating medical residents. Both the podcast and recorded presentation were emailed to the entire medical staff with a brief introduction of the practice change. Additionally, the transition process was added as a standing item on the monthly antimicrobial stewardship meeting agenda.

The standardized pharmacokinetic model at the study facility consisted of a vancomycin volume of distribution of 0.7 mg/kg and elimination rate constant (Ke) by Matzke and colleagues for total daily dose calculations.¹² Obese patients (BMI ≥ 30) undergo alternative clearance equations described by Crass and colleagues.¹³ Cockcroft-Gault methods using ideal body weight (or actual body weight if < ideal body weight) are used for determining creatinine clearance. In patients aged ≥ 65 years with a serum creatinine < 1.0 mg/dL, facility guidance was to round serum creatinine up to 1.0 mg/dL. Loading doses were determined on a case-by-case basis with a cap of 2,000 mg, maintenance doses were rounded to the nearest 250 mg.

Vancomycin levels typically are drawn at steady state and analyzed using the logarithmic trapezoidal rule.¹⁴ The pharmacy and medical staff were educated to provide details on timing and coordination in nursing and laboratory orders (Table 1). Two-level AUC monitoring typically is not performed in patients with acute renal failure, expected duration of therapy < 72 hours, urinary tract infections, skin and soft tissue infections, or in renal replacement therapy.⁵

This gap analysis consisted of a retrospective chart review of vancomycin levels ordered after the implementation of AUC-based monitoring to determine the effectiveness of the transition. Three months of data were collected between April 2019 and June 2019. Vancomycin levels were deemed either appropriate or inappropriate based on timing and type (peak, trough, or random) of the laboratory test in relation to the previously administered vancomycin dose. Appropriate peaks were drawn within 2 hours after the end of infusion and troughs at least 1 half-life after the dose or just prior to the next dose and within the same dosing interval as the peak. Tests drawn outside of the specified time range, trough-only laboratory tests, or those drawn after vancomycin had been discontinued were considered inappropriate. Peaks and troughs drawn from separate dosing intervals also were considered inappropriate. Random levels were considered appropriate only if they fit the clinical context in acute renal failure or renal replacement therapy. An effective transition was defined as ≥ 80% of all vancomycin treated patients monitored with AUC methods rather than trough-based methods.

Inclusion criteria included all vancomycin levels ordered during the study period with no exclusions. The primary endpoint was the proportion of vancomycin levels drawn appropriately. Secondary endpoints were the proportion of AUC₂₄ calculations within therapeutic range and a stratification of reasons for inappropriate levels. Descriptive statistics were collected to describe the scope of the project. Levels drawn from various shifts were compared (ie, day, night, or weekend). Calculated AUC₂₄ levels between 400 and 600 mg.h/L were considered therapeutic unless treating CNS infection (600-700 mg.h/L). Given the operational outcomes (rather than clinical outcomes) and no comparator group, patient specific data were not collected.

Descriptive statistics without further analysis were used to describe proportions. The goal level for compliance was set at 100%. These methods were reviewed by the VHSO Institutional Review Board and granted nonresearch status, waiving the requirement for informed consent.

Results

The transition was effective with 97% of all cases utilizing AUC-based methods for monitoring. A total of 65 vancomycin levels were drawn in the study period; 32 peaks, 32 troughs, and 1 random level (drawn appropriately during acute renal failure 24 hours after starting therapy). All shifts were affected proportionately; days (n = 26, 40%), nights (n = 18, 27.7%), and weekends (n = 21, 32.3%). Based on time of dosage administration and laboratory test, there were 9 levels (13.8%) deemed inappropriate, 56 levels (86.1%) were appropriate. Reasons for inappropriate levels gleaned from chart review are presented in Table 2. Four levels had to be repeated for accurate calculations.

From the peak/trough couplets drawn appropriately, calculated AUC₂₄ fell with the desired range in 61% (n = 17) of cases. Of the 11 that fell outside of range, 8 were subtherapeutic (< 400 mg.h/L) and 3 were supratherapeutic (> 600 mg.h/L). All levels were drawn at steady state. Indications for vancomycin monitoring were osteomyelitis (n = 13, 43%), sepsis (n = 10, 33%), pneumonia (n = 6, 20%), and 1 case of meningitis (3%).

Discussion

To the author’s knowledge, this is the first report of a vancomycin AUC₂₄ monitoring conversion in a rural facility. This study adds to the existing medical literature in that it demonstrates that: (1) implementation methods described in large, tertiary centers can be effectively utilized in primary care, rural facilities; (2) the gap analysis used can be duplicated with minimal personnel and resources to ensure effective implementation (Table 3); and (3) the reported improvement needs can serve as a model for preventative measures at other facilities. The incidence of appropriate vancomycin levels was notably better than those reported in other single center studies.^15-17 However, given variations in study design and facility operating procedures, it would be difficult to compare incidence among medical facilities. As such, there are no consensus benchmarks for comparison. The majority of inappropriate levels occurred early in the study period and on weekends. Appropriateness of drug levels may have improved with continued feedback and familiarity.

The calculated AUC₂₄ fell within predicted range in 61% of cases. For comparison, a recent study from a large academic medical center reported that 73.5% of 2-level AUC₂₄ cases had initial values within the therapeutic range.¹⁸ Of note, the target range used was much wider (400 - 800 mg.h/L) than the present study. Another study reported dose adjustments for subtherapeutic AUC levels in 25% of cases and dose reductions for supratherapeutic levels in 33.3% of cases.¹⁹

Of the AUC₂₄ calculations that fell outside of therapeutic range, the majority (n = 8, 73%) were subtherapeutic (< 400 mg.h/L), half of these were for patients who were obese. It was unclear in the medical record which equation was used for initial dosing (Matzke vs Crass), or whether more conservative AUCs were used for calculating the total daily dose. The VHSO policy limiting loading doses also may have played a role; indeed the updated guidelines recommend a maximum loading dose of 3,000 mg depending on the severity of infection.⁴ Two of the 3 supratherapeutic levels were thought to be due to accumulation with long-term therapy.

Given such a large change from long-standing practices, there was surprisingly little resistance from the various clinical services. A recent survey of academic medical centers reported that the majority (88%) of all respondents who did not currently utilize AUC₂₄ monitoring did not plan on making this immediate transition, largely citing unfamiliarity and training requirements.²⁰ It is conceivable that the transition to AUC monitoring in smaller facilities may have fewer barriers than those seen in tertiary care centers. There are fewer health care providers and pharmacists to educate with the primary responsibilities falling on relatively few clinicians. There is little question as to who will be conducting follow up or whom to contact for questions. A smaller patient load and lesser patient acuity may translate to fewer vancomycin cases that require monitoring.

The interactive meetings were an important element for facility implementation. Research shows that emails alone are not effective for health care provider education, and interactive methods are recommended over passive methods.^21,22 Assessing and avoiding barriers up front such as unclear laboratory orders, or communication failures is paramount to successful implementation strategies.²³ Additionally, the detailed written ordering communication may have contributed to a smoother transition. The educational recording proved to be helpful in educating new staff and residents. An identified logistical error was that laboratory orders entered while patients were enrolled in sham clinics for electronic workload capture (eg, Pharmacy Inpatient Clinic) created confusion on the physical location of the patient for the phlebotomists, potentially causing delays in specimen collection.

A major development that stemmed from this intervention was that the Medical Service asked that policy changes be made so that the Pharmacy Service take over all vancomycin dosing at the facility. Previously, this had been done on a collaborative basis. Similar facilities with a collaborative practice model may need to anticipate such a request as this may present a new set of challenges. Accordingly, the pharmacy department is in the process of establishing standing operating procedures, pharmacist competencies, and a facility memorandum. Future research should evaluate the safety and efficacy of vancomycin therapy after the switch to AUC-based monitoring.

Limitations

There are several limitations to consider with this study. Operating procedures and implementation processes may vary between facilities, which could limit the generalizability of these results. Given the small facility size, the overall number of laboratory tests drawn was much smaller than those seen in larger facilities. The time needed for AUC calculations is notably longer than older methods of monitoring; however, this was not objectively assessed. It is important to note that clinical outcomes were beyond the scope of this gap analysis and this is an area of future research at the study facility. Vancomycin laboratory tests that were missed due to procedures and subsequently rescheduled were occasionally observed but not accounted for in this analysis. Additionally, vancomycin courses without monitoring (appropriate or otherwise) when indicated were not assessed. However, anecdotally speaking, this would be a very unlikely occurrence.

Conclusion

Conversion to AUC-based vancomycin monitoring is feasible in primary, rural medical centers. Implementation strategies from tertiary facilities can be successfully utilized in smaller hospitals. Quality assessment strategies such as a gap analysis can be utilized with minimal resources for facility uptake of new clinical practices.

The use of weight-based dosing with trough-based monitoring of vancomycin has been in clinical practice for more than a decade. The American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP) published the first guidelines for vancomycin monitoring in 2009.¹ Although it has been well established that area under the curve (AUC) over the minimal inhibitory concentration (MIC) ratio > 400 mg.h/L is the best predictor of clinical efficacy, obtaining this value in clinical practice was not pragmatic. Therefore, the 2009 guidelines recommended a goal vancomycin trough of 15 to 20 mcg/ml as a surrogate marker for AUC/MIC > 400 mg.hr/L. This has since become a common practice despite little data that support this recommendation.

The efficacy and safety of trough-based monitoring has been evaluated extensively over the past several years and more recent data suggest that there is wide patient variability in AUC with this method and higher trough levels are associated with more nephrotoxicity.^2,3 ASHP, IDSA, SIDP, and the Pediatric Infectious Diseases Society (PIDS) updated the consensus guidelines in 2020.⁴ Trough-based monitoring is no longer recommended. Instead AUC₂₄ monitoring should be implemented with a goal range of 400 to 600 mg.h/L for efficacy and safety. Given concerns for vancomycin penetration into the central nervous system (CNS), many facility protocols utilize higher targets (> 600 mg.h/L) for CNS infections.

Some hospitals have been utilizing AUC-based monitoring for years. There are strategies from tertiary care centers that drive this practice change in the medical literature.^5,6 However, it is important to reproduce these implementation practices in small, rural facilities that may face unique challenges with limited resources and may be slower to implement consensus guidelines.^7,8 As this is a major practice change, it is imperative to evaluate the extent of transition and identify areas of needed improvement.

Accurate therapeutic drug monitoring ensures both the safety and efficacy of vancomycin therapy. Unfortunately, research shows that inappropriate laboratory tests are common in medical facilities.⁹ Drug levels taken inappropriately can lead to delays in therapeutic decision-making, inappropriate dosage adjustments and create a need for repeated drug levels, which increases the overall cost of admission.

Given the multiple affected services needed to make successful practice transitions, it is paramount that facilities evaluate progress during the transition phase. The Agency for Healthcare Research and Quality and the Institute for Healthcare Improvement provide guidance in the Plan-Do-Study-Act Cycle for quality assessment and improvement of new initiatives.^10,11 A gap analysis can be used as a simple tool for evaluating the transition of research into practice and to identify areas of needed improvement.

The Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas made the transition from trough-based monitoring to 2-level AUC-based monitoring on April 1, 2019. The purpose of this study was to evaluate the effectiveness of transition methods used to implement AUC-monitoring for vancomycin treated patients in a small, primary facility. A further goal of the study was to identify areas of needed improvement and education and whether the problems derived from deficiencies in knowledge and ordering (medical and pharmacy services) or execution (nursing and laboratory services).

Methods

VHSO is a 52-bed US Department of Veterans Affairs primary care hospital. The pharmacy and laboratory are staffed 24 hours each day. There is 1 clinical pharmacy specialist (CPS) available for therapeutic drug monitoring consults Monday through Friday between the hours of 7:30 AM and 4:00 PM. No partial full-time equivalent employees were added for this conversion. Pharmacy-driven vancomycin dosing and monitoring is conducted on a collaborative basis, with pharmacy managing the majority of vancomycin treated patients. Night and weekend pharmacy staff provide cross-coverage on vancomycin consultations. Laboratory orders and medication dosage adjustments fall within the CPS scope of practice. Nurses do not perform laboratory draws for therapeutic drug monitoring; this is done solely by phlebotomists. There is no infectious diseases specialist at the facility to champion antibiotic dosing initiatives.

The implementation strategy largely reflected those outlined from tertiary care centers.^5,6 First, key personnel from the laboratory department met to discuss this practice change and to add vancomycin peaks to the ordering menu. A critical value was set at 40 mcg/ml. Vancomycin troughs and random levels already were orderable items. A comment field was added to all laboratory orders for further clarification. Verbiage was added to laboratory reports in the computerized medical record to assist clinicians in determining the appropriateness of the level. This was followed by an educational email to both the nursing and laboratory departments explaining the practice change and included a link to the Pharmacy Joe “Vancomycin Dosing by AUC:MIC Instead of Trough-level” podcast (www.pharmacyjoe.com episode 356).

The pharmacy department received an interactive 30-minute presentation, followed immediately by a group activity to discuss practice problems. This presentation was condensed, recorded, and emailed to all VHSO pharmacists. A shared folder contained pertinent material on AUC monitoring.

Finally, an interactive presentation was set up for hospitalists and a video teleconferencing was conducted for rotating medical residents. Both the podcast and recorded presentation were emailed to the entire medical staff with a brief introduction of the practice change. Additionally, the transition process was added as a standing item on the monthly antimicrobial stewardship meeting agenda.

The standardized pharmacokinetic model at the study facility consisted of a vancomycin volume of distribution of 0.7 mg/kg and elimination rate constant (Ke) by Matzke and colleagues for total daily dose calculations.¹² Obese patients (BMI ≥ 30) undergo alternative clearance equations described by Crass and colleagues.¹³ Cockcroft-Gault methods using ideal body weight (or actual body weight if < ideal body weight) are used for determining creatinine clearance. In patients aged ≥ 65 years with a serum creatinine < 1.0 mg/dL, facility guidance was to round serum creatinine up to 1.0 mg/dL. Loading doses were determined on a case-by-case basis with a cap of 2,000 mg, maintenance doses were rounded to the nearest 250 mg.

Vancomycin levels typically are drawn at steady state and analyzed using the logarithmic trapezoidal rule.¹⁴ The pharmacy and medical staff were educated to provide details on timing and coordination in nursing and laboratory orders (Table 1). Two-level AUC monitoring typically is not performed in patients with acute renal failure, expected duration of therapy < 72 hours, urinary tract infections, skin and soft tissue infections, or in renal replacement therapy.⁵

This gap analysis consisted of a retrospective chart review of vancomycin levels ordered after the implementation of AUC-based monitoring to determine the effectiveness of the transition. Three months of data were collected between April 2019 and June 2019. Vancomycin levels were deemed either appropriate or inappropriate based on timing and type (peak, trough, or random) of the laboratory test in relation to the previously administered vancomycin dose. Appropriate peaks were drawn within 2 hours after the end of infusion and troughs at least 1 half-life after the dose or just prior to the next dose and within the same dosing interval as the peak. Tests drawn outside of the specified time range, trough-only laboratory tests, or those drawn after vancomycin had been discontinued were considered inappropriate. Peaks and troughs drawn from separate dosing intervals also were considered inappropriate. Random levels were considered appropriate only if they fit the clinical context in acute renal failure or renal replacement therapy. An effective transition was defined as ≥ 80% of all vancomycin treated patients monitored with AUC methods rather than trough-based methods.

Inclusion criteria included all vancomycin levels ordered during the study period with no exclusions. The primary endpoint was the proportion of vancomycin levels drawn appropriately. Secondary endpoints were the proportion of AUC₂₄ calculations within therapeutic range and a stratification of reasons for inappropriate levels. Descriptive statistics were collected to describe the scope of the project. Levels drawn from various shifts were compared (ie, day, night, or weekend). Calculated AUC₂₄ levels between 400 and 600 mg.h/L were considered therapeutic unless treating CNS infection (600-700 mg.h/L). Given the operational outcomes (rather than clinical outcomes) and no comparator group, patient specific data were not collected.

Descriptive statistics without further analysis were used to describe proportions. The goal level for compliance was set at 100%. These methods were reviewed by the VHSO Institutional Review Board and granted nonresearch status, waiving the requirement for informed consent.

Results

The transition was effective with 97% of all cases utilizing AUC-based methods for monitoring. A total of 65 vancomycin levels were drawn in the study period; 32 peaks, 32 troughs, and 1 random level (drawn appropriately during acute renal failure 24 hours after starting therapy). All shifts were affected proportionately; days (n = 26, 40%), nights (n = 18, 27.7%), and weekends (n = 21, 32.3%). Based on time of dosage administration and laboratory test, there were 9 levels (13.8%) deemed inappropriate, 56 levels (86.1%) were appropriate. Reasons for inappropriate levels gleaned from chart review are presented in Table 2. Four levels had to be repeated for accurate calculations.

From the peak/trough couplets drawn appropriately, calculated AUC₂₄ fell with the desired range in 61% (n = 17) of cases. Of the 11 that fell outside of range, 8 were subtherapeutic (< 400 mg.h/L) and 3 were supratherapeutic (> 600 mg.h/L). All levels were drawn at steady state. Indications for vancomycin monitoring were osteomyelitis (n = 13, 43%), sepsis (n = 10, 33%), pneumonia (n = 6, 20%), and 1 case of meningitis (3%).

Discussion

To the author’s knowledge, this is the first report of a vancomycin AUC₂₄ monitoring conversion in a rural facility. This study adds to the existing medical literature in that it demonstrates that: (1) implementation methods described in large, tertiary centers can be effectively utilized in primary care, rural facilities; (2) the gap analysis used can be duplicated with minimal personnel and resources to ensure effective implementation (Table 3); and (3) the reported improvement needs can serve as a model for preventative measures at other facilities. The incidence of appropriate vancomycin levels was notably better than those reported in other single center studies.^15-17 However, given variations in study design and facility operating procedures, it would be difficult to compare incidence among medical facilities. As such, there are no consensus benchmarks for comparison. The majority of inappropriate levels occurred early in the study period and on weekends. Appropriateness of drug levels may have improved with continued feedback and familiarity.

The calculated AUC₂₄ fell within predicted range in 61% of cases. For comparison, a recent study from a large academic medical center reported that 73.5% of 2-level AUC₂₄ cases had initial values within the therapeutic range.¹⁸ Of note, the target range used was much wider (400 - 800 mg.h/L) than the present study. Another study reported dose adjustments for subtherapeutic AUC levels in 25% of cases and dose reductions for supratherapeutic levels in 33.3% of cases.¹⁹

Of the AUC₂₄ calculations that fell outside of therapeutic range, the majority (n = 8, 73%) were subtherapeutic (< 400 mg.h/L), half of these were for patients who were obese. It was unclear in the medical record which equation was used for initial dosing (Matzke vs Crass), or whether more conservative AUCs were used for calculating the total daily dose. The VHSO policy limiting loading doses also may have played a role; indeed the updated guidelines recommend a maximum loading dose of 3,000 mg depending on the severity of infection.⁴ Two of the 3 supratherapeutic levels were thought to be due to accumulation with long-term therapy.

Given such a large change from long-standing practices, there was surprisingly little resistance from the various clinical services. A recent survey of academic medical centers reported that the majority (88%) of all respondents who did not currently utilize AUC₂₄ monitoring did not plan on making this immediate transition, largely citing unfamiliarity and training requirements.²⁰ It is conceivable that the transition to AUC monitoring in smaller facilities may have fewer barriers than those seen in tertiary care centers. There are fewer health care providers and pharmacists to educate with the primary responsibilities falling on relatively few clinicians. There is little question as to who will be conducting follow up or whom to contact for questions. A smaller patient load and lesser patient acuity may translate to fewer vancomycin cases that require monitoring.

The interactive meetings were an important element for facility implementation. Research shows that emails alone are not effective for health care provider education, and interactive methods are recommended over passive methods.^21,22 Assessing and avoiding barriers up front such as unclear laboratory orders, or communication failures is paramount to successful implementation strategies.²³ Additionally, the detailed written ordering communication may have contributed to a smoother transition. The educational recording proved to be helpful in educating new staff and residents. An identified logistical error was that laboratory orders entered while patients were enrolled in sham clinics for electronic workload capture (eg, Pharmacy Inpatient Clinic) created confusion on the physical location of the patient for the phlebotomists, potentially causing delays in specimen collection.

A major development that stemmed from this intervention was that the Medical Service asked that policy changes be made so that the Pharmacy Service take over all vancomycin dosing at the facility. Previously, this had been done on a collaborative basis. Similar facilities with a collaborative practice model may need to anticipate such a request as this may present a new set of challenges. Accordingly, the pharmacy department is in the process of establishing standing operating procedures, pharmacist competencies, and a facility memorandum. Future research should evaluate the safety and efficacy of vancomycin therapy after the switch to AUC-based monitoring.

Limitations

There are several limitations to consider with this study. Operating procedures and implementation processes may vary between facilities, which could limit the generalizability of these results. Given the small facility size, the overall number of laboratory tests drawn was much smaller than those seen in larger facilities. The time needed for AUC calculations is notably longer than older methods of monitoring; however, this was not objectively assessed. It is important to note that clinical outcomes were beyond the scope of this gap analysis and this is an area of future research at the study facility. Vancomycin laboratory tests that were missed due to procedures and subsequently rescheduled were occasionally observed but not accounted for in this analysis. Additionally, vancomycin courses without monitoring (appropriate or otherwise) when indicated were not assessed. However, anecdotally speaking, this would be a very unlikely occurrence.

Conclusion

Conversion to AUC-based vancomycin monitoring is feasible in primary, rural medical centers. Implementation strategies from tertiary facilities can be successfully utilized in smaller hospitals. Quality assessment strategies such as a gap analysis can be utilized with minimal resources for facility uptake of new clinical practices.

The use of weight-based dosing with trough-based monitoring of vancomycin has been in clinical practice for more than a decade. The American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP) published the first guidelines for vancomycin monitoring in 2009.¹ Although it has been well established that area under the curve (AUC) over the minimal inhibitory concentration (MIC) ratio > 400 mg.h/L is the best predictor of clinical efficacy, obtaining this value in clinical practice was not pragmatic. Therefore, the 2009 guidelines recommended a goal vancomycin trough of 15 to 20 mcg/ml as a surrogate marker for AUC/MIC > 400 mg.hr/L. This has since become a common practice despite little data that support this recommendation.

The efficacy and safety of trough-based monitoring has been evaluated extensively over the past several years and more recent data suggest that there is wide patient variability in AUC with this method and higher trough levels are associated with more nephrotoxicity.^2,3 ASHP, IDSA, SIDP, and the Pediatric Infectious Diseases Society (PIDS) updated the consensus guidelines in 2020.⁴ Trough-based monitoring is no longer recommended. Instead AUC₂₄ monitoring should be implemented with a goal range of 400 to 600 mg.h/L for efficacy and safety. Given concerns for vancomycin penetration into the central nervous system (CNS), many facility protocols utilize higher targets (> 600 mg.h/L) for CNS infections.

Some hospitals have been utilizing AUC-based monitoring for years. There are strategies from tertiary care centers that drive this practice change in the medical literature.^5,6 However, it is important to reproduce these implementation practices in small, rural facilities that may face unique challenges with limited resources and may be slower to implement consensus guidelines.^7,8 As this is a major practice change, it is imperative to evaluate the extent of transition and identify areas of needed improvement.

Accurate therapeutic drug monitoring ensures both the safety and efficacy of vancomycin therapy. Unfortunately, research shows that inappropriate laboratory tests are common in medical facilities.⁹ Drug levels taken inappropriately can lead to delays in therapeutic decision-making, inappropriate dosage adjustments and create a need for repeated drug levels, which increases the overall cost of admission.

Given the multiple affected services needed to make successful practice transitions, it is paramount that facilities evaluate progress during the transition phase. The Agency for Healthcare Research and Quality and the Institute for Healthcare Improvement provide guidance in the Plan-Do-Study-Act Cycle for quality assessment and improvement of new initiatives.^10,11 A gap analysis can be used as a simple tool for evaluating the transition of research into practice and to identify areas of needed improvement.

The Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas made the transition from trough-based monitoring to 2-level AUC-based monitoring on April 1, 2019. The purpose of this study was to evaluate the effectiveness of transition methods used to implement AUC-monitoring for vancomycin treated patients in a small, primary facility. A further goal of the study was to identify areas of needed improvement and education and whether the problems derived from deficiencies in knowledge and ordering (medical and pharmacy services) or execution (nursing and laboratory services).

Methods

VHSO is a 52-bed US Department of Veterans Affairs primary care hospital. The pharmacy and laboratory are staffed 24 hours each day. There is 1 clinical pharmacy specialist (CPS) available for therapeutic drug monitoring consults Monday through Friday between the hours of 7:30 AM and 4:00 PM. No partial full-time equivalent employees were added for this conversion. Pharmacy-driven vancomycin dosing and monitoring is conducted on a collaborative basis, with pharmacy managing the majority of vancomycin treated patients. Night and weekend pharmacy staff provide cross-coverage on vancomycin consultations. Laboratory orders and medication dosage adjustments fall within the CPS scope of practice. Nurses do not perform laboratory draws for therapeutic drug monitoring; this is done solely by phlebotomists. There is no infectious diseases specialist at the facility to champion antibiotic dosing initiatives.

The implementation strategy largely reflected those outlined from tertiary care centers.^5,6 First, key personnel from the laboratory department met to discuss this practice change and to add vancomycin peaks to the ordering menu. A critical value was set at 40 mcg/ml. Vancomycin troughs and random levels already were orderable items. A comment field was added to all laboratory orders for further clarification. Verbiage was added to laboratory reports in the computerized medical record to assist clinicians in determining the appropriateness of the level. This was followed by an educational email to both the nursing and laboratory departments explaining the practice change and included a link to the Pharmacy Joe “Vancomycin Dosing by AUC:MIC Instead of Trough-level” podcast (www.pharmacyjoe.com episode 356).

The pharmacy department received an interactive 30-minute presentation, followed immediately by a group activity to discuss practice problems. This presentation was condensed, recorded, and emailed to all VHSO pharmacists. A shared folder contained pertinent material on AUC monitoring.

Finally, an interactive presentation was set up for hospitalists and a video teleconferencing was conducted for rotating medical residents. Both the podcast and recorded presentation were emailed to the entire medical staff with a brief introduction of the practice change. Additionally, the transition process was added as a standing item on the monthly antimicrobial stewardship meeting agenda.

The standardized pharmacokinetic model at the study facility consisted of a vancomycin volume of distribution of 0.7 mg/kg and elimination rate constant (Ke) by Matzke and colleagues for total daily dose calculations.¹² Obese patients (BMI ≥ 30) undergo alternative clearance equations described by Crass and colleagues.¹³ Cockcroft-Gault methods using ideal body weight (or actual body weight if < ideal body weight) are used for determining creatinine clearance. In patients aged ≥ 65 years with a serum creatinine < 1.0 mg/dL, facility guidance was to round serum creatinine up to 1.0 mg/dL. Loading doses were determined on a case-by-case basis with a cap of 2,000 mg, maintenance doses were rounded to the nearest 250 mg.

Vancomycin levels typically are drawn at steady state and analyzed using the logarithmic trapezoidal rule.¹⁴ The pharmacy and medical staff were educated to provide details on timing and coordination in nursing and laboratory orders (Table 1). Two-level AUC monitoring typically is not performed in patients with acute renal failure, expected duration of therapy < 72 hours, urinary tract infections, skin and soft tissue infections, or in renal replacement therapy.⁵

This gap analysis consisted of a retrospective chart review of vancomycin levels ordered after the implementation of AUC-based monitoring to determine the effectiveness of the transition. Three months of data were collected between April 2019 and June 2019. Vancomycin levels were deemed either appropriate or inappropriate based on timing and type (peak, trough, or random) of the laboratory test in relation to the previously administered vancomycin dose. Appropriate peaks were drawn within 2 hours after the end of infusion and troughs at least 1 half-life after the dose or just prior to the next dose and within the same dosing interval as the peak. Tests drawn outside of the specified time range, trough-only laboratory tests, or those drawn after vancomycin had been discontinued were considered inappropriate. Peaks and troughs drawn from separate dosing intervals also were considered inappropriate. Random levels were considered appropriate only if they fit the clinical context in acute renal failure or renal replacement therapy. An effective transition was defined as ≥ 80% of all vancomycin treated patients monitored with AUC methods rather than trough-based methods.

Inclusion criteria included all vancomycin levels ordered during the study period with no exclusions. The primary endpoint was the proportion of vancomycin levels drawn appropriately. Secondary endpoints were the proportion of AUC₂₄ calculations within therapeutic range and a stratification of reasons for inappropriate levels. Descriptive statistics were collected to describe the scope of the project. Levels drawn from various shifts were compared (ie, day, night, or weekend). Calculated AUC₂₄ levels between 400 and 600 mg.h/L were considered therapeutic unless treating CNS infection (600-700 mg.h/L). Given the operational outcomes (rather than clinical outcomes) and no comparator group, patient specific data were not collected.

Descriptive statistics without further analysis were used to describe proportions. The goal level for compliance was set at 100%. These methods were reviewed by the VHSO Institutional Review Board and granted nonresearch status, waiving the requirement for informed consent.

Results

The transition was effective with 97% of all cases utilizing AUC-based methods for monitoring. A total of 65 vancomycin levels were drawn in the study period; 32 peaks, 32 troughs, and 1 random level (drawn appropriately during acute renal failure 24 hours after starting therapy). All shifts were affected proportionately; days (n = 26, 40%), nights (n = 18, 27.7%), and weekends (n = 21, 32.3%). Based on time of dosage administration and laboratory test, there were 9 levels (13.8%) deemed inappropriate, 56 levels (86.1%) were appropriate. Reasons for inappropriate levels gleaned from chart review are presented in Table 2. Four levels had to be repeated for accurate calculations.

From the peak/trough couplets drawn appropriately, calculated AUC₂₄ fell with the desired range in 61% (n = 17) of cases. Of the 11 that fell outside of range, 8 were subtherapeutic (< 400 mg.h/L) and 3 were supratherapeutic (> 600 mg.h/L). All levels were drawn at steady state. Indications for vancomycin monitoring were osteomyelitis (n = 13, 43%), sepsis (n = 10, 33%), pneumonia (n = 6, 20%), and 1 case of meningitis (3%).

Discussion

To the author’s knowledge, this is the first report of a vancomycin AUC₂₄ monitoring conversion in a rural facility. This study adds to the existing medical literature in that it demonstrates that: (1) implementation methods described in large, tertiary centers can be effectively utilized in primary care, rural facilities; (2) the gap analysis used can be duplicated with minimal personnel and resources to ensure effective implementation (Table 3); and (3) the reported improvement needs can serve as a model for preventative measures at other facilities. The incidence of appropriate vancomycin levels was notably better than those reported in other single center studies.^15-17 However, given variations in study design and facility operating procedures, it would be difficult to compare incidence among medical facilities. As such, there are no consensus benchmarks for comparison. The majority of inappropriate levels occurred early in the study period and on weekends. Appropriateness of drug levels may have improved with continued feedback and familiarity.

The calculated AUC₂₄ fell within predicted range in 61% of cases. For comparison, a recent study from a large academic medical center reported that 73.5% of 2-level AUC₂₄ cases had initial values within the therapeutic range.¹⁸ Of note, the target range used was much wider (400 - 800 mg.h/L) than the present study. Another study reported dose adjustments for subtherapeutic AUC levels in 25% of cases and dose reductions for supratherapeutic levels in 33.3% of cases.¹⁹

Of the AUC₂₄ calculations that fell outside of therapeutic range, the majority (n = 8, 73%) were subtherapeutic (< 400 mg.h/L), half of these were for patients who were obese. It was unclear in the medical record which equation was used for initial dosing (Matzke vs Crass), or whether more conservative AUCs were used for calculating the total daily dose. The VHSO policy limiting loading doses also may have played a role; indeed the updated guidelines recommend a maximum loading dose of 3,000 mg depending on the severity of infection.⁴ Two of the 3 supratherapeutic levels were thought to be due to accumulation with long-term therapy.

Given such a large change from long-standing practices, there was surprisingly little resistance from the various clinical services. A recent survey of academic medical centers reported that the majority (88%) of all respondents who did not currently utilize AUC₂₄ monitoring did not plan on making this immediate transition, largely citing unfamiliarity and training requirements.²⁰ It is conceivable that the transition to AUC monitoring in smaller facilities may have fewer barriers than those seen in tertiary care centers. There are fewer health care providers and pharmacists to educate with the primary responsibilities falling on relatively few clinicians. There is little question as to who will be conducting follow up or whom to contact for questions. A smaller patient load and lesser patient acuity may translate to fewer vancomycin cases that require monitoring.

The interactive meetings were an important element for facility implementation. Research shows that emails alone are not effective for health care provider education, and interactive methods are recommended over passive methods.^21,22 Assessing and avoiding barriers up front such as unclear laboratory orders, or communication failures is paramount to successful implementation strategies.²³ Additionally, the detailed written ordering communication may have contributed to a smoother transition. The educational recording proved to be helpful in educating new staff and residents. An identified logistical error was that laboratory orders entered while patients were enrolled in sham clinics for electronic workload capture (eg, Pharmacy Inpatient Clinic) created confusion on the physical location of the patient for the phlebotomists, potentially causing delays in specimen collection.

A major development that stemmed from this intervention was that the Medical Service asked that policy changes be made so that the Pharmacy Service take over all vancomycin dosing at the facility. Previously, this had been done on a collaborative basis. Similar facilities with a collaborative practice model may need to anticipate such a request as this may present a new set of challenges. Accordingly, the pharmacy department is in the process of establishing standing operating procedures, pharmacist competencies, and a facility memorandum. Future research should evaluate the safety and efficacy of vancomycin therapy after the switch to AUC-based monitoring.

Limitations

There are several limitations to consider with this study. Operating procedures and implementation processes may vary between facilities, which could limit the generalizability of these results. Given the small facility size, the overall number of laboratory tests drawn was much smaller than those seen in larger facilities. The time needed for AUC calculations is notably longer than older methods of monitoring; however, this was not objectively assessed. It is important to note that clinical outcomes were beyond the scope of this gap analysis and this is an area of future research at the study facility. Vancomycin laboratory tests that were missed due to procedures and subsequently rescheduled were occasionally observed but not accounted for in this analysis. Additionally, vancomycin courses without monitoring (appropriate or otherwise) when indicated were not assessed. However, anecdotally speaking, this would be a very unlikely occurrence.

Conclusion

Conversion to AUC-based vancomycin monitoring is feasible in primary, rural medical centers. Implementation strategies from tertiary facilities can be successfully utilized in smaller hospitals. Quality assessment strategies such as a gap analysis can be utilized with minimal resources for facility uptake of new clinical practices.

Statins are one of the most common medications dispensed in the US and are associated with clinically significant drug interactions.^1,2 The most common adverse drug reaction (ADR) of statin drug interactions is muscle-related toxicities.² Despite technology advances to alert clinicians to drug interactions, updated statin manufacturer labeling, and guideline recommendations, inappropriate prescribing and dispensing of statin drug interactions continues to occur in health care systems.^2-10

The medical literature has demonstrated many opportunities for pharmacists to prevent and mitigate drug interactions. At the points of prescribing and dispensing, pharmacists can reduce the number of potential drug interactions for the patient.^11-13 Pharmacists also have identified and resolved drug interactions through quality assurance review after dispensing to a patient.^7,8

Regardless of the time point of an intervention, the most common method pharmacists used to resolve drug interactions was through recommendations to a prescriber. The recommendations were generated through academic detailing, clinical decision support algorithms, drug conversions, or the pharmacist’s expertise. Regardless of the method the pharmacist used, the prescriber had the final authority to accept or decline the recommendation.^7,8,11-13 Although these interventions were effective, pharmacists could further streamline the process by autonomously resolving drug interactions. However, these types of interventions are not well described in the medical literature.

Background

The US Department of Veterans Affairs (VA) Veterans Integrated Service Network (VISN), established the Safety Target of Polypharmacy (STOP) report in 2015. At each facility in the network, the report identified patients who were dispensed medications known to have drug interactions. The interactions were chosen by the VISN, and the severity of the interactions was based on coding parameters within the VA computerized order entry system, which uses a severity score based on First Databank data. At the Harry S. Truman Memorial Veterans’ Hospital (Truman VA) in Columbia, Missouri, > 500 drug interactions were initially active on the STOP report. The most common drug interactions were statins with gemfibrozil and statins with niacin.1^4-18 The Truman VA Pharmacy Service was charged with resolving the interactions for the facility.

The Truman VA employs 3 Patient Aligned Care Team (PACT) Clinical Pharmacy Specialists (CPS) practicing within primary care clinics. PACT is the patientcentered medical home model used by the VA. PACT CPS are ambulatory care pharmacists who assist providers in managing diseases using a scope of practice. Having a scope of practice would have allowed the PACT CPS to manage drug interactions with independent prescribing authority. However, due to the high volume of STOP report interactions and limited PACT CPS resources, the Pharmacy Service needed to develop an efficient, patient-centered method to resolve them. The intervention also needed to allow pharmacists, both with and without a scope of practice, to address the interactions.

Methods

The Truman VA Pharmacy Service developed protocols, approved by the Pharmacy and Therapeutics (P&T) Committee, to manage the specific gemfibrozil-statin and niacinstatin interactions chosen for the VISN 15 STOP report (Figures 1 and 2). The protocols were designed to identify patients who did not have a clear indication for gemfibrozil or niacin, were likely to maintain triglycerides (TGs) < 500 mg/dL without these medications, and would not likely require close monitoring after discontinuation^.19 The protocols allowed pharmacists to autonomously discontinue gemfibrozil or niacin if patients did not have a history of pancreatitis, TGs ≥ 400 mg/dL or a nonlipid indication for niacin (eg, pellagra) after establishing care at Truman VA. Additionally, both interacting medications had to be dispensed by the VA. When pharmacists discontinued a medication, it was documented in a note in the patient electronic health record. The prescriber was notified through the note and the patient received a notification letter. Follow-up laboratory monitoring was not required as part of the protocol.

If patients met any of the exclusion criteria for discontinuation, the primary care provider (PCP) was notified to place a consult to the PACT Pharmacy Clinic for individualized interventions and close monitoring. Patients prescribed niacin for nonlipid indications were allowed to continue with their current drug regimen. At each encounter, the PACT CPS assessed for ADRs, made individualized medication changes, and arranged follow-up appointments. Once the interaction was resolved and treatment goals met, the PCP resumed monitoring of the patient’s lipid therapy.

Following all pharmacist interventions, a retrospective quality improvement analysis was conducted. The primary outcome was to evaluate the impact of discontinuing gemfibrozil and niacin by protocol on patients’ laboratory results. The coprimary endpoints were to describe the change in TG levels and the percentage of patients with TGs ≥ 500 mg/dL at least 5 weeks following the pharmacist-directed discontinuation by protocol. Secondary outcomes included the time required to resolve the interactions and a description of the PACT CPS pharmacologic interventions. Additionally, a quality assurance peer review was used to ensure the pharmacists appropriately utilized the protocols.

Data were collected from August 2016 to September 2017 for patients prescribed gemfibrozil and from May 2017 to January 2018 for patients prescribed niacin. The time spent resolving interactions was quantified based on encounter data. Descriptive statistics were used to analyze demographic information and the endpoints associated with each outcome. The project was reviewed by the University of Missouri Institutional Review Board, Truman VA privacy and information security officers, and was determined to meet guidelines for quality improvement.

Results

The original STOP report included 397 drug interactions involving statins with gemfibrozil or niacin (Table 1). The majority of patients were white and male aged 60 to 79 years. Gemfibrozil was the most common drug involved in all interactions (79.8%). The most common statins were atorvastatin (40%) and simvastatin (36.5%).

Gemfibrozil-Statin Interactions

Pharmacists discontinued gemfibrozil by protocol for 94 patients (29.6%), and 107 patients (33.8%) were referred to the PACT Pharmacy Clinic (Figure 3). For the remaining 116 patients (36.6%), the drug interaction was addressed outside of the protocol for the following reasons: the drug interaction was resolved prior to pharmacist review; an interacting prescription was expired and not to be continued; the patient self-discontinued ≥ 1 interacting medications; the patient was deceased; the patient moved; the patient was receiving ≥ 1 interacting medications outside of the VA; or the prescriber resolved the interaction following notification by the pharmacist.

Ultimately, the interaction was resolved for all patients with a gemfibrozil-statin interaction on the STOP report. Following gemfibrozil discontinuation by protocol, 76 patients (80.9%) had TG laboratory results available and were included in the analysis. Sixty-two patients’ (82%) TG levels decreased or increased by < 100 mg/dL (Figure 4), and the TG levels of 1 patient (1.3%) increased above the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter was 6.5 (3.6) months (range, 1-17). The pharmacists spent a mean of 16 minutes per patient resolving each interaction.

Of the 107 patients referred to the PACT Pharmacy Clinic, 80 (74.8%) had TG laboratory results available and were included in the analysis. These patients were followed by the PACT CPS until the drug interaction was resolved and confirmed to have TG levels at goal (< 500 mg/dL). Gemfibrozil doses ranged from 300 mg daily to 600 mg twice daily, with 70% (n = 56) of patients taking 600 mg twice daily. The PACT CPS made 148 interventions (Table 2). Twenty-three (29%) patients required only gemfibrozil discontinuation. The remaining 57 patients (71%) required at least 2 medication interventions. The PACT CPS generated 213 encounters for resolving drug interactions with a median of 2 encounters per patient.

Quality assurance review identified 5 patients (5.3%) who underwent gemfibrozil discontinuation by protocol, despite having criteria that would have recommended against discontinuation. In accordance with the protocol criteria, these patients were later referred to the PACT Pharmacy Clinic. None of these patients experienced a TG increase at or above the threshold of 500 mg/dL after gemfibrozil was initially discontinued but were excluded from the earlier analysis.

Niacin-Statin Interactions

Pharmacists discontinued niacin by protocol for 48 patients (60.0%), and 22 patients (27.5%) were referred to the PACT Pharmacy Clinic (Figure 5). For the remaining 5 patients (6.3%), the interaction was either addressed outside the protocol prior to pharmacist review, or an interacting prescription was expired and not to be continued. Additionally, niacin was continued per prescriber preference in 5 patients (6.3%).

Thirty-six patients (75%) had TG laboratory results available following niacin discontinuation by protocol and were included in the analysis. Most patients’ (n = 33, 91.7%) TG levels decreased or increased by < 100 mg/dL. No patient had a TG level that increased higher than the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter, was 5.3 (2.5) months (range, 1.2-9.8). The pharmacists spent a mean of 15 minutes per patient resolving each interaction. The quality assurance review found no discrepancies in the pharmacists’ application of the protocol.

Of the 22 patients referred to the PACT Pharmacy Clinic, 16 (72.7%) patients had TG laboratory results available and were included in the analysis. As with the gemfibrozil interactions, these patients were followed by the PACT Pharmacy Clinic until the drug interaction was resolved and confirmed to have TGs at goal (< 500 mg/dL). Niacin doses ranged from 500 mg daily to 2,000 mg daily, with the majority of patients taking 1,000 mg daily. The PACT CPS made 23 interventions. The PACT CPS generated 46 encounters for resolving drug interactions with a median of 2 encounters per patient.

Discussion

Following gemfibrozil or niacin discontinuation by protocol, most patients with available laboratory results experienced either a decrease or modest TG elevation. The proportion of patients experiencing a decrease in TGs was unexpected but potentially multifactorial. Individual causes for the decrease in TGs were beyond the scope of this analysis. The retrospective design limited the ability to identify variables that could have impacted TG levels when gemfibrozil or niacin were started and discontinued. Although the treatment of TG levels is not indicated until it is ≥ 500 mg/dL, due to an increased risk of pancreatitis, both protocols excluded patients with a history of TGs ≥ 400 mg/dL.¹⁹ The lower threshold was set to compensate for anticipated increase in TG levels, following gemfibrozil or niacin discontinuation, and to minimize the number of patients with TG levels ≥ 500 mg/dL. The actual impact on patients’ TG levels supports the use of this lower threshold in the protocol.

When TG levels increased by 200 to 249 mg/dL after gemfibrozil or niacin discontinuation, patients were evaluated for possible underlying causes, which occurred for 4 gemfibrozil and 1 niacin patient. One patient started a β-blocker after gemfibrozil was initiated, and 3 patients were taking gemfibrozil prior to establishing care at the VA. The TG levels of the patient taking niacin correlated with an increased hemoglobin A1c. The TG level for only 1 patient taking gemfibrozil increased above the 500 mg/dL threshold. The patient had several comorbidities known to increase TG levels, but the comorbidities were previously well controlled. No additional medication changes were made at that time, and the TG levels on the next fasting lipid panel decreased to goal. The patient did not experience any negative clinical sequelae from the elevated TG levels.

Thirty-five patients (36%) who were referred to the PACT Pharmacy Clinic required only either gemfibrozil or niacin discontinuation. These patients were evaluated to identify whether adjustments to the protocols would have allowed for pharmacist discontinuation without referral to the PACT Pharmacy Clinic. Twenty-four of these patients (69%) had repeated TG levels ≥ 400 mg/dL prior to referral to the PACT Pharmacy Clinic. Additionally, there was no correlation between the gemfibrozil or niacin doses and the change in TG levels following discontinuation. These data indicate the protocols appropriately identified patients who did not have an indication for gemfibrozil or niacin.

In addition to drug interactions identified on the STOP report, the PACT CPS resolved 12 additional interactions involving simvastatin and gemfibrozil. Additionally, unnecessary lipid medications were deprescribed. The PACT CPS identified 13 patients who experienced myalgias, an ADR attributed to the gemfibrozil- statin interaction. Of those, 9 patients’ ADRs resolved after discontinuing gemfibrozil alone. For the remaining 4 patients, additional interventions to convert the patient to another statin were required to resolve the ADR.

Using pharmacists to address the drug interactions shifted workload from the prescribers and other primary care team members. The mean time spent to resolve both gemfibrozil and niacin interactions by protocol was 15.5 minutes. One hundred fortytwo patients (35.8%) had drug interactions resolved by protocol, saving the PACT CPS’ expertise for patients requiring individualized interventions. Drug interactions were resolved within 4 PACT CPS encounters for 93.8% of the patients taking gemfibrozil and within 3 PACT CPS encounters for 93.8% of the patients taking niacin.

The protocols allowed 12 additional pharmacists who did not have an ambulatory care scope of practice to assist the PACT CPS in mitigating the STOP drug interactions. These pharmacists otherwise would have been limited to making consultative recommendations. Simultaneously, the design allowed for the PACT pharmacists’ expertise to be allocated for patients most likely to require interventions beyond the protocols. This type of intraprofessional referral process is not well described in the medical literature. To the authors’ knowledge, the only studies described referrals from hospital pharmacists to community pharmacists during transitions of care on hospital discharge.^20,21

Limitations

The results of this study are derived from a retrospective chart review at a single VA facility. The autonomous nature of PACT CPS interventions may be difficult to replicate in other settings that do not permit pharmacists the same prescriptive authority. This analysis was designed to demonstrate the impact of the pharmacist in resolving major drug interactions. Patients referred to the PACT Pharmacy Clinic who also had their lipid medications adjusted by a nonpharmacist provider were excluded. However, this may have minimized the impact of the PACT CPS on the patient care provided. As postintervention laboratory results were not available for all patients, some patients’ TG levels could have increased above the 500 mg/dL threshold but were not identified. The time investment was extensive and likely underestimates the true cost of implementing the interventions.

Because notification letters were used to instruct patients to stop gemfibrozil or niacin, several considerations need to be addressed when interpreting the follow-up laboratory results. First, we cannot confirm whether the patients received the letter or the exact date the letter was received. Additionally, we cannot confirm whether the patients followed the instructions to stop the interacting medications or the date the medications were stopped. It is possible some patients were still taking the interacting medication when the first laboratory was drawn. Should a patient have continued the interacting medication, most would have run out and been unable to obtain a refill within 90 days of receiving the letter, as this is the maximum amount dispensed at one time. The mean time to the first laboratory result for both gemfibrozil and niacin was 6.5 and 5.3 months, respectively. Approximately 85% of patients completed the first laboratory test at least 3 months after the letter was mailed.

The protocols were designed to assess whether gemfibrozil or niacin was indicated and did not assess whether the statin was indicated. Therefore, discontinuing the statin also could have resolved the interaction appropriately. However, due to characteristics of the patient population and recommendations in current lipid guidelines, it was more likely the statin would be indicated.22,23 The protocols also assumed that patients eligible for gemfibrozil or niacin discontinuation would not need additional changes to their lipid medications. The medication changes made by the PACT CPS may have gone beyond those minimally necessary to resolve the drug interaction and maintain TG goals. Patients who had gemfibrozil or niacin discontinued by protocol also may have benefited from additional optimization of their lipid medications.

Conclusions

This quality improvement analysis supports further evaluation of the complementary use of protocols and PACT CPS prescriptive authority to resolve statin drug interactions. The gemfibrozil and niacin protocols appropriately identified patients who were less likely to experience an adverse change in TG laboratory results. Patients more likely to require additional medication interventions were appropriately referred to the PACT Pharmacy Clinics for individualized care. These data support expanded roles for pharmacists, across various settings, to mitigate select drug interactions at the Truman VA.

Acknowledgments
This quality improvement project is the result of work supported with resources and use of the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.

Statins are one of the most common medications dispensed in the US and are associated with clinically significant drug interactions.^1,2 The most common adverse drug reaction (ADR) of statin drug interactions is muscle-related toxicities.² Despite technology advances to alert clinicians to drug interactions, updated statin manufacturer labeling, and guideline recommendations, inappropriate prescribing and dispensing of statin drug interactions continues to occur in health care systems.^2-10

The medical literature has demonstrated many opportunities for pharmacists to prevent and mitigate drug interactions. At the points of prescribing and dispensing, pharmacists can reduce the number of potential drug interactions for the patient.^11-13 Pharmacists also have identified and resolved drug interactions through quality assurance review after dispensing to a patient.^7,8

Regardless of the time point of an intervention, the most common method pharmacists used to resolve drug interactions was through recommendations to a prescriber. The recommendations were generated through academic detailing, clinical decision support algorithms, drug conversions, or the pharmacist’s expertise. Regardless of the method the pharmacist used, the prescriber had the final authority to accept or decline the recommendation.^7,8,11-13 Although these interventions were effective, pharmacists could further streamline the process by autonomously resolving drug interactions. However, these types of interventions are not well described in the medical literature.

Background

The US Department of Veterans Affairs (VA) Veterans Integrated Service Network (VISN), established the Safety Target of Polypharmacy (STOP) report in 2015. At each facility in the network, the report identified patients who were dispensed medications known to have drug interactions. The interactions were chosen by the VISN, and the severity of the interactions was based on coding parameters within the VA computerized order entry system, which uses a severity score based on First Databank data. At the Harry S. Truman Memorial Veterans’ Hospital (Truman VA) in Columbia, Missouri, > 500 drug interactions were initially active on the STOP report. The most common drug interactions were statins with gemfibrozil and statins with niacin.1^4-18 The Truman VA Pharmacy Service was charged with resolving the interactions for the facility.

The Truman VA employs 3 Patient Aligned Care Team (PACT) Clinical Pharmacy Specialists (CPS) practicing within primary care clinics. PACT is the patientcentered medical home model used by the VA. PACT CPS are ambulatory care pharmacists who assist providers in managing diseases using a scope of practice. Having a scope of practice would have allowed the PACT CPS to manage drug interactions with independent prescribing authority. However, due to the high volume of STOP report interactions and limited PACT CPS resources, the Pharmacy Service needed to develop an efficient, patient-centered method to resolve them. The intervention also needed to allow pharmacists, both with and without a scope of practice, to address the interactions.

Methods

The Truman VA Pharmacy Service developed protocols, approved by the Pharmacy and Therapeutics (P&T) Committee, to manage the specific gemfibrozil-statin and niacinstatin interactions chosen for the VISN 15 STOP report (Figures 1 and 2). The protocols were designed to identify patients who did not have a clear indication for gemfibrozil or niacin, were likely to maintain triglycerides (TGs) < 500 mg/dL without these medications, and would not likely require close monitoring after discontinuation^.19 The protocols allowed pharmacists to autonomously discontinue gemfibrozil or niacin if patients did not have a history of pancreatitis, TGs ≥ 400 mg/dL or a nonlipid indication for niacin (eg, pellagra) after establishing care at Truman VA. Additionally, both interacting medications had to be dispensed by the VA. When pharmacists discontinued a medication, it was documented in a note in the patient electronic health record. The prescriber was notified through the note and the patient received a notification letter. Follow-up laboratory monitoring was not required as part of the protocol.

If patients met any of the exclusion criteria for discontinuation, the primary care provider (PCP) was notified to place a consult to the PACT Pharmacy Clinic for individualized interventions and close monitoring. Patients prescribed niacin for nonlipid indications were allowed to continue with their current drug regimen. At each encounter, the PACT CPS assessed for ADRs, made individualized medication changes, and arranged follow-up appointments. Once the interaction was resolved and treatment goals met, the PCP resumed monitoring of the patient’s lipid therapy.

Following all pharmacist interventions, a retrospective quality improvement analysis was conducted. The primary outcome was to evaluate the impact of discontinuing gemfibrozil and niacin by protocol on patients’ laboratory results. The coprimary endpoints were to describe the change in TG levels and the percentage of patients with TGs ≥ 500 mg/dL at least 5 weeks following the pharmacist-directed discontinuation by protocol. Secondary outcomes included the time required to resolve the interactions and a description of the PACT CPS pharmacologic interventions. Additionally, a quality assurance peer review was used to ensure the pharmacists appropriately utilized the protocols.

Data were collected from August 2016 to September 2017 for patients prescribed gemfibrozil and from May 2017 to January 2018 for patients prescribed niacin. The time spent resolving interactions was quantified based on encounter data. Descriptive statistics were used to analyze demographic information and the endpoints associated with each outcome. The project was reviewed by the University of Missouri Institutional Review Board, Truman VA privacy and information security officers, and was determined to meet guidelines for quality improvement.

Results

The original STOP report included 397 drug interactions involving statins with gemfibrozil or niacin (Table 1). The majority of patients were white and male aged 60 to 79 years. Gemfibrozil was the most common drug involved in all interactions (79.8%). The most common statins were atorvastatin (40%) and simvastatin (36.5%).

Gemfibrozil-Statin Interactions

Pharmacists discontinued gemfibrozil by protocol for 94 patients (29.6%), and 107 patients (33.8%) were referred to the PACT Pharmacy Clinic (Figure 3). For the remaining 116 patients (36.6%), the drug interaction was addressed outside of the protocol for the following reasons: the drug interaction was resolved prior to pharmacist review; an interacting prescription was expired and not to be continued; the patient self-discontinued ≥ 1 interacting medications; the patient was deceased; the patient moved; the patient was receiving ≥ 1 interacting medications outside of the VA; or the prescriber resolved the interaction following notification by the pharmacist.

Ultimately, the interaction was resolved for all patients with a gemfibrozil-statin interaction on the STOP report. Following gemfibrozil discontinuation by protocol, 76 patients (80.9%) had TG laboratory results available and were included in the analysis. Sixty-two patients’ (82%) TG levels decreased or increased by < 100 mg/dL (Figure 4), and the TG levels of 1 patient (1.3%) increased above the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter was 6.5 (3.6) months (range, 1-17). The pharmacists spent a mean of 16 minutes per patient resolving each interaction.

Of the 107 patients referred to the PACT Pharmacy Clinic, 80 (74.8%) had TG laboratory results available and were included in the analysis. These patients were followed by the PACT CPS until the drug interaction was resolved and confirmed to have TG levels at goal (< 500 mg/dL). Gemfibrozil doses ranged from 300 mg daily to 600 mg twice daily, with 70% (n = 56) of patients taking 600 mg twice daily. The PACT CPS made 148 interventions (Table 2). Twenty-three (29%) patients required only gemfibrozil discontinuation. The remaining 57 patients (71%) required at least 2 medication interventions. The PACT CPS generated 213 encounters for resolving drug interactions with a median of 2 encounters per patient.

Quality assurance review identified 5 patients (5.3%) who underwent gemfibrozil discontinuation by protocol, despite having criteria that would have recommended against discontinuation. In accordance with the protocol criteria, these patients were later referred to the PACT Pharmacy Clinic. None of these patients experienced a TG increase at or above the threshold of 500 mg/dL after gemfibrozil was initially discontinued but were excluded from the earlier analysis.

Niacin-Statin Interactions

Pharmacists discontinued niacin by protocol for 48 patients (60.0%), and 22 patients (27.5%) were referred to the PACT Pharmacy Clinic (Figure 5). For the remaining 5 patients (6.3%), the interaction was either addressed outside the protocol prior to pharmacist review, or an interacting prescription was expired and not to be continued. Additionally, niacin was continued per prescriber preference in 5 patients (6.3%).

Thirty-six patients (75%) had TG laboratory results available following niacin discontinuation by protocol and were included in the analysis. Most patients’ (n = 33, 91.7%) TG levels decreased or increased by < 100 mg/dL. No patient had a TG level that increased higher than the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter, was 5.3 (2.5) months (range, 1.2-9.8). The pharmacists spent a mean of 15 minutes per patient resolving each interaction. The quality assurance review found no discrepancies in the pharmacists’ application of the protocol.

Of the 22 patients referred to the PACT Pharmacy Clinic, 16 (72.7%) patients had TG laboratory results available and were included in the analysis. As with the gemfibrozil interactions, these patients were followed by the PACT Pharmacy Clinic until the drug interaction was resolved and confirmed to have TGs at goal (< 500 mg/dL). Niacin doses ranged from 500 mg daily to 2,000 mg daily, with the majority of patients taking 1,000 mg daily. The PACT CPS made 23 interventions. The PACT CPS generated 46 encounters for resolving drug interactions with a median of 2 encounters per patient.

Discussion

Following gemfibrozil or niacin discontinuation by protocol, most patients with available laboratory results experienced either a decrease or modest TG elevation. The proportion of patients experiencing a decrease in TGs was unexpected but potentially multifactorial. Individual causes for the decrease in TGs were beyond the scope of this analysis. The retrospective design limited the ability to identify variables that could have impacted TG levels when gemfibrozil or niacin were started and discontinued. Although the treatment of TG levels is not indicated until it is ≥ 500 mg/dL, due to an increased risk of pancreatitis, both protocols excluded patients with a history of TGs ≥ 400 mg/dL.¹⁹ The lower threshold was set to compensate for anticipated increase in TG levels, following gemfibrozil or niacin discontinuation, and to minimize the number of patients with TG levels ≥ 500 mg/dL. The actual impact on patients’ TG levels supports the use of this lower threshold in the protocol.

When TG levels increased by 200 to 249 mg/dL after gemfibrozil or niacin discontinuation, patients were evaluated for possible underlying causes, which occurred for 4 gemfibrozil and 1 niacin patient. One patient started a β-blocker after gemfibrozil was initiated, and 3 patients were taking gemfibrozil prior to establishing care at the VA. The TG levels of the patient taking niacin correlated with an increased hemoglobin A1c. The TG level for only 1 patient taking gemfibrozil increased above the 500 mg/dL threshold. The patient had several comorbidities known to increase TG levels, but the comorbidities were previously well controlled. No additional medication changes were made at that time, and the TG levels on the next fasting lipid panel decreased to goal. The patient did not experience any negative clinical sequelae from the elevated TG levels.

Thirty-five patients (36%) who were referred to the PACT Pharmacy Clinic required only either gemfibrozil or niacin discontinuation. These patients were evaluated to identify whether adjustments to the protocols would have allowed for pharmacist discontinuation without referral to the PACT Pharmacy Clinic. Twenty-four of these patients (69%) had repeated TG levels ≥ 400 mg/dL prior to referral to the PACT Pharmacy Clinic. Additionally, there was no correlation between the gemfibrozil or niacin doses and the change in TG levels following discontinuation. These data indicate the protocols appropriately identified patients who did not have an indication for gemfibrozil or niacin.

In addition to drug interactions identified on the STOP report, the PACT CPS resolved 12 additional interactions involving simvastatin and gemfibrozil. Additionally, unnecessary lipid medications were deprescribed. The PACT CPS identified 13 patients who experienced myalgias, an ADR attributed to the gemfibrozil- statin interaction. Of those, 9 patients’ ADRs resolved after discontinuing gemfibrozil alone. For the remaining 4 patients, additional interventions to convert the patient to another statin were required to resolve the ADR.

Using pharmacists to address the drug interactions shifted workload from the prescribers and other primary care team members. The mean time spent to resolve both gemfibrozil and niacin interactions by protocol was 15.5 minutes. One hundred fortytwo patients (35.8%) had drug interactions resolved by protocol, saving the PACT CPS’ expertise for patients requiring individualized interventions. Drug interactions were resolved within 4 PACT CPS encounters for 93.8% of the patients taking gemfibrozil and within 3 PACT CPS encounters for 93.8% of the patients taking niacin.

The protocols allowed 12 additional pharmacists who did not have an ambulatory care scope of practice to assist the PACT CPS in mitigating the STOP drug interactions. These pharmacists otherwise would have been limited to making consultative recommendations. Simultaneously, the design allowed for the PACT pharmacists’ expertise to be allocated for patients most likely to require interventions beyond the protocols. This type of intraprofessional referral process is not well described in the medical literature. To the authors’ knowledge, the only studies described referrals from hospital pharmacists to community pharmacists during transitions of care on hospital discharge.^20,21

Limitations

The results of this study are derived from a retrospective chart review at a single VA facility. The autonomous nature of PACT CPS interventions may be difficult to replicate in other settings that do not permit pharmacists the same prescriptive authority. This analysis was designed to demonstrate the impact of the pharmacist in resolving major drug interactions. Patients referred to the PACT Pharmacy Clinic who also had their lipid medications adjusted by a nonpharmacist provider were excluded. However, this may have minimized the impact of the PACT CPS on the patient care provided. As postintervention laboratory results were not available for all patients, some patients’ TG levels could have increased above the 500 mg/dL threshold but were not identified. The time investment was extensive and likely underestimates the true cost of implementing the interventions.

Because notification letters were used to instruct patients to stop gemfibrozil or niacin, several considerations need to be addressed when interpreting the follow-up laboratory results. First, we cannot confirm whether the patients received the letter or the exact date the letter was received. Additionally, we cannot confirm whether the patients followed the instructions to stop the interacting medications or the date the medications were stopped. It is possible some patients were still taking the interacting medication when the first laboratory was drawn. Should a patient have continued the interacting medication, most would have run out and been unable to obtain a refill within 90 days of receiving the letter, as this is the maximum amount dispensed at one time. The mean time to the first laboratory result for both gemfibrozil and niacin was 6.5 and 5.3 months, respectively. Approximately 85% of patients completed the first laboratory test at least 3 months after the letter was mailed.

The protocols were designed to assess whether gemfibrozil or niacin was indicated and did not assess whether the statin was indicated. Therefore, discontinuing the statin also could have resolved the interaction appropriately. However, due to characteristics of the patient population and recommendations in current lipid guidelines, it was more likely the statin would be indicated.22,23 The protocols also assumed that patients eligible for gemfibrozil or niacin discontinuation would not need additional changes to their lipid medications. The medication changes made by the PACT CPS may have gone beyond those minimally necessary to resolve the drug interaction and maintain TG goals. Patients who had gemfibrozil or niacin discontinued by protocol also may have benefited from additional optimization of their lipid medications.

Conclusions

This quality improvement analysis supports further evaluation of the complementary use of protocols and PACT CPS prescriptive authority to resolve statin drug interactions. The gemfibrozil and niacin protocols appropriately identified patients who were less likely to experience an adverse change in TG laboratory results. Patients more likely to require additional medication interventions were appropriately referred to the PACT Pharmacy Clinics for individualized care. These data support expanded roles for pharmacists, across various settings, to mitigate select drug interactions at the Truman VA.

Acknowledgments
This quality improvement project is the result of work supported with resources and use of the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.

Statins are one of the most common medications dispensed in the US and are associated with clinically significant drug interactions.^1,2 The most common adverse drug reaction (ADR) of statin drug interactions is muscle-related toxicities.² Despite technology advances to alert clinicians to drug interactions, updated statin manufacturer labeling, and guideline recommendations, inappropriate prescribing and dispensing of statin drug interactions continues to occur in health care systems.^2-10

The medical literature has demonstrated many opportunities for pharmacists to prevent and mitigate drug interactions. At the points of prescribing and dispensing, pharmacists can reduce the number of potential drug interactions for the patient.^11-13 Pharmacists also have identified and resolved drug interactions through quality assurance review after dispensing to a patient.^7,8

Regardless of the time point of an intervention, the most common method pharmacists used to resolve drug interactions was through recommendations to a prescriber. The recommendations were generated through academic detailing, clinical decision support algorithms, drug conversions, or the pharmacist’s expertise. Regardless of the method the pharmacist used, the prescriber had the final authority to accept or decline the recommendation.^7,8,11-13 Although these interventions were effective, pharmacists could further streamline the process by autonomously resolving drug interactions. However, these types of interventions are not well described in the medical literature.

Background

The US Department of Veterans Affairs (VA) Veterans Integrated Service Network (VISN), established the Safety Target of Polypharmacy (STOP) report in 2015. At each facility in the network, the report identified patients who were dispensed medications known to have drug interactions. The interactions were chosen by the VISN, and the severity of the interactions was based on coding parameters within the VA computerized order entry system, which uses a severity score based on First Databank data. At the Harry S. Truman Memorial Veterans’ Hospital (Truman VA) in Columbia, Missouri, > 500 drug interactions were initially active on the STOP report. The most common drug interactions were statins with gemfibrozil and statins with niacin.1^4-18 The Truman VA Pharmacy Service was charged with resolving the interactions for the facility.

The Truman VA employs 3 Patient Aligned Care Team (PACT) Clinical Pharmacy Specialists (CPS) practicing within primary care clinics. PACT is the patientcentered medical home model used by the VA. PACT CPS are ambulatory care pharmacists who assist providers in managing diseases using a scope of practice. Having a scope of practice would have allowed the PACT CPS to manage drug interactions with independent prescribing authority. However, due to the high volume of STOP report interactions and limited PACT CPS resources, the Pharmacy Service needed to develop an efficient, patient-centered method to resolve them. The intervention also needed to allow pharmacists, both with and without a scope of practice, to address the interactions.

Methods

The Truman VA Pharmacy Service developed protocols, approved by the Pharmacy and Therapeutics (P&T) Committee, to manage the specific gemfibrozil-statin and niacinstatin interactions chosen for the VISN 15 STOP report (Figures 1 and 2). The protocols were designed to identify patients who did not have a clear indication for gemfibrozil or niacin, were likely to maintain triglycerides (TGs) < 500 mg/dL without these medications, and would not likely require close monitoring after discontinuation^.19 The protocols allowed pharmacists to autonomously discontinue gemfibrozil or niacin if patients did not have a history of pancreatitis, TGs ≥ 400 mg/dL or a nonlipid indication for niacin (eg, pellagra) after establishing care at Truman VA. Additionally, both interacting medications had to be dispensed by the VA. When pharmacists discontinued a medication, it was documented in a note in the patient electronic health record. The prescriber was notified through the note and the patient received a notification letter. Follow-up laboratory monitoring was not required as part of the protocol.

If patients met any of the exclusion criteria for discontinuation, the primary care provider (PCP) was notified to place a consult to the PACT Pharmacy Clinic for individualized interventions and close monitoring. Patients prescribed niacin for nonlipid indications were allowed to continue with their current drug regimen. At each encounter, the PACT CPS assessed for ADRs, made individualized medication changes, and arranged follow-up appointments. Once the interaction was resolved and treatment goals met, the PCP resumed monitoring of the patient’s lipid therapy.

Following all pharmacist interventions, a retrospective quality improvement analysis was conducted. The primary outcome was to evaluate the impact of discontinuing gemfibrozil and niacin by protocol on patients’ laboratory results. The coprimary endpoints were to describe the change in TG levels and the percentage of patients with TGs ≥ 500 mg/dL at least 5 weeks following the pharmacist-directed discontinuation by protocol. Secondary outcomes included the time required to resolve the interactions and a description of the PACT CPS pharmacologic interventions. Additionally, a quality assurance peer review was used to ensure the pharmacists appropriately utilized the protocols.

Data were collected from August 2016 to September 2017 for patients prescribed gemfibrozil and from May 2017 to January 2018 for patients prescribed niacin. The time spent resolving interactions was quantified based on encounter data. Descriptive statistics were used to analyze demographic information and the endpoints associated with each outcome. The project was reviewed by the University of Missouri Institutional Review Board, Truman VA privacy and information security officers, and was determined to meet guidelines for quality improvement.

Results

The original STOP report included 397 drug interactions involving statins with gemfibrozil or niacin (Table 1). The majority of patients were white and male aged 60 to 79 years. Gemfibrozil was the most common drug involved in all interactions (79.8%). The most common statins were atorvastatin (40%) and simvastatin (36.5%).

Gemfibrozil-Statin Interactions

Pharmacists discontinued gemfibrozil by protocol for 94 patients (29.6%), and 107 patients (33.8%) were referred to the PACT Pharmacy Clinic (Figure 3). For the remaining 116 patients (36.6%), the drug interaction was addressed outside of the protocol for the following reasons: the drug interaction was resolved prior to pharmacist review; an interacting prescription was expired and not to be continued; the patient self-discontinued ≥ 1 interacting medications; the patient was deceased; the patient moved; the patient was receiving ≥ 1 interacting medications outside of the VA; or the prescriber resolved the interaction following notification by the pharmacist.

Ultimately, the interaction was resolved for all patients with a gemfibrozil-statin interaction on the STOP report. Following gemfibrozil discontinuation by protocol, 76 patients (80.9%) had TG laboratory results available and were included in the analysis. Sixty-two patients’ (82%) TG levels decreased or increased by < 100 mg/dL (Figure 4), and the TG levels of 1 patient (1.3%) increased above the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter was 6.5 (3.6) months (range, 1-17). The pharmacists spent a mean of 16 minutes per patient resolving each interaction.

Of the 107 patients referred to the PACT Pharmacy Clinic, 80 (74.8%) had TG laboratory results available and were included in the analysis. These patients were followed by the PACT CPS until the drug interaction was resolved and confirmed to have TG levels at goal (< 500 mg/dL). Gemfibrozil doses ranged from 300 mg daily to 600 mg twice daily, with 70% (n = 56) of patients taking 600 mg twice daily. The PACT CPS made 148 interventions (Table 2). Twenty-three (29%) patients required only gemfibrozil discontinuation. The remaining 57 patients (71%) required at least 2 medication interventions. The PACT CPS generated 213 encounters for resolving drug interactions with a median of 2 encounters per patient.

Quality assurance review identified 5 patients (5.3%) who underwent gemfibrozil discontinuation by protocol, despite having criteria that would have recommended against discontinuation. In accordance with the protocol criteria, these patients were later referred to the PACT Pharmacy Clinic. None of these patients experienced a TG increase at or above the threshold of 500 mg/dL after gemfibrozil was initially discontinued but were excluded from the earlier analysis.

Niacin-Statin Interactions

Pharmacists discontinued niacin by protocol for 48 patients (60.0%), and 22 patients (27.5%) were referred to the PACT Pharmacy Clinic (Figure 5). For the remaining 5 patients (6.3%), the interaction was either addressed outside the protocol prior to pharmacist review, or an interacting prescription was expired and not to be continued. Additionally, niacin was continued per prescriber preference in 5 patients (6.3%).

Thirty-six patients (75%) had TG laboratory results available following niacin discontinuation by protocol and were included in the analysis. Most patients’ (n = 33, 91.7%) TG levels decreased or increased by < 100 mg/dL. No patient had a TG level that increased higher than the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter, was 5.3 (2.5) months (range, 1.2-9.8). The pharmacists spent a mean of 15 minutes per patient resolving each interaction. The quality assurance review found no discrepancies in the pharmacists’ application of the protocol.

Of the 22 patients referred to the PACT Pharmacy Clinic, 16 (72.7%) patients had TG laboratory results available and were included in the analysis. As with the gemfibrozil interactions, these patients were followed by the PACT Pharmacy Clinic until the drug interaction was resolved and confirmed to have TGs at goal (< 500 mg/dL). Niacin doses ranged from 500 mg daily to 2,000 mg daily, with the majority of patients taking 1,000 mg daily. The PACT CPS made 23 interventions. The PACT CPS generated 46 encounters for resolving drug interactions with a median of 2 encounters per patient.

Discussion

Following gemfibrozil or niacin discontinuation by protocol, most patients with available laboratory results experienced either a decrease or modest TG elevation. The proportion of patients experiencing a decrease in TGs was unexpected but potentially multifactorial. Individual causes for the decrease in TGs were beyond the scope of this analysis. The retrospective design limited the ability to identify variables that could have impacted TG levels when gemfibrozil or niacin were started and discontinued. Although the treatment of TG levels is not indicated until it is ≥ 500 mg/dL, due to an increased risk of pancreatitis, both protocols excluded patients with a history of TGs ≥ 400 mg/dL.¹⁹ The lower threshold was set to compensate for anticipated increase in TG levels, following gemfibrozil or niacin discontinuation, and to minimize the number of patients with TG levels ≥ 500 mg/dL. The actual impact on patients’ TG levels supports the use of this lower threshold in the protocol.

When TG levels increased by 200 to 249 mg/dL after gemfibrozil or niacin discontinuation, patients were evaluated for possible underlying causes, which occurred for 4 gemfibrozil and 1 niacin patient. One patient started a β-blocker after gemfibrozil was initiated, and 3 patients were taking gemfibrozil prior to establishing care at the VA. The TG levels of the patient taking niacin correlated with an increased hemoglobin A1c. The TG level for only 1 patient taking gemfibrozil increased above the 500 mg/dL threshold. The patient had several comorbidities known to increase TG levels, but the comorbidities were previously well controlled. No additional medication changes were made at that time, and the TG levels on the next fasting lipid panel decreased to goal. The patient did not experience any negative clinical sequelae from the elevated TG levels.

Thirty-five patients (36%) who were referred to the PACT Pharmacy Clinic required only either gemfibrozil or niacin discontinuation. These patients were evaluated to identify whether adjustments to the protocols would have allowed for pharmacist discontinuation without referral to the PACT Pharmacy Clinic. Twenty-four of these patients (69%) had repeated TG levels ≥ 400 mg/dL prior to referral to the PACT Pharmacy Clinic. Additionally, there was no correlation between the gemfibrozil or niacin doses and the change in TG levels following discontinuation. These data indicate the protocols appropriately identified patients who did not have an indication for gemfibrozil or niacin.

In addition to drug interactions identified on the STOP report, the PACT CPS resolved 12 additional interactions involving simvastatin and gemfibrozil. Additionally, unnecessary lipid medications were deprescribed. The PACT CPS identified 13 patients who experienced myalgias, an ADR attributed to the gemfibrozil- statin interaction. Of those, 9 patients’ ADRs resolved after discontinuing gemfibrozil alone. For the remaining 4 patients, additional interventions to convert the patient to another statin were required to resolve the ADR.

Using pharmacists to address the drug interactions shifted workload from the prescribers and other primary care team members. The mean time spent to resolve both gemfibrozil and niacin interactions by protocol was 15.5 minutes. One hundred fortytwo patients (35.8%) had drug interactions resolved by protocol, saving the PACT CPS’ expertise for patients requiring individualized interventions. Drug interactions were resolved within 4 PACT CPS encounters for 93.8% of the patients taking gemfibrozil and within 3 PACT CPS encounters for 93.8% of the patients taking niacin.

The protocols allowed 12 additional pharmacists who did not have an ambulatory care scope of practice to assist the PACT CPS in mitigating the STOP drug interactions. These pharmacists otherwise would have been limited to making consultative recommendations. Simultaneously, the design allowed for the PACT pharmacists’ expertise to be allocated for patients most likely to require interventions beyond the protocols. This type of intraprofessional referral process is not well described in the medical literature. To the authors’ knowledge, the only studies described referrals from hospital pharmacists to community pharmacists during transitions of care on hospital discharge.^20,21

Limitations

The results of this study are derived from a retrospective chart review at a single VA facility. The autonomous nature of PACT CPS interventions may be difficult to replicate in other settings that do not permit pharmacists the same prescriptive authority. This analysis was designed to demonstrate the impact of the pharmacist in resolving major drug interactions. Patients referred to the PACT Pharmacy Clinic who also had their lipid medications adjusted by a nonpharmacist provider were excluded. However, this may have minimized the impact of the PACT CPS on the patient care provided. As postintervention laboratory results were not available for all patients, some patients’ TG levels could have increased above the 500 mg/dL threshold but were not identified. The time investment was extensive and likely underestimates the true cost of implementing the interventions.

Because notification letters were used to instruct patients to stop gemfibrozil or niacin, several considerations need to be addressed when interpreting the follow-up laboratory results. First, we cannot confirm whether the patients received the letter or the exact date the letter was received. Additionally, we cannot confirm whether the patients followed the instructions to stop the interacting medications or the date the medications were stopped. It is possible some patients were still taking the interacting medication when the first laboratory was drawn. Should a patient have continued the interacting medication, most would have run out and been unable to obtain a refill within 90 days of receiving the letter, as this is the maximum amount dispensed at one time. The mean time to the first laboratory result for both gemfibrozil and niacin was 6.5 and 5.3 months, respectively. Approximately 85% of patients completed the first laboratory test at least 3 months after the letter was mailed.

The protocols were designed to assess whether gemfibrozil or niacin was indicated and did not assess whether the statin was indicated. Therefore, discontinuing the statin also could have resolved the interaction appropriately. However, due to characteristics of the patient population and recommendations in current lipid guidelines, it was more likely the statin would be indicated.22,23 The protocols also assumed that patients eligible for gemfibrozil or niacin discontinuation would not need additional changes to their lipid medications. The medication changes made by the PACT CPS may have gone beyond those minimally necessary to resolve the drug interaction and maintain TG goals. Patients who had gemfibrozil or niacin discontinued by protocol also may have benefited from additional optimization of their lipid medications.

Conclusions

This quality improvement analysis supports further evaluation of the complementary use of protocols and PACT CPS prescriptive authority to resolve statin drug interactions. The gemfibrozil and niacin protocols appropriately identified patients who were less likely to experience an adverse change in TG laboratory results. Patients more likely to require additional medication interventions were appropriately referred to the PACT Pharmacy Clinics for individualized care. These data support expanded roles for pharmacists, across various settings, to mitigate select drug interactions at the Truman VA.

Acknowledgments
This quality improvement project is the result of work supported with resources and use of the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy approved by the US Food and Drug Administration (FDA) for mental health indications but not widely available in the US Department of Veterans Affairs (VA). rTMS uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain.¹ The area of the brain targeted depends on the shape of the magnetic coil and dose of stimulation (Figures 1 and 2). The most common coil shape is the figure-8 coil, which is believed to stimulate about a 2- to 3-cm² area of the brain at a depth of about 2 cm from the coil surface. The stimulus is thought to activate certain nerve growth factors and ultimately relevant neurotransmitters in the stimulated areas and parts of the brain connected to where the stimulus occurs.²

The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The FDA has approved rTMS for the treatment of MDD and for at least 4 device manufacturers. The treatment has been studied in multiple clinical trials.³ An overview of these trials, additional rTMS training and educational materials, and device information can be accessed at www.mirecc.va.gov/visn21/education/tms_education.asp. rTMS for MDD administers a personalized dose with stimulation delivered over the dorsolateral prefrontal cortex. A typical clinical course runs for 40 minutes a day for 20 to 30 sessions. In addition to studies of depression,^1,4-7 rTMS has been studied for the following diseases and conditions:

• Headache (especially migraine)⁸
• Alzheimer disease⁹
• Obsessive compulsive disorder (OCD)¹⁰
• Obesity¹¹
• Schizophrenia¹²
• Posttraumatic stress disorder (PTSD)¹³
• Alcohol and nicotine dependence¹⁴

The FDA also has approved the use of rTMS for OCD. In addition, some health care providers (HCPs) are treating depression with rTMS in conjunction with electroconvulsive therapy (ECT).

Treatment for Veterans

MDD is one of the most significant risk factors for suicide. Therefore, treating depression with rTMS would likely diminish suicide risk. The annual suicide rate among veterans has been higher than the national average.¹⁵ However, most of these veterans are not getting their care at the Veterans Health Administration (VHA). Major efforts at the VA have been made to address this problem, including modification and promotion of the Veterans Crisis Line, increased mental health clinic hours, mental health same-day appointment availability for veterans, as well as raising awareness of suicide and suicidal ideation.¹⁶ George and colleagues showed that it is safe and feasible to treat acutely suicidal inpatients at a VA or US Department of Defense hospital over an intensive 3 day, 3 treatments per day regimen. This regimen would be potentially useful in a suicidal inpatient population, a technically and ethically difficult group to study.¹⁷

MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief.¹⁷ There clearly is a need for additional treatment options. MDD and OCD are the only indications that have received FDA approval for rTMS use. The initial FDA approval for MDD was based on a 2007 study of medication-free patients who had failed previous therapy and found a significant effect of rTMS compared with a sham procedure.⁷ MDD remains a common problem among veterans who have failed one or more antidepressant medications. Such patients might benefit from rTMS.^6,18

rTMS has several advantages over ECT, another significant FDA-approved, nonpharmacologic treatment alternative for medication-refractory MDD. rTMS is less invasive, requires fewer resources, does not require anesthesia or restrict activities, and does not cause memory loss. After an rTMS treatment, the patient can drive home.

Nationwide Pilot Program

The VA pilot program was created to supply rTMS machines nationwide to VHA sites and to offer a framework for establishing a clinical program. Preliminary program evaluation data suggest patients experienced a reduction in depression and suicidal ideation.

There were many challenges to implementation; for example, one VA site was eager to start using the device but could not secure space or personnel. An interdisciplinary team consisting of physicians, nurses, psychologists, suicide prevention coordinators, and others in the VA Palo Alto Health Care System (VAPAHCS) Precision Neurostimulation Clinic (PNC) has been instrumental in overcoming these challenges. VAPAHCS oversees the pilot and employs the national director.

Thirty-five sites nationwide were initially selected due to their ability to provide space for a rTMS machine and appropriate staffing to set up and run a Clinic (Figure 3). The pilot started with tertiary care VA medical centers then expanded to include community-based outpatient clinics as resources permitted. Sites that were unable to meet these standards were not included. Of these 35 original sites, 26 are treating patients and collecting data. Some early delays were due to unassigned relative value units (RVUs) to rTMS, which since have been revised as imputed RVU values. The American Medical Association established and defined RVUs to compare the value of different health care roles.¹⁹ The clinics have been established with smooth operations as the pilot program has provided the infrastructure.

REDCap (www.project-redcap.org), a data collection tool used primarily in academic research settings, was selected to gather program evaluation data through patient questionnaires informed by the VHA measurement-based care initiative. Standard psychometrics were readily available in the VHA application and REDCap Mental Health Assistant includes the Patient Health Questionnaire 9 (PHQ-9) Brief Symptom Inventory 18, Posttraumatic Checklist 5, Beck Scale for Suicidal Ideation, and Quality of Life Inventory. The Timberlawn Couple and Family Evaluation Scale (TCFES), which can be completed in 30 to 35 minutes and is a measure of overall function of relevant relationships, also may be added. Future studies are needed to confirm psychometrics of this scale in this setting, but the TCFES metric is widely used for similar purposes.

Nationwide, more than 950 patients have started treatment (ie, including active, completed, and discontinued treatment) and 412 veterans have completed the rTMS treatment. The goal of the program evaluation is to examine large scale rTMS efficacy in a large veteran population as well as determine predictors of individual patient response. Nationwide, PHQ-9 depression scores declined from a pretreatment average (SD) of 18.2 (5.5; range, 5-27) to a posttreatment average (SD) of 11.0 (7.1; range, 0-27). Patients also have indicated a high level of satisfaction with the treatment (Figure 4). Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response that might be lost in a smaller subset of cases.

Implementation

It took 11 months for the VA contracting department to determine which machine to buy. However, the lengthy process assured that the equipment selected met all standards for clinical safety and efficacy. Furthermore, provision was made to allow for additional orders as new sites came online as well as upgrading the equipment for advances in technology.

The PNC set up several training programs to ensure proper use of this novel treatment. The education is ongoing and available as new sites are identified and initiated. The education includes, but is not limited to, in-person onsite and offsite training programs, online training modules that are available in the VA Electronic Educational Services (EES), and video telehealth consultations. Participants can view online lectures and then receive hands-on training as part of the educational program. Up to 3 HCPs for each site can receive funding to attend. Online programs also are available for new material to support continuing medical education. However, hands-on training is essential to understand how to obtain the motor threshold, which is used to determine the strength of the rTMS stimulus dose. Furthermore, hands-on training is essential for the proper localization of the stimulus, which is determined by certain anatomical landmarks. A phantom mannequin (ERIK [Evaluating Resting motor threshold and Insuring Kappa]) has been developed to assist in the hands-on learning.²⁰

Relative Value Units

The VHA uses RVUs to properly account for workload and clinician activities. As a result, RVUs play an essential role as a currency that denotes the relative value of one type of clinical activity when compared with other activities. Depending on the treating specialty, clinicians generally use procedure codes outlined in the Current Procedural Terminology (CPT) code set or the Healthcare Common Procedure Coding System (HCPCS) for medical billing. Most insurance carriers use RVUs set by the Centers for Medicare and Medicaid Services (CMS) system as a standard system to determine HCP reimbursement for medical procedures.

The CPT codes associated with rTMS currently are 90867 to 90869. CMS had initially assigned a zero RVU to these CPT codes due to wide variations in the cost of performing rTMS. When we began implementing rTMS in the VHA, the lack of RVUs for rTMS rendered it impossible to show clinical workload for this activity using established VHA clinical accounting methods. The lack of RVUs assigned to rTMS CPT codes made justification for this treatment to clinical management difficult, which limited its clinical use in the VHA. In addition, HCPs who were using rTMS to treat severely ill veterans appeared artificially unproductive despite a significant patient workload. As we and VHA leadership became aware the program could not be staffed locally without getting workload credit for work done, the value was raised to 1.37 for treatment (90868) and 2.12 and 1.93 for evaluations (90867) and reevaluations (90869), respectively, thus reducing a potential roadblock to implementation.

Challenges as the Program Expands

Future challenges include upgrading machines to do intermittent θ burst stimulation (iTBS), which decreases the standard treatment time from 37.5 minutes to 3 minutes. Both patients and HCPs find iTBS to have similar tolerability to standard rTMS but in much less time. iTBS mimics endogenous θ rhythms and has been shown to be noninferior to rTMS for depression.^21,22 Several devices have received FDA approval to treat MDD, including the Magstim and MagVenture TMS devices used in this program.

A major challenge for the VHA with rTMS will be to maintain a consistent level of competence and training. There is a need for continued maintenance of staff competence with ongoing training and training for new staff. Novel ways of training operators have been developed including ERIK.

Determining treatment interaction with other psychotherapies and pharmacotherapies is another challenge. Currently, rTMS is considered an adjunctive treatment added to the current patient treatment plan. We do not know yet how best to incorporate this somatic treatment with other approaches, and further research is necessary. A key issue is to determine which approach provides the best long-term results for a patient at risk for recurrence of depression. In addition, more research into maintaining healthy relationships for veterans with both MDD and PTSD is needed.

Many misconceptions exist about rTMS and HCPs need to be educated about the benefits of this modality. In addition, patients should understand the differences between rTMS and ECT. Even with newer approaches that streamline rTMS, the therapy remains costly in terms of direct costs as well as patient and HCP time.

Streamlining rTMS treatment remains an important concern. Compressing treatment schedules (ie, many treatments delivered to a patient in a single day) would allow the entire process to be delivered in days, not weeks. This would be especially advantageous to patients who live far from a treatment site. Performing multiple rTMS daily treatments is especially feasible with iTBS with its short treatment time.

Conclusions

rTMS is an emerging modality with both established and novel applications. The best studied application is treatment resistant MDD. Currently, rTMS has only been approved by the FDA for treatment of MDD. A pilot program was established by the VHA to distribute 30 rTMS machines sites nationwide. Results from data collected by these sites have shown patients improving on standard psychometric scales. Future changes include upgrading the machines to provide θ bursts, which has been shown to be faster and noninferior. Integrating rTMS with other pharmacotherapies and psychotherapies remains poorly understood and needs more research.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy approved by the US Food and Drug Administration (FDA) for mental health indications but not widely available in the US Department of Veterans Affairs (VA). rTMS uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain.¹ The area of the brain targeted depends on the shape of the magnetic coil and dose of stimulation (Figures 1 and 2). The most common coil shape is the figure-8 coil, which is believed to stimulate about a 2- to 3-cm² area of the brain at a depth of about 2 cm from the coil surface. The stimulus is thought to activate certain nerve growth factors and ultimately relevant neurotransmitters in the stimulated areas and parts of the brain connected to where the stimulus occurs.²

The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The FDA has approved rTMS for the treatment of MDD and for at least 4 device manufacturers. The treatment has been studied in multiple clinical trials.³ An overview of these trials, additional rTMS training and educational materials, and device information can be accessed at www.mirecc.va.gov/visn21/education/tms_education.asp. rTMS for MDD administers a personalized dose with stimulation delivered over the dorsolateral prefrontal cortex. A typical clinical course runs for 40 minutes a day for 20 to 30 sessions. In addition to studies of depression,^1,4-7 rTMS has been studied for the following diseases and conditions:

• Headache (especially migraine)⁸
• Alzheimer disease⁹
• Obsessive compulsive disorder (OCD)¹⁰
• Obesity¹¹
• Schizophrenia¹²
• Posttraumatic stress disorder (PTSD)¹³
• Alcohol and nicotine dependence¹⁴

The FDA also has approved the use of rTMS for OCD. In addition, some health care providers (HCPs) are treating depression with rTMS in conjunction with electroconvulsive therapy (ECT).

Treatment for Veterans

MDD is one of the most significant risk factors for suicide. Therefore, treating depression with rTMS would likely diminish suicide risk. The annual suicide rate among veterans has been higher than the national average.¹⁵ However, most of these veterans are not getting their care at the Veterans Health Administration (VHA). Major efforts at the VA have been made to address this problem, including modification and promotion of the Veterans Crisis Line, increased mental health clinic hours, mental health same-day appointment availability for veterans, as well as raising awareness of suicide and suicidal ideation.¹⁶ George and colleagues showed that it is safe and feasible to treat acutely suicidal inpatients at a VA or US Department of Defense hospital over an intensive 3 day, 3 treatments per day regimen. This regimen would be potentially useful in a suicidal inpatient population, a technically and ethically difficult group to study.¹⁷

MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief.¹⁷ There clearly is a need for additional treatment options. MDD and OCD are the only indications that have received FDA approval for rTMS use. The initial FDA approval for MDD was based on a 2007 study of medication-free patients who had failed previous therapy and found a significant effect of rTMS compared with a sham procedure.⁷ MDD remains a common problem among veterans who have failed one or more antidepressant medications. Such patients might benefit from rTMS.^6,18

rTMS has several advantages over ECT, another significant FDA-approved, nonpharmacologic treatment alternative for medication-refractory MDD. rTMS is less invasive, requires fewer resources, does not require anesthesia or restrict activities, and does not cause memory loss. After an rTMS treatment, the patient can drive home.

Nationwide Pilot Program

The VA pilot program was created to supply rTMS machines nationwide to VHA sites and to offer a framework for establishing a clinical program. Preliminary program evaluation data suggest patients experienced a reduction in depression and suicidal ideation.

There were many challenges to implementation; for example, one VA site was eager to start using the device but could not secure space or personnel. An interdisciplinary team consisting of physicians, nurses, psychologists, suicide prevention coordinators, and others in the VA Palo Alto Health Care System (VAPAHCS) Precision Neurostimulation Clinic (PNC) has been instrumental in overcoming these challenges. VAPAHCS oversees the pilot and employs the national director.

Thirty-five sites nationwide were initially selected due to their ability to provide space for a rTMS machine and appropriate staffing to set up and run a Clinic (Figure 3). The pilot started with tertiary care VA medical centers then expanded to include community-based outpatient clinics as resources permitted. Sites that were unable to meet these standards were not included. Of these 35 original sites, 26 are treating patients and collecting data. Some early delays were due to unassigned relative value units (RVUs) to rTMS, which since have been revised as imputed RVU values. The American Medical Association established and defined RVUs to compare the value of different health care roles.¹⁹ The clinics have been established with smooth operations as the pilot program has provided the infrastructure.

REDCap (www.project-redcap.org), a data collection tool used primarily in academic research settings, was selected to gather program evaluation data through patient questionnaires informed by the VHA measurement-based care initiative. Standard psychometrics were readily available in the VHA application and REDCap Mental Health Assistant includes the Patient Health Questionnaire 9 (PHQ-9) Brief Symptom Inventory 18, Posttraumatic Checklist 5, Beck Scale for Suicidal Ideation, and Quality of Life Inventory. The Timberlawn Couple and Family Evaluation Scale (TCFES), which can be completed in 30 to 35 minutes and is a measure of overall function of relevant relationships, also may be added. Future studies are needed to confirm psychometrics of this scale in this setting, but the TCFES metric is widely used for similar purposes.

Nationwide, more than 950 patients have started treatment (ie, including active, completed, and discontinued treatment) and 412 veterans have completed the rTMS treatment. The goal of the program evaluation is to examine large scale rTMS efficacy in a large veteran population as well as determine predictors of individual patient response. Nationwide, PHQ-9 depression scores declined from a pretreatment average (SD) of 18.2 (5.5; range, 5-27) to a posttreatment average (SD) of 11.0 (7.1; range, 0-27). Patients also have indicated a high level of satisfaction with the treatment (Figure 4). Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response that might be lost in a smaller subset of cases.

Implementation

It took 11 months for the VA contracting department to determine which machine to buy. However, the lengthy process assured that the equipment selected met all standards for clinical safety and efficacy. Furthermore, provision was made to allow for additional orders as new sites came online as well as upgrading the equipment for advances in technology.

The PNC set up several training programs to ensure proper use of this novel treatment. The education is ongoing and available as new sites are identified and initiated. The education includes, but is not limited to, in-person onsite and offsite training programs, online training modules that are available in the VA Electronic Educational Services (EES), and video telehealth consultations. Participants can view online lectures and then receive hands-on training as part of the educational program. Up to 3 HCPs for each site can receive funding to attend. Online programs also are available for new material to support continuing medical education. However, hands-on training is essential to understand how to obtain the motor threshold, which is used to determine the strength of the rTMS stimulus dose. Furthermore, hands-on training is essential for the proper localization of the stimulus, which is determined by certain anatomical landmarks. A phantom mannequin (ERIK [Evaluating Resting motor threshold and Insuring Kappa]) has been developed to assist in the hands-on learning.²⁰

Relative Value Units

The VHA uses RVUs to properly account for workload and clinician activities. As a result, RVUs play an essential role as a currency that denotes the relative value of one type of clinical activity when compared with other activities. Depending on the treating specialty, clinicians generally use procedure codes outlined in the Current Procedural Terminology (CPT) code set or the Healthcare Common Procedure Coding System (HCPCS) for medical billing. Most insurance carriers use RVUs set by the Centers for Medicare and Medicaid Services (CMS) system as a standard system to determine HCP reimbursement for medical procedures.

The CPT codes associated with rTMS currently are 90867 to 90869. CMS had initially assigned a zero RVU to these CPT codes due to wide variations in the cost of performing rTMS. When we began implementing rTMS in the VHA, the lack of RVUs for rTMS rendered it impossible to show clinical workload for this activity using established VHA clinical accounting methods. The lack of RVUs assigned to rTMS CPT codes made justification for this treatment to clinical management difficult, which limited its clinical use in the VHA. In addition, HCPs who were using rTMS to treat severely ill veterans appeared artificially unproductive despite a significant patient workload. As we and VHA leadership became aware the program could not be staffed locally without getting workload credit for work done, the value was raised to 1.37 for treatment (90868) and 2.12 and 1.93 for evaluations (90867) and reevaluations (90869), respectively, thus reducing a potential roadblock to implementation.

Challenges as the Program Expands

Future challenges include upgrading machines to do intermittent θ burst stimulation (iTBS), which decreases the standard treatment time from 37.5 minutes to 3 minutes. Both patients and HCPs find iTBS to have similar tolerability to standard rTMS but in much less time. iTBS mimics endogenous θ rhythms and has been shown to be noninferior to rTMS for depression.^21,22 Several devices have received FDA approval to treat MDD, including the Magstim and MagVenture TMS devices used in this program.

A major challenge for the VHA with rTMS will be to maintain a consistent level of competence and training. There is a need for continued maintenance of staff competence with ongoing training and training for new staff. Novel ways of training operators have been developed including ERIK.

Determining treatment interaction with other psychotherapies and pharmacotherapies is another challenge. Currently, rTMS is considered an adjunctive treatment added to the current patient treatment plan. We do not know yet how best to incorporate this somatic treatment with other approaches, and further research is necessary. A key issue is to determine which approach provides the best long-term results for a patient at risk for recurrence of depression. In addition, more research into maintaining healthy relationships for veterans with both MDD and PTSD is needed.

Many misconceptions exist about rTMS and HCPs need to be educated about the benefits of this modality. In addition, patients should understand the differences between rTMS and ECT. Even with newer approaches that streamline rTMS, the therapy remains costly in terms of direct costs as well as patient and HCP time.

Streamlining rTMS treatment remains an important concern. Compressing treatment schedules (ie, many treatments delivered to a patient in a single day) would allow the entire process to be delivered in days, not weeks. This would be especially advantageous to patients who live far from a treatment site. Performing multiple rTMS daily treatments is especially feasible with iTBS with its short treatment time.

Conclusions

rTMS is an emerging modality with both established and novel applications. The best studied application is treatment resistant MDD. Currently, rTMS has only been approved by the FDA for treatment of MDD. A pilot program was established by the VHA to distribute 30 rTMS machines sites nationwide. Results from data collected by these sites have shown patients improving on standard psychometric scales. Future changes include upgrading the machines to provide θ bursts, which has been shown to be faster and noninferior. Integrating rTMS with other pharmacotherapies and psychotherapies remains poorly understood and needs more research.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy approved by the US Food and Drug Administration (FDA) for mental health indications but not widely available in the US Department of Veterans Affairs (VA). rTMS uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain.¹ The area of the brain targeted depends on the shape of the magnetic coil and dose of stimulation (Figures 1 and 2). The most common coil shape is the figure-8 coil, which is believed to stimulate about a 2- to 3-cm² area of the brain at a depth of about 2 cm from the coil surface. The stimulus is thought to activate certain nerve growth factors and ultimately relevant neurotransmitters in the stimulated areas and parts of the brain connected to where the stimulus occurs.²

The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The FDA has approved rTMS for the treatment of MDD and for at least 4 device manufacturers. The treatment has been studied in multiple clinical trials.³ An overview of these trials, additional rTMS training and educational materials, and device information can be accessed at www.mirecc.va.gov/visn21/education/tms_education.asp. rTMS for MDD administers a personalized dose with stimulation delivered over the dorsolateral prefrontal cortex. A typical clinical course runs for 40 minutes a day for 20 to 30 sessions. In addition to studies of depression,^1,4-7 rTMS has been studied for the following diseases and conditions:

• Headache (especially migraine)⁸
• Alzheimer disease⁹
• Obsessive compulsive disorder (OCD)¹⁰
• Obesity¹¹
• Schizophrenia¹²
• Posttraumatic stress disorder (PTSD)¹³
• Alcohol and nicotine dependence¹⁴

The FDA also has approved the use of rTMS for OCD. In addition, some health care providers (HCPs) are treating depression with rTMS in conjunction with electroconvulsive therapy (ECT).

Treatment for Veterans

MDD is one of the most significant risk factors for suicide. Therefore, treating depression with rTMS would likely diminish suicide risk. The annual suicide rate among veterans has been higher than the national average.¹⁵ However, most of these veterans are not getting their care at the Veterans Health Administration (VHA). Major efforts at the VA have been made to address this problem, including modification and promotion of the Veterans Crisis Line, increased mental health clinic hours, mental health same-day appointment availability for veterans, as well as raising awareness of suicide and suicidal ideation.¹⁶ George and colleagues showed that it is safe and feasible to treat acutely suicidal inpatients at a VA or US Department of Defense hospital over an intensive 3 day, 3 treatments per day regimen. This regimen would be potentially useful in a suicidal inpatient population, a technically and ethically difficult group to study.¹⁷

MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief.¹⁷ There clearly is a need for additional treatment options. MDD and OCD are the only indications that have received FDA approval for rTMS use. The initial FDA approval for MDD was based on a 2007 study of medication-free patients who had failed previous therapy and found a significant effect of rTMS compared with a sham procedure.⁷ MDD remains a common problem among veterans who have failed one or more antidepressant medications. Such patients might benefit from rTMS.^6,18

rTMS has several advantages over ECT, another significant FDA-approved, nonpharmacologic treatment alternative for medication-refractory MDD. rTMS is less invasive, requires fewer resources, does not require anesthesia or restrict activities, and does not cause memory loss. After an rTMS treatment, the patient can drive home.

Nationwide Pilot Program

The VA pilot program was created to supply rTMS machines nationwide to VHA sites and to offer a framework for establishing a clinical program. Preliminary program evaluation data suggest patients experienced a reduction in depression and suicidal ideation.

There were many challenges to implementation; for example, one VA site was eager to start using the device but could not secure space or personnel. An interdisciplinary team consisting of physicians, nurses, psychologists, suicide prevention coordinators, and others in the VA Palo Alto Health Care System (VAPAHCS) Precision Neurostimulation Clinic (PNC) has been instrumental in overcoming these challenges. VAPAHCS oversees the pilot and employs the national director.

Thirty-five sites nationwide were initially selected due to their ability to provide space for a rTMS machine and appropriate staffing to set up and run a Clinic (Figure 3). The pilot started with tertiary care VA medical centers then expanded to include community-based outpatient clinics as resources permitted. Sites that were unable to meet these standards were not included. Of these 35 original sites, 26 are treating patients and collecting data. Some early delays were due to unassigned relative value units (RVUs) to rTMS, which since have been revised as imputed RVU values. The American Medical Association established and defined RVUs to compare the value of different health care roles.¹⁹ The clinics have been established with smooth operations as the pilot program has provided the infrastructure.

REDCap (www.project-redcap.org), a data collection tool used primarily in academic research settings, was selected to gather program evaluation data through patient questionnaires informed by the VHA measurement-based care initiative. Standard psychometrics were readily available in the VHA application and REDCap Mental Health Assistant includes the Patient Health Questionnaire 9 (PHQ-9) Brief Symptom Inventory 18, Posttraumatic Checklist 5, Beck Scale for Suicidal Ideation, and Quality of Life Inventory. The Timberlawn Couple and Family Evaluation Scale (TCFES), which can be completed in 30 to 35 minutes and is a measure of overall function of relevant relationships, also may be added. Future studies are needed to confirm psychometrics of this scale in this setting, but the TCFES metric is widely used for similar purposes.

Nationwide, more than 950 patients have started treatment (ie, including active, completed, and discontinued treatment) and 412 veterans have completed the rTMS treatment. The goal of the program evaluation is to examine large scale rTMS efficacy in a large veteran population as well as determine predictors of individual patient response. Nationwide, PHQ-9 depression scores declined from a pretreatment average (SD) of 18.2 (5.5; range, 5-27) to a posttreatment average (SD) of 11.0 (7.1; range, 0-27). Patients also have indicated a high level of satisfaction with the treatment (Figure 4). Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response that might be lost in a smaller subset of cases.

Implementation

It took 11 months for the VA contracting department to determine which machine to buy. However, the lengthy process assured that the equipment selected met all standards for clinical safety and efficacy. Furthermore, provision was made to allow for additional orders as new sites came online as well as upgrading the equipment for advances in technology.

The PNC set up several training programs to ensure proper use of this novel treatment. The education is ongoing and available as new sites are identified and initiated. The education includes, but is not limited to, in-person onsite and offsite training programs, online training modules that are available in the VA Electronic Educational Services (EES), and video telehealth consultations. Participants can view online lectures and then receive hands-on training as part of the educational program. Up to 3 HCPs for each site can receive funding to attend. Online programs also are available for new material to support continuing medical education. However, hands-on training is essential to understand how to obtain the motor threshold, which is used to determine the strength of the rTMS stimulus dose. Furthermore, hands-on training is essential for the proper localization of the stimulus, which is determined by certain anatomical landmarks. A phantom mannequin (ERIK [Evaluating Resting motor threshold and Insuring Kappa]) has been developed to assist in the hands-on learning.²⁰

Relative Value Units

The VHA uses RVUs to properly account for workload and clinician activities. As a result, RVUs play an essential role as a currency that denotes the relative value of one type of clinical activity when compared with other activities. Depending on the treating specialty, clinicians generally use procedure codes outlined in the Current Procedural Terminology (CPT) code set or the Healthcare Common Procedure Coding System (HCPCS) for medical billing. Most insurance carriers use RVUs set by the Centers for Medicare and Medicaid Services (CMS) system as a standard system to determine HCP reimbursement for medical procedures.

The CPT codes associated with rTMS currently are 90867 to 90869. CMS had initially assigned a zero RVU to these CPT codes due to wide variations in the cost of performing rTMS. When we began implementing rTMS in the VHA, the lack of RVUs for rTMS rendered it impossible to show clinical workload for this activity using established VHA clinical accounting methods. The lack of RVUs assigned to rTMS CPT codes made justification for this treatment to clinical management difficult, which limited its clinical use in the VHA. In addition, HCPs who were using rTMS to treat severely ill veterans appeared artificially unproductive despite a significant patient workload. As we and VHA leadership became aware the program could not be staffed locally without getting workload credit for work done, the value was raised to 1.37 for treatment (90868) and 2.12 and 1.93 for evaluations (90867) and reevaluations (90869), respectively, thus reducing a potential roadblock to implementation.

Challenges as the Program Expands

Future challenges include upgrading machines to do intermittent θ burst stimulation (iTBS), which decreases the standard treatment time from 37.5 minutes to 3 minutes. Both patients and HCPs find iTBS to have similar tolerability to standard rTMS but in much less time. iTBS mimics endogenous θ rhythms and has been shown to be noninferior to rTMS for depression.^21,22 Several devices have received FDA approval to treat MDD, including the Magstim and MagVenture TMS devices used in this program.

A major challenge for the VHA with rTMS will be to maintain a consistent level of competence and training. There is a need for continued maintenance of staff competence with ongoing training and training for new staff. Novel ways of training operators have been developed including ERIK.

Determining treatment interaction with other psychotherapies and pharmacotherapies is another challenge. Currently, rTMS is considered an adjunctive treatment added to the current patient treatment plan. We do not know yet how best to incorporate this somatic treatment with other approaches, and further research is necessary. A key issue is to determine which approach provides the best long-term results for a patient at risk for recurrence of depression. In addition, more research into maintaining healthy relationships for veterans with both MDD and PTSD is needed.

Many misconceptions exist about rTMS and HCPs need to be educated about the benefits of this modality. In addition, patients should understand the differences between rTMS and ECT. Even with newer approaches that streamline rTMS, the therapy remains costly in terms of direct costs as well as patient and HCP time.

Streamlining rTMS treatment remains an important concern. Compressing treatment schedules (ie, many treatments delivered to a patient in a single day) would allow the entire process to be delivered in days, not weeks. This would be especially advantageous to patients who live far from a treatment site. Performing multiple rTMS daily treatments is especially feasible with iTBS with its short treatment time.

Conclusions

rTMS is an emerging modality with both established and novel applications. The best studied application is treatment resistant MDD. Currently, rTMS has only been approved by the FDA for treatment of MDD. A pilot program was established by the VHA to distribute 30 rTMS machines sites nationwide. Results from data collected by these sites have shown patients improving on standard psychometric scales. Future changes include upgrading the machines to provide θ bursts, which has been shown to be faster and noninferior. Integrating rTMS with other pharmacotherapies and psychotherapies remains poorly understood and needs more research.

Sleep disturbance in the critically ill has received much attention over recent years as this is a common result of intensive care unit (ICU) admission. Disruptions in sleep not only can, at a minimum, cause distress and lower patient satisfaction, but also inhibit recovery from illness and increase morbidity.^1,2 Several studies have been conducted highlighting the altered sleep patterns of critically ill patients; although total sleep time may seem normal (7-9 hours), patients can experience multiple awakenings per hour, more time in light sleep (stages 1 and 2), and less time in restorative sleep (stages 3 and 4, [REM]rapid eye movement).^2-5

There are several hypothesized physiologic detriments that contribute to slower ICU recovery with sleep deprivation. Research in noncritically ill subjects suggests that sleep deprivation contributes to hypoventilation and potentially prolonged time on the ventilator.^6-9 Cardiovascular morbidity may be adversely affected by inflammatory cytokine release seen in sleep disruption.^10,11 Studies of noncritically ill patients also suggest that immune response is impaired, potentially protracting infection recovery.^12,13 Finally, although not directly investigated, sleep deprivation may contribute to ICU delirium, an independent adverse effect (AE) associated with increased mortality and worse long-term outcomes.^14-16

The Society of Critical Care Medicine (SCCM) recently updated its consensus guidelines for the management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients.¹⁷ These guidelines offer limited interventions to promote sleep in ICU patients based on available evidence and steer the clinician toward minimizing exacerbating factors. Although factors that affect sleep patterns are multifactorial, such as noise levels, pain, mechanical ventilation, and inflammatory mediators, medication therapy is a known modifiable risk factor for sleep disturbance in critically ill patients.² This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.

To include articles relevant to a critically ill population, a systematic search of MEDLINE and PubMed from 1966 to 2019 was performed using the following Medical Subject Headings (MeSH) terms: delirium/etiology, psychoses, substance-induced/etiology, sleep-wake disorders/chemically induced, neurocognitive disorders/chemically induced, dyssomnias/drug effects plus glucocorticoids/adverse effects, adrenal cortex hormones/adverse effects, prednisone/adverse effects, methylprednisolone/adverse effects, and hydrocortisone/adverse effects. The initial search produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion (Table 1).^18-25

ICU Steroid Use

Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.²⁶ Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.

At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A₂. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.^27,28

By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.^27,28

The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.²⁹

Steroid-Induced Sleep Disruption and Psychosis

Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.³⁰ Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”¹⁷ For this review, these AEs will be discussed as related events.

The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).

HPA Axis Modification

Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.³¹ DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.^32,33

Steroid receptors are densely located in behavior centers in the brain: the amygdala, septum, and hippocampus. Pharmacologic changes in gene expression alter norepinephrine and serotonin levels in the brain as well as their receptors.³² Prolonged exposure to exogenous steroids has been shown to decrease amygdala and hippocampal volumes.^34,35 Furthermore, prolonged corticosteroid exposure has been shown to decrease the number of steroid receptors in the hippocampus, pituitary gland, and amygdala.³⁶ In a somewhat paradoxical finding, the production of CNS proinflammatory cytokines like interleuken-1β and tumor necrosis factor α has been seen after steroid administration, suggesting alternate gene signaling in the CNS.³⁷ Although not proven conclusively, it is felt that these physiologic changes and hyperactivity of the HPA axis are predominantly responsible for changes in behavior, mood, memory, and eventually psychosis in steroid-treated patients.^33,38

Finally, alterations in cognition and behavior may be related to steroid-induced changes in CNS carbohydrate, protein, and lipid metabolism with subsequent cellular neurotoxicity.^32,38 Glucose uptake into the hippocampus is decreased with steroid exposure. Additionally, breakdown of metabolic compounds to produce energy can be destructive if left unchecked for prolonged periods. DHEA, growth hormone, and testosterone work to repair catabolic damage produced by cortisol, known as anabolic balance. A low anabolic balance (low DHEA levels to high cortisol levels) leads to a cascade of dysregulation in brain activity.³⁹

Changes in Natural Sleep-Wake Cycles

Natural sleep pathways are also affected by steroids. The sleep-wake cycle is primarily regulated in the hypothalamus with circadian release of melatonin from the pineal gland. Melatonin release is highest at night, where it promotes sleep onset and continuity. Upstream, tryptophan is an amino acid that serves as a precursor to serotonin and melatonin.⁴⁰ Both endogenous and exogenous corticosteroids decrease serum melatonin levels with a markedly diminished circadian rhythm secretion.^41,42Demish and colleagues found a significant decrease in mean (SD) nocturnal melatonin plasma levels after the evening administration of oral dexamethasone 1 mg in 11 healthy volunteers: 127 (42) pg/mL before vs 73 (38) pg/mL after; P < .01.⁴² This result is likely due to decreased cellular metabolism and melatonin synthesis in the pineal gland. Of note, melatonin has neuroprotective affects, and the administration of melatonin has been shown to reverse some steroid-induced neurotoxicities in animal models.⁴³

Steroids also reduce the uptake of tryptophan into the brain.³³ Additionally, in animal models, dexamethasone administration caused a significant decrease in the gene expression of tryptophan hydroxylase, which is part of the multistep pathway in synthesizing serotonin from L-tryptophan. These effects upstream could inhibit the biosynthetic capacity of both melatonin and serotonin.⁴⁴

A third pathway investigated in sleep regulation are the orexin neuropeptides. Orexins are produced in the hypothalamus and stimulate daytime wake activity in monoaminergic and cholinergic neurons. Subsequently, orexin receptor antagonists are a newer class of drugs aimed at mitigating nighttime hyperarousal and sleep disruption. Orexin overexpression may be a causal factor in steroid-induced sleep disturbance. However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8.⁴⁵

Hyperarousal State

Finally, a hyperarousal state is thought to be produced by nongenomic changes to natural neuroinhibitory regulation seen with nonclassical steroid production called neurosteroids. Animal studies revealed that high levels of steroids were found in the CNS long after adrenalectomy, suggesting CNS de novo synthesis.⁴⁶ In addition to altering gene expression at classic intercellular steroid receptors, neurosteroids can alter neurotransmission by direct interaction on ion-gated membranes and other receptors on the cell surface. Restlessness and insomnia could be due to γ-aminobutyric acid type A (GABA_A) receptor modulation in the CNS where neuroactive steroids slow the rate of recovery of GABA_A and potentially inhibit postsynaptic GABAergic transmission. It also is hypothesized that neuroactive steroids have excitatory action at nicotinic acetylcholine, 5HT₃ receptors, and through increasing the fractional open time of the N-methyl-D-aspartate -activated channels.⁴⁷ Allopregnanolone and DHEA are neurosteroids that act as GABA_A agonists and have neuroprotective effects with anxiolytic, antidepressant, and antiaggressive properties.

Neurosteroids are synthesized from cholesterol in the hippocampus. Neurosteroids are upregulated in response to stress by CNS cortisol effects on various enzyme expressions.⁴⁷ Whether exogenous steroid administration affects this biosynthesis vs the stress response in the HPA axis itself is not fully elucidated. Monteleone and colleagues found that dexamethasone 1 mg given orally significantly reduced cortisol and DHEA and allopregnanolone levels in both healthy volunteers and anorexia nervosa patients.⁴⁸ Similarly, Genazzani and colleagues demonstrated that oral dexamethasone administration (0.5 mg every 6 hours) caused significant reductions in both serum allopregnanolone and DHEA levels.⁴⁹

Outcomes Studies

The majority of reported data in steroid-induced insomnia and psychosis is in noncritically ill populations. In a randomized, prospective crossover study of healthy volunteers, dexamethasone administration (3 mg every 8 hours for 48 hours) resulted in significant changes in sleep patterns measured with polysomnography. Compared with placebo, steroid treatment showed significantly longer percentage (SD) of stage 0/awake times (11.7% [11.4] vs 2.9% [1.8]; P < .05); longer percentage (SD) of REM sleep latency (363.8 [74.5] minutes vs 202.8 [79.6] minutes; P < .01), and a reduced number (SD) of REM periods (3.8 [2.6] vs 9.7 [3.6]; P < .01).⁵⁰ Insomnia was one of the most commonly self-reported AEs (> 60%) in a survey of 2,446 chronic steroid users, and the incidence increased as steroid doses increased.⁵¹

A prospective, open-label study of 240 patients with cancer demonstrated significant sleep disruptions using the Pittsburgh Sleep Quality Index with the use of high-dose steroids in chemotherapy.⁵² Naber and colleagues evaluated 50 previously healthy patients taking methylprednisolone 119 mg (41 mg/d) for retinitis and uveitis.⁵³ They reported 26% to 34% of subjects experienced hypomanic syndrome based on a semistructured interview examination. Symptoms developed within 3 days and persisted for the 8-day course of therapy. Brown and colleagues prospectively evaluated 32 asthmatic patients prescribed bursts of prednisone > 40 mg daily. They observed significantly increased scores in the Young Mania Rating Scale within 3 to 7 days of starting therapy, which dissipated to baseline after stopping therapy.⁵⁴

Despite a high reported incidence of neurologic AEs, outcomes in critically ill populations are mixed. Study methods are varied, and many were largely observational. No prospective, randomized studies exist to date specifically aimed and powered to evaluate the effects of steroids on sleep disturbances or delirium in a critically ill population. Furthermore, sleep quality is difficult to measure in this population, and self-reporting often is not an option. In critical care trials, if AEs such as insomnia, delirium, or psychosis are recorded at all, there is heterogeneity in the definitions, and these AEs are generally poorly defined (eg, psychiatric or neurologic disorder not otherwise specified), making pooled analysis of this outcome difficult.⁵⁵

One of the largest observational studies in hospitalized patients was through the Boston Collaborative Drug Surveillance Program. A total of 718 consecutively enrolled inpatients who received prednisone were monitored for acute reactions. Psychiatric AEs were rare (1.3%) with low doses (< 40 mg/d), more prevalent (4.6%) with higher doses (41-80 mg/d), and most prevalent (18.4%) with the highest doses (> 80 mg/d), suggesting CNS AEs are dose dependent.¹⁸ A single-center, retrospective review of 755 psychiatric consults in hospitalized patients revealed that 54% of manic patients were due to corticosteroid administration.¹⁹ In a prospective observational study of 206 consecutive ICU admissions, steroid administration was an independent risk factor for development of ICU delirium, using the Confusion Assessment Method-ICU (CAM-ICU) at a single center (odds ratio [OR], 2.8; 95% CI, 1.05-7.28).²⁵

Two studies in hospitalized oncology patients found conflicting results using the Nursing Delirium Screening Scale (Nu-DESC). One did not find a significant association between delirium and dexamethasone equivalent doses > 15 mg, while the second found an increased hazard ratio (HR) for a positive Nu-DESC score (HR, 2.67; 95% CI, 1.18-6.03).^20,21 Similarly, conflicting results were found in 2 studies using first-order Markov models. In one prospective cohort study, 520 consecutive mechanically ventilated patients in 13 ICUs were monitored for the transition to delirium (CAM-ICU positive) from nondelirium states. Steroid administration was significantly associated with transitioning to delirium (OR, 1.52; 95% CI, 1.05-2.21).²² This conflicts with a similar study by Wolters and colleagues, which monitored 1,112 ICU patients who were given a median prednisone equivalent of 50 mg (interquartile range, 25-75 mg). Steroid administration was not significantly associated with the transition to delirium from an awake without delirium state (OR, 1.08; 95% CI, 0.89-1.32; adjusted OR, 1.00; 95% CI, 0.99-1.01 per 10-mg increase in prednisone equivalent).²³

Mitigating Effects

Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in ICUs.^56,57 Minimizing dosage and duration are important ways clinicians can mitigate unwanted effects. CNS AEs seen with steroids often can be reversed once therapy is discontinued. Avoiding split-dose administration has been proposed given the natural diurnal production of cortisol.⁵⁸ A review by Flaherty discusses the importance of avoiding pharmacologic agents in hospitalized older patients if possible due to known risks (falls, dependency, hip fractures, rebound insomnia, and risk of delirium) and provides a HELP ME SLEEP nomogram for nonpharmacologic interventions in hospitalized patients (Table 4).⁵⁹

Historically, lithium has been recommended for steroid-induced mania with chronic steroid use; however, given the large volume and electrolyte shifts seen in critically ill patients, this may not be a viable option. Antidepressants, especially tricyclics, should generally be avoided in steroid-induced psychosis as these may exacerbate symptoms. If symptoms are severe, either typical (haloperidol) or atypical (olanzapine, quetiapine, risperidone) antipsychotics have been used with success.⁶⁰ Given the known depletion of serum melatonin levels, melatonin supplements are an attractive and relatively safe option for steroid-induced insomnia; however, there are no robust studies specifically aimed at this intervention for this population.

Conclusions

With known, multimodal foci driving sleep impairment in ICU patients, PADIS guidelines recommend myriad interventions for improvement. Recommendations include noise and light reduction with earplugs and/or eyeshades to improve sleep quality. Nocturnal assist-control ventilation may improve sleep quality in ventilated patients. Finally, the development of institutional protocols for promoting sleep quality in ICU patients is recommended.¹⁷

Sleep disturbance in the critically ill has received much attention over recent years as this is a common result of intensive care unit (ICU) admission. Disruptions in sleep not only can, at a minimum, cause distress and lower patient satisfaction, but also inhibit recovery from illness and increase morbidity.^1,2 Several studies have been conducted highlighting the altered sleep patterns of critically ill patients; although total sleep time may seem normal (7-9 hours), patients can experience multiple awakenings per hour, more time in light sleep (stages 1 and 2), and less time in restorative sleep (stages 3 and 4, [REM]rapid eye movement).^2-5

There are several hypothesized physiologic detriments that contribute to slower ICU recovery with sleep deprivation. Research in noncritically ill subjects suggests that sleep deprivation contributes to hypoventilation and potentially prolonged time on the ventilator.^6-9 Cardiovascular morbidity may be adversely affected by inflammatory cytokine release seen in sleep disruption.^10,11 Studies of noncritically ill patients also suggest that immune response is impaired, potentially protracting infection recovery.^12,13 Finally, although not directly investigated, sleep deprivation may contribute to ICU delirium, an independent adverse effect (AE) associated with increased mortality and worse long-term outcomes.^14-16

The Society of Critical Care Medicine (SCCM) recently updated its consensus guidelines for the management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients.¹⁷ These guidelines offer limited interventions to promote sleep in ICU patients based on available evidence and steer the clinician toward minimizing exacerbating factors. Although factors that affect sleep patterns are multifactorial, such as noise levels, pain, mechanical ventilation, and inflammatory mediators, medication therapy is a known modifiable risk factor for sleep disturbance in critically ill patients.² This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.

To include articles relevant to a critically ill population, a systematic search of MEDLINE and PubMed from 1966 to 2019 was performed using the following Medical Subject Headings (MeSH) terms: delirium/etiology, psychoses, substance-induced/etiology, sleep-wake disorders/chemically induced, neurocognitive disorders/chemically induced, dyssomnias/drug effects plus glucocorticoids/adverse effects, adrenal cortex hormones/adverse effects, prednisone/adverse effects, methylprednisolone/adverse effects, and hydrocortisone/adverse effects. The initial search produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion (Table 1).^18-25

ICU Steroid Use

Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.²⁶ Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.

At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A₂. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.^27,28

By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.^27,28

The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.²⁹

Steroid-Induced Sleep Disruption and Psychosis

Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.³⁰ Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”¹⁷ For this review, these AEs will be discussed as related events.

The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).

HPA Axis Modification

Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.³¹ DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.^32,33

Steroid receptors are densely located in behavior centers in the brain: the amygdala, septum, and hippocampus. Pharmacologic changes in gene expression alter norepinephrine and serotonin levels in the brain as well as their receptors.³² Prolonged exposure to exogenous steroids has been shown to decrease amygdala and hippocampal volumes.^34,35 Furthermore, prolonged corticosteroid exposure has been shown to decrease the number of steroid receptors in the hippocampus, pituitary gland, and amygdala.³⁶ In a somewhat paradoxical finding, the production of CNS proinflammatory cytokines like interleuken-1β and tumor necrosis factor α has been seen after steroid administration, suggesting alternate gene signaling in the CNS.³⁷ Although not proven conclusively, it is felt that these physiologic changes and hyperactivity of the HPA axis are predominantly responsible for changes in behavior, mood, memory, and eventually psychosis in steroid-treated patients.^33,38

Finally, alterations in cognition and behavior may be related to steroid-induced changes in CNS carbohydrate, protein, and lipid metabolism with subsequent cellular neurotoxicity.^32,38 Glucose uptake into the hippocampus is decreased with steroid exposure. Additionally, breakdown of metabolic compounds to produce energy can be destructive if left unchecked for prolonged periods. DHEA, growth hormone, and testosterone work to repair catabolic damage produced by cortisol, known as anabolic balance. A low anabolic balance (low DHEA levels to high cortisol levels) leads to a cascade of dysregulation in brain activity.³⁹

Changes in Natural Sleep-Wake Cycles

Natural sleep pathways are also affected by steroids. The sleep-wake cycle is primarily regulated in the hypothalamus with circadian release of melatonin from the pineal gland. Melatonin release is highest at night, where it promotes sleep onset and continuity. Upstream, tryptophan is an amino acid that serves as a precursor to serotonin and melatonin.⁴⁰ Both endogenous and exogenous corticosteroids decrease serum melatonin levels with a markedly diminished circadian rhythm secretion.^41,42Demish and colleagues found a significant decrease in mean (SD) nocturnal melatonin plasma levels after the evening administration of oral dexamethasone 1 mg in 11 healthy volunteers: 127 (42) pg/mL before vs 73 (38) pg/mL after; P < .01.⁴² This result is likely due to decreased cellular metabolism and melatonin synthesis in the pineal gland. Of note, melatonin has neuroprotective affects, and the administration of melatonin has been shown to reverse some steroid-induced neurotoxicities in animal models.⁴³

Steroids also reduce the uptake of tryptophan into the brain.³³ Additionally, in animal models, dexamethasone administration caused a significant decrease in the gene expression of tryptophan hydroxylase, which is part of the multistep pathway in synthesizing serotonin from L-tryptophan. These effects upstream could inhibit the biosynthetic capacity of both melatonin and serotonin.⁴⁴

A third pathway investigated in sleep regulation are the orexin neuropeptides. Orexins are produced in the hypothalamus and stimulate daytime wake activity in monoaminergic and cholinergic neurons. Subsequently, orexin receptor antagonists are a newer class of drugs aimed at mitigating nighttime hyperarousal and sleep disruption. Orexin overexpression may be a causal factor in steroid-induced sleep disturbance. However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8.⁴⁵

Hyperarousal State

Finally, a hyperarousal state is thought to be produced by nongenomic changes to natural neuroinhibitory regulation seen with nonclassical steroid production called neurosteroids. Animal studies revealed that high levels of steroids were found in the CNS long after adrenalectomy, suggesting CNS de novo synthesis.⁴⁶ In addition to altering gene expression at classic intercellular steroid receptors, neurosteroids can alter neurotransmission by direct interaction on ion-gated membranes and other receptors on the cell surface. Restlessness and insomnia could be due to γ-aminobutyric acid type A (GABA_A) receptor modulation in the CNS where neuroactive steroids slow the rate of recovery of GABA_A and potentially inhibit postsynaptic GABAergic transmission. It also is hypothesized that neuroactive steroids have excitatory action at nicotinic acetylcholine, 5HT₃ receptors, and through increasing the fractional open time of the N-methyl-D-aspartate -activated channels.⁴⁷ Allopregnanolone and DHEA are neurosteroids that act as GABA_A agonists and have neuroprotective effects with anxiolytic, antidepressant, and antiaggressive properties.

Neurosteroids are synthesized from cholesterol in the hippocampus. Neurosteroids are upregulated in response to stress by CNS cortisol effects on various enzyme expressions.⁴⁷ Whether exogenous steroid administration affects this biosynthesis vs the stress response in the HPA axis itself is not fully elucidated. Monteleone and colleagues found that dexamethasone 1 mg given orally significantly reduced cortisol and DHEA and allopregnanolone levels in both healthy volunteers and anorexia nervosa patients.⁴⁸ Similarly, Genazzani and colleagues demonstrated that oral dexamethasone administration (0.5 mg every 6 hours) caused significant reductions in both serum allopregnanolone and DHEA levels.⁴⁹

Outcomes Studies

The majority of reported data in steroid-induced insomnia and psychosis is in noncritically ill populations. In a randomized, prospective crossover study of healthy volunteers, dexamethasone administration (3 mg every 8 hours for 48 hours) resulted in significant changes in sleep patterns measured with polysomnography. Compared with placebo, steroid treatment showed significantly longer percentage (SD) of stage 0/awake times (11.7% [11.4] vs 2.9% [1.8]; P < .05); longer percentage (SD) of REM sleep latency (363.8 [74.5] minutes vs 202.8 [79.6] minutes; P < .01), and a reduced number (SD) of REM periods (3.8 [2.6] vs 9.7 [3.6]; P < .01).⁵⁰ Insomnia was one of the most commonly self-reported AEs (> 60%) in a survey of 2,446 chronic steroid users, and the incidence increased as steroid doses increased.⁵¹

A prospective, open-label study of 240 patients with cancer demonstrated significant sleep disruptions using the Pittsburgh Sleep Quality Index with the use of high-dose steroids in chemotherapy.⁵² Naber and colleagues evaluated 50 previously healthy patients taking methylprednisolone 119 mg (41 mg/d) for retinitis and uveitis.⁵³ They reported 26% to 34% of subjects experienced hypomanic syndrome based on a semistructured interview examination. Symptoms developed within 3 days and persisted for the 8-day course of therapy. Brown and colleagues prospectively evaluated 32 asthmatic patients prescribed bursts of prednisone > 40 mg daily. They observed significantly increased scores in the Young Mania Rating Scale within 3 to 7 days of starting therapy, which dissipated to baseline after stopping therapy.⁵⁴

Despite a high reported incidence of neurologic AEs, outcomes in critically ill populations are mixed. Study methods are varied, and many were largely observational. No prospective, randomized studies exist to date specifically aimed and powered to evaluate the effects of steroids on sleep disturbances or delirium in a critically ill population. Furthermore, sleep quality is difficult to measure in this population, and self-reporting often is not an option. In critical care trials, if AEs such as insomnia, delirium, or psychosis are recorded at all, there is heterogeneity in the definitions, and these AEs are generally poorly defined (eg, psychiatric or neurologic disorder not otherwise specified), making pooled analysis of this outcome difficult.⁵⁵

One of the largest observational studies in hospitalized patients was through the Boston Collaborative Drug Surveillance Program. A total of 718 consecutively enrolled inpatients who received prednisone were monitored for acute reactions. Psychiatric AEs were rare (1.3%) with low doses (< 40 mg/d), more prevalent (4.6%) with higher doses (41-80 mg/d), and most prevalent (18.4%) with the highest doses (> 80 mg/d), suggesting CNS AEs are dose dependent.¹⁸ A single-center, retrospective review of 755 psychiatric consults in hospitalized patients revealed that 54% of manic patients were due to corticosteroid administration.¹⁹ In a prospective observational study of 206 consecutive ICU admissions, steroid administration was an independent risk factor for development of ICU delirium, using the Confusion Assessment Method-ICU (CAM-ICU) at a single center (odds ratio [OR], 2.8; 95% CI, 1.05-7.28).²⁵

Two studies in hospitalized oncology patients found conflicting results using the Nursing Delirium Screening Scale (Nu-DESC). One did not find a significant association between delirium and dexamethasone equivalent doses > 15 mg, while the second found an increased hazard ratio (HR) for a positive Nu-DESC score (HR, 2.67; 95% CI, 1.18-6.03).^20,21 Similarly, conflicting results were found in 2 studies using first-order Markov models. In one prospective cohort study, 520 consecutive mechanically ventilated patients in 13 ICUs were monitored for the transition to delirium (CAM-ICU positive) from nondelirium states. Steroid administration was significantly associated with transitioning to delirium (OR, 1.52; 95% CI, 1.05-2.21).²² This conflicts with a similar study by Wolters and colleagues, which monitored 1,112 ICU patients who were given a median prednisone equivalent of 50 mg (interquartile range, 25-75 mg). Steroid administration was not significantly associated with the transition to delirium from an awake without delirium state (OR, 1.08; 95% CI, 0.89-1.32; adjusted OR, 1.00; 95% CI, 0.99-1.01 per 10-mg increase in prednisone equivalent).²³

Mitigating Effects

Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in ICUs.^56,57 Minimizing dosage and duration are important ways clinicians can mitigate unwanted effects. CNS AEs seen with steroids often can be reversed once therapy is discontinued. Avoiding split-dose administration has been proposed given the natural diurnal production of cortisol.⁵⁸ A review by Flaherty discusses the importance of avoiding pharmacologic agents in hospitalized older patients if possible due to known risks (falls, dependency, hip fractures, rebound insomnia, and risk of delirium) and provides a HELP ME SLEEP nomogram for nonpharmacologic interventions in hospitalized patients (Table 4).⁵⁹

Historically, lithium has been recommended for steroid-induced mania with chronic steroid use; however, given the large volume and electrolyte shifts seen in critically ill patients, this may not be a viable option. Antidepressants, especially tricyclics, should generally be avoided in steroid-induced psychosis as these may exacerbate symptoms. If symptoms are severe, either typical (haloperidol) or atypical (olanzapine, quetiapine, risperidone) antipsychotics have been used with success.⁶⁰ Given the known depletion of serum melatonin levels, melatonin supplements are an attractive and relatively safe option for steroid-induced insomnia; however, there are no robust studies specifically aimed at this intervention for this population.

Conclusions

With known, multimodal foci driving sleep impairment in ICU patients, PADIS guidelines recommend myriad interventions for improvement. Recommendations include noise and light reduction with earplugs and/or eyeshades to improve sleep quality. Nocturnal assist-control ventilation may improve sleep quality in ventilated patients. Finally, the development of institutional protocols for promoting sleep quality in ICU patients is recommended.¹⁷

Sleep disturbance in the critically ill has received much attention over recent years as this is a common result of intensive care unit (ICU) admission. Disruptions in sleep not only can, at a minimum, cause distress and lower patient satisfaction, but also inhibit recovery from illness and increase morbidity.^1,2 Several studies have been conducted highlighting the altered sleep patterns of critically ill patients; although total sleep time may seem normal (7-9 hours), patients can experience multiple awakenings per hour, more time in light sleep (stages 1 and 2), and less time in restorative sleep (stages 3 and 4, [REM]rapid eye movement).^2-5

There are several hypothesized physiologic detriments that contribute to slower ICU recovery with sleep deprivation. Research in noncritically ill subjects suggests that sleep deprivation contributes to hypoventilation and potentially prolonged time on the ventilator.^6-9 Cardiovascular morbidity may be adversely affected by inflammatory cytokine release seen in sleep disruption.^10,11 Studies of noncritically ill patients also suggest that immune response is impaired, potentially protracting infection recovery.^12,13 Finally, although not directly investigated, sleep deprivation may contribute to ICU delirium, an independent adverse effect (AE) associated with increased mortality and worse long-term outcomes.^14-16

The Society of Critical Care Medicine (SCCM) recently updated its consensus guidelines for the management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients.¹⁷ These guidelines offer limited interventions to promote sleep in ICU patients based on available evidence and steer the clinician toward minimizing exacerbating factors. Although factors that affect sleep patterns are multifactorial, such as noise levels, pain, mechanical ventilation, and inflammatory mediators, medication therapy is a known modifiable risk factor for sleep disturbance in critically ill patients.² This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.

To include articles relevant to a critically ill population, a systematic search of MEDLINE and PubMed from 1966 to 2019 was performed using the following Medical Subject Headings (MeSH) terms: delirium/etiology, psychoses, substance-induced/etiology, sleep-wake disorders/chemically induced, neurocognitive disorders/chemically induced, dyssomnias/drug effects plus glucocorticoids/adverse effects, adrenal cortex hormones/adverse effects, prednisone/adverse effects, methylprednisolone/adverse effects, and hydrocortisone/adverse effects. The initial search produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion (Table 1).^18-25

ICU Steroid Use

Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.²⁶ Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.

At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A₂. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.^27,28

By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.^27,28

The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.²⁹

Steroid-Induced Sleep Disruption and Psychosis

Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.³⁰ Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”¹⁷ For this review, these AEs will be discussed as related events.

The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).

HPA Axis Modification

Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.³¹ DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.^32,33

Steroid receptors are densely located in behavior centers in the brain: the amygdala, septum, and hippocampus. Pharmacologic changes in gene expression alter norepinephrine and serotonin levels in the brain as well as their receptors.³² Prolonged exposure to exogenous steroids has been shown to decrease amygdala and hippocampal volumes.^34,35 Furthermore, prolonged corticosteroid exposure has been shown to decrease the number of steroid receptors in the hippocampus, pituitary gland, and amygdala.³⁶ In a somewhat paradoxical finding, the production of CNS proinflammatory cytokines like interleuken-1β and tumor necrosis factor α has been seen after steroid administration, suggesting alternate gene signaling in the CNS.³⁷ Although not proven conclusively, it is felt that these physiologic changes and hyperactivity of the HPA axis are predominantly responsible for changes in behavior, mood, memory, and eventually psychosis in steroid-treated patients.^33,38

Finally, alterations in cognition and behavior may be related to steroid-induced changes in CNS carbohydrate, protein, and lipid metabolism with subsequent cellular neurotoxicity.^32,38 Glucose uptake into the hippocampus is decreased with steroid exposure. Additionally, breakdown of metabolic compounds to produce energy can be destructive if left unchecked for prolonged periods. DHEA, growth hormone, and testosterone work to repair catabolic damage produced by cortisol, known as anabolic balance. A low anabolic balance (low DHEA levels to high cortisol levels) leads to a cascade of dysregulation in brain activity.³⁹

Changes in Natural Sleep-Wake Cycles

Natural sleep pathways are also affected by steroids. The sleep-wake cycle is primarily regulated in the hypothalamus with circadian release of melatonin from the pineal gland. Melatonin release is highest at night, where it promotes sleep onset and continuity. Upstream, tryptophan is an amino acid that serves as a precursor to serotonin and melatonin.⁴⁰ Both endogenous and exogenous corticosteroids decrease serum melatonin levels with a markedly diminished circadian rhythm secretion.^41,42Demish and colleagues found a significant decrease in mean (SD) nocturnal melatonin plasma levels after the evening administration of oral dexamethasone 1 mg in 11 healthy volunteers: 127 (42) pg/mL before vs 73 (38) pg/mL after; P < .01.⁴² This result is likely due to decreased cellular metabolism and melatonin synthesis in the pineal gland. Of note, melatonin has neuroprotective affects, and the administration of melatonin has been shown to reverse some steroid-induced neurotoxicities in animal models.⁴³

Steroids also reduce the uptake of tryptophan into the brain.³³ Additionally, in animal models, dexamethasone administration caused a significant decrease in the gene expression of tryptophan hydroxylase, which is part of the multistep pathway in synthesizing serotonin from L-tryptophan. These effects upstream could inhibit the biosynthetic capacity of both melatonin and serotonin.⁴⁴

A third pathway investigated in sleep regulation are the orexin neuropeptides. Orexins are produced in the hypothalamus and stimulate daytime wake activity in monoaminergic and cholinergic neurons. Subsequently, orexin receptor antagonists are a newer class of drugs aimed at mitigating nighttime hyperarousal and sleep disruption. Orexin overexpression may be a causal factor in steroid-induced sleep disturbance. However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8.⁴⁵

Hyperarousal State

Finally, a hyperarousal state is thought to be produced by nongenomic changes to natural neuroinhibitory regulation seen with nonclassical steroid production called neurosteroids. Animal studies revealed that high levels of steroids were found in the CNS long after adrenalectomy, suggesting CNS de novo synthesis.⁴⁶ In addition to altering gene expression at classic intercellular steroid receptors, neurosteroids can alter neurotransmission by direct interaction on ion-gated membranes and other receptors on the cell surface. Restlessness and insomnia could be due to γ-aminobutyric acid type A (GABA_A) receptor modulation in the CNS where neuroactive steroids slow the rate of recovery of GABA_A and potentially inhibit postsynaptic GABAergic transmission. It also is hypothesized that neuroactive steroids have excitatory action at nicotinic acetylcholine, 5HT₃ receptors, and through increasing the fractional open time of the N-methyl-D-aspartate -activated channels.⁴⁷ Allopregnanolone and DHEA are neurosteroids that act as GABA_A agonists and have neuroprotective effects with anxiolytic, antidepressant, and antiaggressive properties.

Neurosteroids are synthesized from cholesterol in the hippocampus. Neurosteroids are upregulated in response to stress by CNS cortisol effects on various enzyme expressions.⁴⁷ Whether exogenous steroid administration affects this biosynthesis vs the stress response in the HPA axis itself is not fully elucidated. Monteleone and colleagues found that dexamethasone 1 mg given orally significantly reduced cortisol and DHEA and allopregnanolone levels in both healthy volunteers and anorexia nervosa patients.⁴⁸ Similarly, Genazzani and colleagues demonstrated that oral dexamethasone administration (0.5 mg every 6 hours) caused significant reductions in both serum allopregnanolone and DHEA levels.⁴⁹

Outcomes Studies

The majority of reported data in steroid-induced insomnia and psychosis is in noncritically ill populations. In a randomized, prospective crossover study of healthy volunteers, dexamethasone administration (3 mg every 8 hours for 48 hours) resulted in significant changes in sleep patterns measured with polysomnography. Compared with placebo, steroid treatment showed significantly longer percentage (SD) of stage 0/awake times (11.7% [11.4] vs 2.9% [1.8]; P < .05); longer percentage (SD) of REM sleep latency (363.8 [74.5] minutes vs 202.8 [79.6] minutes; P < .01), and a reduced number (SD) of REM periods (3.8 [2.6] vs 9.7 [3.6]; P < .01).⁵⁰ Insomnia was one of the most commonly self-reported AEs (> 60%) in a survey of 2,446 chronic steroid users, and the incidence increased as steroid doses increased.⁵¹

A prospective, open-label study of 240 patients with cancer demonstrated significant sleep disruptions using the Pittsburgh Sleep Quality Index with the use of high-dose steroids in chemotherapy.⁵² Naber and colleagues evaluated 50 previously healthy patients taking methylprednisolone 119 mg (41 mg/d) for retinitis and uveitis.⁵³ They reported 26% to 34% of subjects experienced hypomanic syndrome based on a semistructured interview examination. Symptoms developed within 3 days and persisted for the 8-day course of therapy. Brown and colleagues prospectively evaluated 32 asthmatic patients prescribed bursts of prednisone > 40 mg daily. They observed significantly increased scores in the Young Mania Rating Scale within 3 to 7 days of starting therapy, which dissipated to baseline after stopping therapy.⁵⁴

Despite a high reported incidence of neurologic AEs, outcomes in critically ill populations are mixed. Study methods are varied, and many were largely observational. No prospective, randomized studies exist to date specifically aimed and powered to evaluate the effects of steroids on sleep disturbances or delirium in a critically ill population. Furthermore, sleep quality is difficult to measure in this population, and self-reporting often is not an option. In critical care trials, if AEs such as insomnia, delirium, or psychosis are recorded at all, there is heterogeneity in the definitions, and these AEs are generally poorly defined (eg, psychiatric or neurologic disorder not otherwise specified), making pooled analysis of this outcome difficult.⁵⁵

One of the largest observational studies in hospitalized patients was through the Boston Collaborative Drug Surveillance Program. A total of 718 consecutively enrolled inpatients who received prednisone were monitored for acute reactions. Psychiatric AEs were rare (1.3%) with low doses (< 40 mg/d), more prevalent (4.6%) with higher doses (41-80 mg/d), and most prevalent (18.4%) with the highest doses (> 80 mg/d), suggesting CNS AEs are dose dependent.¹⁸ A single-center, retrospective review of 755 psychiatric consults in hospitalized patients revealed that 54% of manic patients were due to corticosteroid administration.¹⁹ In a prospective observational study of 206 consecutive ICU admissions, steroid administration was an independent risk factor for development of ICU delirium, using the Confusion Assessment Method-ICU (CAM-ICU) at a single center (odds ratio [OR], 2.8; 95% CI, 1.05-7.28).²⁵

Two studies in hospitalized oncology patients found conflicting results using the Nursing Delirium Screening Scale (Nu-DESC). One did not find a significant association between delirium and dexamethasone equivalent doses > 15 mg, while the second found an increased hazard ratio (HR) for a positive Nu-DESC score (HR, 2.67; 95% CI, 1.18-6.03).^20,21 Similarly, conflicting results were found in 2 studies using first-order Markov models. In one prospective cohort study, 520 consecutive mechanically ventilated patients in 13 ICUs were monitored for the transition to delirium (CAM-ICU positive) from nondelirium states. Steroid administration was significantly associated with transitioning to delirium (OR, 1.52; 95% CI, 1.05-2.21).²² This conflicts with a similar study by Wolters and colleagues, which monitored 1,112 ICU patients who were given a median prednisone equivalent of 50 mg (interquartile range, 25-75 mg). Steroid administration was not significantly associated with the transition to delirium from an awake without delirium state (OR, 1.08; 95% CI, 0.89-1.32; adjusted OR, 1.00; 95% CI, 0.99-1.01 per 10-mg increase in prednisone equivalent).²³

Mitigating Effects

Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in ICUs.^56,57 Minimizing dosage and duration are important ways clinicians can mitigate unwanted effects. CNS AEs seen with steroids often can be reversed once therapy is discontinued. Avoiding split-dose administration has been proposed given the natural diurnal production of cortisol.⁵⁸ A review by Flaherty discusses the importance of avoiding pharmacologic agents in hospitalized older patients if possible due to known risks (falls, dependency, hip fractures, rebound insomnia, and risk of delirium) and provides a HELP ME SLEEP nomogram for nonpharmacologic interventions in hospitalized patients (Table 4).⁵⁹

Historically, lithium has been recommended for steroid-induced mania with chronic steroid use; however, given the large volume and electrolyte shifts seen in critically ill patients, this may not be a viable option. Antidepressants, especially tricyclics, should generally be avoided in steroid-induced psychosis as these may exacerbate symptoms. If symptoms are severe, either typical (haloperidol) or atypical (olanzapine, quetiapine, risperidone) antipsychotics have been used with success.⁶⁰ Given the known depletion of serum melatonin levels, melatonin supplements are an attractive and relatively safe option for steroid-induced insomnia; however, there are no robust studies specifically aimed at this intervention for this population.

Conclusions

With known, multimodal foci driving sleep impairment in ICU patients, PADIS guidelines recommend myriad interventions for improvement. Recommendations include noise and light reduction with earplugs and/or eyeshades to improve sleep quality. Nocturnal assist-control ventilation may improve sleep quality in ventilated patients. Finally, the development of institutional protocols for promoting sleep quality in ICU patients is recommended.¹⁷