Abstract
OBJECTIVE
Vitamin D deficiency is commonly found in patients with cystic fibrosis (CF) and can have a negative effect on patients who are not at target goal according to Cystic Fibrosis Foundation's Vitamin D Deficiency Clinical Care Guidelines. The objective of this study is to determine the effectiveness of a pharmacist-driven vitamin D protocol (PDVDP) in improving, achieving, and maintaining 25-hydroxyvitamin D levels of patients in a pediatric CF clinic.
METHODS
A retrospective chart review was conducted for pediatric patients with CF from August 2018 to March 2020 to determine the percent of patients with improvement in 25-hydroxyvitamin D levels to target goal (≥ 30 ng/mL). Patients' 25-hydroxyvitamin D levels at 6, 12, and 18 months after automatic enrollment into the PDVDP were compared to determine if improvement occurred, and to calculate relative percent increase of 25-hydroxyvitamin D levels for these patients.
RESULTS
The mean 25-hydroxyvitamin D levels of the patients at baseline before the protocol and 6, 12, and 18 months after enrollment in the protocol were 23.2, 33.3, 32.7, and 34.6 ng/mL, respectively. These results demonstrate mean 25-hydroxyvitamin D levels at all follow-up time points were significantly greater than baseline (p < 0.001). At 6 months, 50% (n = 20) of pediatric patients reached the target 25-hydroxyvitamin D levels.
CONCLUSIONS
The PDVDP was effective in increasing the number of patients able to reach target 25-hydroxyvitamin D levels. Our PDVDP process may also be used at other CF clinics to improve vitamin D outcomes collaboratively with the interprofessional CF team.
Keywords: cystic fibrosis, pharmacists, protocol, vitamin D, vitamin D deficiency
Introduction
Vitamin D deficiency is found in approximately 90% of patients with cystic fibrosis (CF).1 This is often attributed to impaired absorption of fat-soluble vitamins, coupled with minimal sunlight exposure and reduced intake of vitamin D-containing foods and/or supplements.2 Therefore, these patients have increased difficulty in maintaining 25-hydroxyvitamin D levels at or above the recommended goals. The Cystic Fibrosis Foundation Vitamin D Deficiency Clinical Care Guidelines2 (CFF Vitamin D Deficiency Clinical Care Guidelines) recommend that patients with CF maintain a 25-hydroxyvitamin D level of at least 30 nanograms per milliliter (ng/mL) in order to prevent decreased bone mass in children and minimize the effect on other comorbidities associated with CF, such as CF-related diabetes.3,4 In addition, higher 25-hydroxyvitamin D levels (> 40 ng/mL) in children with CF may correlate with lower rates of pulmonary exacerbations while also improving lung function.5,6
Limited research has explored the beneficial role of pharmacists in the CF outpatient setting specifically in the management of vitamin D dosing and adherence in patients. Although currently listed only as recommended members of the CF multidisciplinary care team, the inclusion of pharmacists has the potential to improve adherence, medication self-management, and overall health-related quality of life for these patients.7 As the medication experts, pharmacists can ensure patients receive the correct vitamins, assist with adherence and access to vitamins, and reinforce knowledge of the importance of supplementation.
As part of the quality improvement process at the University of Mississippi Medical Center (UMMC) Pediatric CF clinic (UMMC CF clinic), a plan, study, do, act (PDSA) cycle was implemented to focus on improving patients' vitamin D levels to target goal. The involvement of pharmacists to support efforts to improve vitamin D outcomes collaboratively with the interprofessional CF team was a focus during this PDSA cycle. After a review of the 25-hydroxyvitamin D levels of patients with CF and the current prescribing and monitoring patterns of vitamin D, the purpose of this study was to evaluate the effectiveness of a pharmacist-driven vitamin D protocol (PDVDP) that was implemented with the goal of achieving target 25-hydroxyvitamin D levels.
Materials and Methods
As part of the first PDSA cycle that occurred, the UMMC CF clinic conducted a retrospective chart review in 2017 to determine the overall 25-hydroxyvitamin D level status in our patient population. This retrospective chart review was conducted for all patients seen at our clinic to evaluate adherence to the CFF Vitamin D Deficiency Clinical Care Guidelines.2 Patients were included if documentation of 25-hydroxyvitamin D levels could be found in the electronic health record during the 2017 calendar year. 25-hydroxyvitamin D samples were analyzed using the 25-hydroxyvitamin D competitive chemiluminescence immunoassay (Abbott Laboratories, Abbott Park, IL) at the UMMC main laboratory. Collected data included the latest 25-hydroxyvitamin D levels obtained along with the corresponding collection date, each patient's multivitamin regimen, and any additional vitamin D3 supplementation, if applicable. Data were entered into REDCap and organized in Excel (Microsoft, Redmond, WA) for analysis.
PDVDP Creation. Based on these data, a second PDSA cycle led to the creation of the PDVDP, which was developed and implemented in the fall of 2018. Vitamin D preparations and dosing escalation strategies used in the PDVDP were based on the CFF Vitamin D Deficiency Clinical Care Guidelines2 and included, but were not limited to, the following: increase in current multivitamin supplement, vitamin D3 oral solutions, softgels, or chewables, based on patient preferences and product availability. As recommended by the CFF Vitamin D Deficiency Clinical Care Guidelines2 for this patient population, vitamin D3 was the preferred product recommended for supplementation. If additional vitamin D or a dose increase was needed for a patient, the patient's regimen was typically altered to a combined multivitamin + D3000 or D5000 (MVW D3000 or MVW D5000) to decrease pill burden. Other vitamin D dosage forms were used as needed based on the availability of the patient's needed dose and any cost or coverage issues for the patient.
PDVDP Study. Any patient < 21 years old with a recorded 25-hydroxyvitamin D level < 30 ng/mL was initiated on the PDVDP by increasing vitamin D supplementation dictated by age and the CFF Vitamin D Deficiency Clinical Care guidelines, as reflected in the PDVDP (Figure 1). 25-hydroxyvitamin D levels were subsequently checked 3 months from the dose escalation, and would result in continued adherence counseling, further dose escalations, or other interventions as clinically appropriate. These interventions were typically provided by pharmacists to patients initiated on the PDVDP during their scheduled clinic visits. These could include providing education on the importance of maintaining adequate 25-hydroxyvitamin D levels, assessing any obstacles to patient's tolerance of vitamin D, and addressing barriers to medication access. In addition, based on the protocol the pharmacists could suggest future 25-hydroxyvitamin D level laboratory checks and recommend total daily vitamin D3 dose increases from those reported levels.
Figure 1.
PDVDP used in clinic, adapted from The Cystic Fibrosis Foundation Vitamin D Deficiency Clinical Care Guidelines.2
In 2018, the processing of pediatric 25-hydroxyvitamin D blood samples moved from the UMMC main laboratory to Batson Children's laboratory. These samples were analyzed in the Batson Children's laboratory using the Total 25-hydroxyvitamin D competitive chemiluminescence immunoassay (Ortho Clinical Diagnostics, Rochester, NY). This assay was performed on an automated Vitros 5600 analyzer (Ortho Clinical Diagnostics).
PDVDP Evaluation and Analysis. An additional retrospective chart review from August 2018 to March 2020 was conducted to determine the number of patients with improvement in 25-hydroxyvitamin D levels to target goal at baseline, 6, 12, and 18 months after intervention. Patients were entered into the protocol on a rolling basis, thus not all data points were measured for all patients. The mean 25-hydroxyvitamin D levels (in ng/mL) were measured at 6, 12, and 18 months after the initiation of the PDVDP and were compared using a 1-way repeated measures analysis of variance. Other data collected via chart review in the electronic health record included patient demographic information, the type of intervention(s) made as summarized above, and clinical outcomes including number of hospitalizations, pulmonary exacerbations, and length of stay for hospitalizations for patients who achieved target 25-hydroxyvitamin D level. Using descriptive statistics, the data were analyzed for the percentage of patients with therapeutic 25-hydroxyvitamin D levels, percentage of patients receiving CF-specific multivitamins and vitamin D supplementation, the time period of sample collection, and the frequency of monitoring.
Results
Vitamin D Status. A total of 95 CF patients' charts were reviewed prior to the initiation of the PDVDP. 25-hydroxyvitamin D levels measured for these patients prior to initiation of the PDVDP are noted in Figure 2. Forty-five percent (n = 43) of patients were found to have a total 25-hydroxyvitamin D level < 30 ng/mL and 55% (n = 52) had levels ≥ 30 ng/mL based on the last reported level. Most patients (98%, n = 93) were prescribed CF-specific multivitamins, and 6% (n = 5) of patients were receiving supplemental doses of vitamin D3.
Figure 2.
25-hydroxyvitamin D levels of CF patients (N = 95) in 2017 prior to initiation of pharmacist-driven vitamin D protocol.
PDVDP Evaluation and Analysis. After the initiation of the PDVDP, 42 patients met eligibility criteria for participation, as 1 patient had aged out of the pediatric clinic. A total of 41 patient charts were then reviewed to evaluate the effectiveness of the PDVDP. One patient passed away during the study period and was not included in the evaluation. Of the 41 patients included, the median (IQR) for age was 8 (3–14) years and the majority were male (59%, n = 24). Eighty percent (n = 33) of patients had at least 1 copy of the F508del gene mutation. Of these, 18 (55%) and 15 (45%) were heterozygous and homozygous, respectively. Most patients (95%, n = 38) had pancreatic insufficiency. The theorized reason for the patients' low 25-hydroxyvitamin D levels was often due to non-adherence (56%, n = 23), was unable to be determined (32%, n = 13), or was due to other reasons such as tolerance issues or reduced dietary intake of vitamin D (12%, n = 5).
The mean 25-hydroxyvitamin D levels (in ng/mL) at baseline, 6, 12, and 18 months after the patient's enrollment in the protocol were 23.2 (n = 41), 33.3 (n = 40), 32.7 (n = 34), and 34.6 (n = 34), respectively. Mean 25-hydroxyvitamin D levels were statistically significantly higher at all time points versus baseline (p < 0.001). Post hoc tests using the Bonferroni correction revealed that mean 25-hydroxyvitamin D levels at 6, 12 and 18 months were all significantly higher compared with baseline levels, but they were not significantly different from each other. Therefore, the effect appears to be greatest by 6 months, then stabilizes, but appears to be sustainable.
At 6 months, 50% of the patients reached the target 25-hydroxyvitamin D levels. This increased to 53% of patients at goal at 12 months and 59% of patients at goal at 18 months. Patients were then further divided into 25-hydroxyvitamin D levels categories of < 10, 10 to 19, 20 to 29, or ≥ 30 ng/mL. More than 80% (n = 34) of patients at baseline were in the 20 to 29 category. The < 10 category included 2 patients at the time of initiation into the protocol, which at 18 months notably included zero patients (Figure 3).
Figure 3.
25-hydroxyvitamin D levels (ng/mL) of patients at specified times after enrollment in PDVDP.
Clinical outcomes for patients who reached target vitamin D level were measured by comparing hospitalizations and the average length of stay for 1 year prior to a patient reaching target level, to 1 year after reaching the target level. Fourteen patients (70%) had no hospitalizations during either timeframe. Four patients (20%) had hospitalizations prior to reaching target level with an average length of stay of 10.2 days, with no hospitalizations after reaching target level. Two patients (10%) had no hospitalizations prior to reaching target level, with 1 hospitalization each after reaching target level, with an average length of stay of 10 days. In all cases, hospitalization was due to a pulmonary exacerbation.
The most frequent intervention provided to patients (n = 41) was a recommendation for total vitamin D dose increase (73%), followed by adherence counseling (71%), and a recommendation for 25-hydroxyvitamin D levels check (22%). 25-hydroxyvitamin D levels were checked appropriately (every 3 months) for 22% of patients.
Discussion
The improvements noted in patients' 25-hydroxyvitamin D levels show that the protocol was effective in improving, achieving, and maintaining 25-hydroxyvitamin D levels for at least 18 months for patients not previously at target goal. At least 50% of patients were able to reach target 25-hydroxyvitamin D levels at 6, 12, and 18 months after enrollment in the protocol. The patients' mean 25-hydroxyvitamin D levels increased by 10.1 ng/mL after 6 months, demonstrating a significant increase from baseline. These target levels were achieved through dose increases as listed in the PDVDP, which were collaboratively discussed and implemented with the dietician, and detailed adherence counseling, which was largely conducted by the pharmacy team.
The theorized reasons for the patients' low 25-hydroxyvitamin D levels were classified as due to non-adherence, unable to be determined, or due to other reasons such as tolerance issues or reduced dietary intake of vitamin D. These were identified as the most common themes as derived from subjective assessment of the individual patients based on chart review and were predetermined by the clinic during the PDVDP implementation.
At the UMMC CF clinic, there are multiple team members providing care, many of whom participated in the creation and implementation of the PDVDP. The team consists of 2 physicians, 1 nurse practitioner, 1 dietician, 1 social worker, 2 respiratory therapists, and the pharmacy team, which consists of a clinical pharmacist, residents, and students. The UMMC CF Clinic team very strongly emphasizes the importance of interprofessional collaboration, which helps ensure that the entire team can have a clearer understanding of some of the challenges a patient might be facing at any given time. To keep everyone on the same page, the entire team meets weekly to discuss the patients with clinic visits scheduled for the upcoming week. Prior to this weekly meeting, the pharmacy team determines a patient's fill history for all CF-related medications since the patient's last visit. This is reported to the rest of the team and provides valuable insight for possible adherence, tolerance, access, formulation, or other availability issues for a patient's medications. Recommendations for laboratory studies that are due or changes to weight-based dosing of medications are also made by the pharmacy team at this time. Although a full-time dietician is part of the UMMC CF Clinic team, a full-time dietician might not be present in all clinics or have the capacity to address vitamin D-related goals with every patient. Additionally, many specific patient care outcomes need to be met at the clinic, which leads to vitamin D-related goals sometimes being overlooked. The pharmacist or pharmacy team could potentially fill some of these gaps and more fully take ownership for these specific outcomes as demonstrated by the PDVDP. This could allow the dietician to focus on other CF patient care needs such as nutrition counseling and enzyme replacement.
The published literature and the CFF Vitamin D Deficiency Clinical Care guidelines support the importance of targeting 25-hydroxyvitamin D levels of ≥ 30 ng/mL. Research has previously been done at other CF centers demonstrating the effect of vitamin D on patient outcomes. Specifically, lower 25-hydroxyvitamin D levels and female sex were associated with increased pulmonary exacerbations and hospitalizations,4 and patients with higher 25-hydroxyvitamin D levels were found to have less pulmonary exacerbations.5 Although this study did not note a significant difference for the number of hospitalizations due to pulmonary exacerbations before and after reaching target 25-hydroxyvitamin D levels, improvements could possibly have been noted elsewhere such as a reduced burden on other comorbidities or less decrease in bone mass, as seen in other studies.2,3 In addition, the PDVDP establishes a pharmacist-driven process to improve 25-hydroxyvitamin D levels in patients with CF that may ultimately contribute to improved clinical outcomes.
The protocol implemented was pharmacist-driven, but recommended interventions were completed by all members of the interprofessional CF team. Most commonly, 25-hydroxyvitamin D levels were not checked every 3 months for patients enrolled in the protocol. In working with the pediatric patient population, labs are coupled together to reduce the amount of labs drawn annually for patients. If the level is needed off-cycle from patients' usual labs or is the only lab ordered, requiring patients to have a lab draw for just 1 level may be traumatizing for the patients. Accordingly, 25-hydroxyvitamin D levels could not always be obtained at each visit, which could account for this difficulty in achieving consistently timed lab draws. Depending on other circumstances or the patient's declining condition, it is not always imperative to have a 25-hydroxyvitamin D level drawn but rather to maintain the patient's pulmonary function through antibiotic regimens or admitting the patient. Additionally, a surprising outcome of evaluation of the PDVDP was the number of recommendations for follow-up 25-hydroxyvitamin D levels. This may be explained by inconsistencies in documentation of the recommendation among the team in the electronic health record. Given the interdisciplinary and collaborative nature of the clinic, responsibilities for addressing laboratory results sometimes overlapped between the pharmacy team and the clinical dietician on the care team. The pharmacist and the dietician often collaborated on new dosing strategies and discussed issues with adherence and access, as we all strived to provide the best care for the patients. This overlap may be addressed in the future by having the pharmacist order labs directly in order to receive immediate results alerts and take more timely action for follow-up measures. Additionally, the pharmacy team could establish a designated time when all of the 25-hydroxyvitamin D levels are reviewed and can then provide patients with telephonic management and further instructions.
There were several limitations to this research that may have affected the results. First, this research was conducted in a treatment center with limited patients and no control group. As with any research with CF, the small patient population will be expected. This project originated out of a quality improvement initiative of the clinic to improve 25-hydroxyvitamin D levels in our patient population; therefore, a control group was not included in the design. Given this design, it is unknown if a patient did not have any intervention what the outcome of their 25-hydroxyvitamin D level might have been. Another limitation is that the timing of the vitamin D lab draw was not identified. The timing of the vitamin D lab draw, if during the summer, could have led to increased levels due to increased sun exposure. Finally, the lab assay was changed during the study period. The procedure for collecting the vitamin D lab at the health system was changed a few months after initiation of the protocol; however, this is not believed to have any major effect on the data collected. The methodology for analyzing pediatric 25-hydroxyvitamin D levels moved from the main hospital laboratory to the children's hospital laboratory, which used a different immunoassay and equipment. The specifications do differ slightly between the 2 methodologies, with the Ortho Clinical Diagnostics immunoassay providing a slightly higher limit on detection (8.64 ng/mL vs 2.2 ng/mL) and a more narrow reporting range (12.8–126 ng/mL vs 3.4–155.9 ng/mL). Discussions with the laboratory director at the time identified no inaccuracy in the reported levels.
The usefulness of this study can be displayed by the improvements in many patients' 25-hydroxyvitamin D levels to target goal. Other CF clinics may find the process outlined here to be helpful to implement a similar protocol and quality improvement project.
Conclusion
The PDVDP was effective in increasing the number of patients able to reach target 25-hydroxyvitamin D levels. Our process of implementation and evaluation of a PDVDP can also be used at other CF clinics to incorporate outpatient clinical pharmacists as part of the interprofessional team to improve patients' 25-hydroxyvitamin D levels. Furthermore, additional research can be done to continue to assess long-term clinical outcomes of patients who reach and maintain therapeutic 25-hydroxyvitamin D levels. The research conducted serves to support the role of the pharmacist as part of the interprofessional CF team and can promote the benefit of the addition of a pharmacist to the CF care team.
Acknowledgments
The authors thank Jonathan Gilmore, for his assistance in data collection. Preliminary results were presented at American Society of Health-System Pharmacists Midyear Clinical Meeting on December 8, 2019, in Las Vegas, NV; and at Midsouth Pharmacy Residents Conference on April 15, 2020, in Jackson, MS.
ABBREVIATIONS
- CF
cystic fibrosis
- PDSA
plan, study, do, act
- PDVDP
pharmacist-driven vitamin D protocol
- UMMC
University of Mississippi Medical Center
Footnotes
Disclosures. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Ethical Approval and Informed Consent. Given the nature of this study, institutional review board/ethics committee review and informed consent were not required.
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