Author:  Ivan Porto, 2020 PharmD Candidate
Mentor: Paul Juang, PharmD, BCPS, BCCCP, FASHP, FCCM; Professor, Department of Pharmacy Practice
St. Louis College of Pharmacy

Introduction

The Surviving Sepsis Campaign (SSG) 2016 makes several recommendations about fluid resuscitation. The current SSG recommendations state that at least 30 mL/kg of IV crystalloid should be given to patients within the first 3 hours of admission, with a target MAP of 65 mmHg.¹  Reassessment of these patients should include the evaluation of several hemodynamic parameters, including heart rate, blood pressure or the use of other dynamic parameters.²  After initial resuscitation, SSG recommends that crystalloids should be used for subsequent intravascular volume replacement¹ (strong recommendation) and that albumin should be added when patients require large amounts of crystalloids (weak recommendation).

However, one area that lacks a definitive recommendation is which crystalloids to use in different situations. The current SSG is unable to recommend one crystalloid solution over another because no direct comparisons have been made between isotonic saline and balanced salt solution in patients with sepsis.¹  Furthermore, the SSG fails to address which fluids to use in non-septic critically ill patients.

When providing IV fluid resuscitation for critically ill patients, the primary goal is for fluids to be given in a fashion that maximizes positive healthcare outcomes. Recent trials have provided insight into the advantages and disadvantages of several IV fluids, which can help direct deciding which fluid to use in patients being held in an ICU.

Normal Saline vs. Balanced Crystalloids

Balanced Crystalloids versus Saline in Critically Ill Adults (SMART) – This trial compared normal saline and balanced crystalloids for use in the fluid resuscitation of critically ill patients.

* Decision to use lactated ringer’s vs Plasma-Lyte depended on the preference of the treating physician

Balanced Crystalloids versus Saline in Noncritically Ill Adults (SALT-ED) – This trial compared normal saline and balanced crystalloids for use in the fluid resuscitation of non-critically ill patients.

* Decision to use lactated ringer’s vs Plasma-Lyte depended on the preference of the treating physician

Summary of Results

Take home points:

• No difference in rate of death, but evidence suggests that balanced crystalloids are overall superior in end organ damage for patients who survive their ICU stay.
• • Lactated Ringer’s is superior to normal saline in patients with sepsis.

• Due to the millions of patients treated with IV crystalloids per year, a number needed to treat of 111 in regards to renal dysfunction suggests that balanced crystalloids are superior to NS.⁷ However, this data is limited to non-critically ill patients.

Crystalloids vs Colloids

A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit (SAFE) – This trial compared 4% albumin and normal saline for use in the fluid resuscitation of critically ill patients.

Albumin Replacement in Patients with Severe Sepsis or Septic Shock (ALBIOS) – This trial compared 20% albumin combined with crystalloids to crystalloids alone for use in the fluid resuscitation of patients with sepsis.

Crystalloids vs. colloids for fluid resuscitation in the Intensive Care Unit: A systematic review and meta-analysis – A systematic review of 55 articles, published in 2019, examining the comparison between crystalloids and colloids for the fluid resuscitation of ICU patients.

Summary of Results

Take home points:

• There is no difference in risk of death between crystalloids and albumin within the first month of treatment^5,7,8
• • Albumin should not be used in patients with traumatic brain injury (weak recommendation, limited evidence)⁸
• Crystalloids are useful, but care needs to be taken on preventing fluid overload. The majority of the crystalloids’ disadvantages stem from their overuse.
• • Liberal use of crystalloids will lead to third spacing, which will complicate treatment for critically ill patients. Patients should be examined in a detailed manner to assess their response to fluid resuscitation. This includes, but is not limited to, heart rate, blood pressure, arterial oxygen saturation, respiratory rate, temperature, urine output.⁶
• Starting with crystalloids and switching to colloids “when patients require substantial amounts of crystalloids”. However, there is no clear recommendation to guide physicians on what constitutes a “substantial amount”.⁵
• • The authors suggest a maximum of 3-4L of crystalloids, but do not provide citation. They also suggest estimating with fluid input/output volumes, but state it is unreliable. Furthermore, the authors suggest that bioelectrical impedance analysis may provide usefulness in the future.⁵

• Using dynamic measures (passive leg raises, variations in systolic pressure and pulse pressure) instead of CVP to monitor response to fluid resuscitation and guide further therapy.^1,5
• Colloids provides no advantage in risk of death. However, in general, they do provide an advantage in end organ damage with the exception of hepatotoxicity and coagulopathy.⁷
• Albumin is significantly more expensive than crystalloids. Being able to raise CVP more effectively, and thus being able to discontinue other vasopressors earlier, could offset that cost. However, need for more PRBC could add to the cost.^7,8
• • Cost benefit analysis could be performed in the future

• No suggestions could be made on different concentrations of albumin fluids.

• Hydroxyethyl starch – While it was a part of the colloid category, it was shown to have clear disadvantages vs other fluids (strong evidence).^1,5
• Dextran & Gelatin – These are not preferred.^5,6

References:

1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. Doi: 10.1007/s00134-017-4683-6.
2. Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy Collaborative Group: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J med 2001; 345:1368-1377.
3. Self W, Semler M, Wanderer JP, et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):819-828. Doi: 10.1056/NEJMoa1711586.
4. Semler M, Self W, Rice T. Balanced Crystalloids vs Saline for Critically Ill Adults. N Engl J Med. 2018 May 17;378(2):1951. doi: 10.1056/NEJMc1804294
5. Martin GS, Bassett P. Crystalloids vs. colloids for fluid resuscitation in the Intensive Care Unit: A systematic review and meta-analysis. J Crit Care. 2019 Apr;50:144-154. Doi: 10.1016/j.crc.2018.11.031.
6. Moeller C, Fleischmann C, Thomas-Reuddel D, et al. How safe is gelatin? A systematic review and meta-analysis of gelatin-containing plasma expanders vs crystalloids and albumin. J Crit Care. 2016; 35:75-83.
7. Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412-21. doi: 10.1056/NEJMoa1305727.
8. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;250(22):2247-56.

Author:  Shannon Mensing, 2019 PharmD Candidate
St. Louis College of Pharmacy

Mentor: Jennifer Rushing, PharmD
Clinical Pharmacist, SSM Health St. Joseph Hospital – St. Charles

According to the Center for Disease Control, more than 26 million Americans suffer from asthma, accounting for approximately 8% of children and 8% of adults. Within this population, 5 to 10% of patients have severe asthma that does not respond to conventional therapy with a short-acting beta-agonist and inhaled corticosteroids. Patients with refractory asthma experience an increased rate of exacerbations, hospital visits, and medical costs.¹ In recent years, monoclonal antibodies have been approved in addition to the standards of care in asthma to treat these patients with type 2 inflammation. Recently, dupilumab (Dupixent) was approved by the FDA to treat for add-on maintenance treatment of patients 12 years or older with moderate to severe asthma with an eosinophilic phenotype or with oral corticosteroid-dependent asthma.³

Dupilumab (Dupixent), manufactured by Regeneron Pharmaceuticals and Sanofi, was originally approved in March of 2017 with an FDA approval to treat adults with moderate to severe atopic dermatitis that is not adequately controlled with topical therapy. It was hypothesized that dupilumab may have a beneficial and therapeutic value in the treatment of asthma after it was found to treat other conditions that are driven by type 2 inflammation, including the aforementioned atopic dermatitis and chronic sinusitis, both of which are commonly found in patients with asthma. After further investigation, it confirmed that dupilumab had a beneficial effect in asthma as well. Currently there are other monoclonal antibodies on the market used to treat asthma that target the IL-5 cytokine pathway. Dupilumab has a different mechanism of action that targets a separate pathway of inflammation by blocking IL-4 and IL-13 pathways, inhibiting type 2 inflammation.²

Three major clinical trials were published that contributed to approval of dupilumab in the treatment of asthma. All were double-blind, randomized, placebo-controlled trials. In a phase 2b dosing trial published in 2016, adult patients with uncontrolled persistent asthma on guideline directed medical therapy were assigned to treatment with dupilumab or placebo. The primary endpoint of the trial was change from baseline at week 12 in forced expiratory volume in 1 second (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per microliter. Dupilumab was found to have the greatest effect in the population with a baseline eosinophil count greater than 300. However, there was a benefit seen in the general population in both improved FEV1 and decreased rates of exacerbations.  Both treatment groups that received the 200 and 300 mg doses had a mean improvement of approximately 0.40 L in FEV1 at 12 weeks when compared to placebo.  Additionally, patients treated with dupilumab also saw a reduction of up to 70% in the rates of annual severe exacerbations.⁵

Another trial looked at patients 12 years of age or older with moderate to severe asthma treated with inhaled corticosteroid and long-acting beta-agonist combination products with moderate to severe uncontrolled asthma. Patients again were assigned to treatment groups with either 200 or 300 mg of dupilumab or matching placebos. Treatment with dupilumab when compared to placebo showed a significant reduction in annualized rates of severe asthma exacerbations with the most benefit in patients with elevated baseline eosinophil counts. Patients in the 200 mg treatment group had an annualized asthma exacerbation rate of 0.46, compared to 0.87 in the placebo group. It also resulted in improved lung function and asthma control, measured by FEV1.  At 12 weeks of treatment, the treatment group that received the lower dose of dupilumab experienced a 0.32 L increase in FEV1 with similar effects noted with the 300 mg dose as well. ⁴

A third trial used to garner approval for dupilumab treatment in asthma looked at asthmatic patients dependent on oral glucocorticoids at the time of randomization. The trial’s primary outcome analyzed the percentage of glucocorticoid reduction at week 24 of therapy compared to placebo. Patients in the population treated with dupilumab saw a reduction in use of oral glucocorticoids, in addition to an improvement in FEV1 and a reduction in rates of exacerbations. The treatment group saw a percentage decrease in glucocorticoid use of approximately 70% with a 0.22 L increase in FEV1.  Treatment with dupilumab also resulted in a 59% lower rate of severe exacerbations when compared with placebo.⁶ 

Each trial showed a benefit with the use of dupilumab in the treatment of asthma. Both initial trials reduced the annual rate of asthma exacerbations per year in the trial population.^4,5  Additionally, the oral glucocorticoid dependent group saw a mean reduction of approximately 70% in the dose of oral steroids they were receiving.6 Dupilumab was shown to have greatest effects in the population subgroup that had an eosinophil count ≥ 300.4,5Among these three trials, similar adverse reactions were observed. Injection site reactions and a transient rise in eosinophils were the two most common reactions associated with treatment.^4-6

Dupilumab dosing is determined based on the severity of disease. Patients with moderate-to-severe asthma are initially treated with a 400 or 600 mg loading dose divided into 2 equal subcutaneous injections via a prefilled syringe, followed by a maintenance dose of 200 mg or 300 mg every 2 weeks, respectively. Patients with oral glucocorticoid dependent disease are treated with a 600 mg loading dose divided into two equal subcutaneous injections, followed by 300 mg given every 2 weeks. Patients may self-administer this medication at home following training by a healthcare provider. When injecting the medications, patient should be instructed to keep the syringe capped and allow the solution to reach room temperature for 30 to 45 minutes prior to use.³

As with many other biologic agents, cost of the medication may be a limiting factor in the utilization. Estimated average wholesale price for the 200 mg pre-filled syringe is around $1,589.⁸  However, dupilumab has shown promising results in the treatment of asthma, especially those with elevated eosinophil counts. It can be considered in patients after maximum use of conventional therapy with inhalers and may provide relief in patients that have exhausted other options.

References

1. Asthma Facts and Figures. Asthma. https://www.aafa.org/asthma-facts/. Published February 2018. Accessed April 23, 2019.
2. Office of the Commissioner. Press Announcements - FDA approves new eczema drug Dupixent. U S Food and Drug Administration Home Page. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm549078.htm. Published March 28, 2017. Accessed April 23, 2019.
3. Dupilumab (Dupixent) for Asthma. The Medical Letter. https://secure.medicalletter.org/w1563c. Published January 14, 2019. Accessed April 23, 2019.
4. Castro M, Corren J, Pavord I. et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. New England Journal of Medicine. 2018;378:2486-2496. doi:10.1056/NEJMoa1804092
5. Wenzel S, Castro M, Corren J. et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. The Lancet. 2016;388(10039):31-48. doi:S0140-6736(16)30307-5
6. Rade K, Nair P, Brusselle G. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. New England Journal of Medicine. 2018;378:2475-2485. doi:10.1056/NEJMoa1804093
7. Dupilumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  http://online.lexi.com . Accessed April 26, 2019

Authors:  Elizabeth Pham, 2019 PharmD Candidate
Alison Stevens PharmD, BCPS; Assistant Director of Health System and Acute Care, Office of Experiential Education/Assistant Professor, Department of Pharmacy Practice
St. Louis College of Pharmacy 

Introduction

Transitions of care (TOC) is a process designed to maintain the safety and care of patients when transferring between different health care settings or different health care professionals within the same setting. However, transitioning patients can be complex, resulting in medication errors. In the United States, medication errors and adverse drug events contribute to almost 700,000 emergency department visits and over 100,000 hospitalizations.Factors often attributed to causing adverse drug events include breakdowns in communication, accountability, incomplete medication reconciliation and insufficient patient and caregiver education.¹ All of these elements contribute to hospital readmissions, stressing the importance of an effective TOC process. Pharmacists can play a fundamental role in this process by providing interventions such as medication reconciliation, patient counseling and follow-up telephone calls. In fact, various institutions that have piloted the use of pharmacists on their TOC team found improvement in outcomes such as a decrease in the number of return emergency department visits and a reduction in medication discrepancies.^2-4

Creating a Transitions of Care Introductory Pharmacy Practice Experience

Pharmacists clearly have a role in the TOC process that continues to expand; therefore, pharmacy schools should start exposing their students to care transitions as a pharmacy practice experience. Though the data on implementing an introductory pharmacy practice experience (IPPE) focused on TOC is lacking, certain institutions have started to pilot advanced pharmacy practice experiences (APPE) concentrated on TOC with positive results. Pharmacy students that participated in these TOC APPEs not only received hands on patient care experience, but also greatly impacted their sites. One institution increased the number of patients assessed by their TOC team from 10 patients to approximately 15 to 20 patients per day with student integration.⁵

At the St. Louis College of Pharmacy, TOC is included in the Pre-APPE curriculum as an IPPE course. The course spans both fall and spring semesters of the third professional year. As part of the course, student pharmacists are made aware of the negative health outcomes of an ineffective TOC process and have an opportunity to impact the TOC process in various settings. Additionally, the students have the chance to act as part of the health care team and interact with other health care professionals to emphasize the importance of collaboration at crucial transitions.

The Student Experience

The majority of the course is spent completing 20 experiential hours in either ambulatory care, long-term care, community or health systems. To understand what TOC looked like in all four health care settings, a student from each setting was interviewed to talk about their experience.

In ambulatory care, patients transition from the inpatient setting to the outpatient setting. Rachel Marchi, a student assigned to the ambulatory care setting, utilized telepharmacy to complete her TOC activities. When she was able to reach the patients, she asked questions regarding their current medications and identified any barriers to adherence. Additionally, each patient interaction lasted approximately 10 to 15 minutes. When talking about her overall experience she stated that, “I feel like we were able to optimize the care of each patient by making their appointment visit more focused on what they wanted to come in for. Overall, I really enjoyed my experience and I feel like it helped prepare me for my future APPE rotations.”

Likewise, in long-term care, patients mainly transition out of the hospital and into a long-term care facility. Bradley Collins, a student that completed his TOC IPPE rotation in long-term care, spent most of his time on the computer analyzing the medication lists for each patient transferred to the nursing facility. According to Bradley, it took about two hours to complete a full assessment for each patient. When talking about his experience, Bradley said that “having the opportunity to see what TOC looks like in a long-term care setting was really awesome, since this is not something we get a lot of exposure to in school.” 

In the community setting, patients transition from the inpatient environment and back into the community, or between different pharmacies. Performing TOC activities in the community setting can be challenging due to communication barriers between the pharmacist and hospital and lack of integration between the computer systems from either setting. Moreover, staffing issues and the amount of time needed to complete a TOC intervention may not always be feasible. Meghin Moynihan, who completed her TOC IPPE rotation in the community setting, was only able to transfer prescriptions and perform patient adherence calls. When talking about her overall experience Meghin said she “really enjoyed her time at the pharmacy” but felt that her TOC experience was very limited.

On the other hand, in the health system setting, patients transition from the outpatient environment to an inpatient setting, and then back to the community. Ivan Porto, a student that completed his TOC IPPE in a hospital, states, “I did a lot of medication reconciliation for patients that were admitted to the service and medication education for patients that were going to be discharged from the hospital.” When talking about his overall experience Ivan claims, “My preceptor gave me a lot of opportunities to really see what TOC looks like in a health systems setting, so I really enjoyed my experience.”

The Preceptor Perspective

In addition to the students’ experience, preceptors from each setting were interviewed to gain perspective on how they integrated the IPPE course into their respective practices. Dr. Justinne Guyton, who practices in ambulatory care at the St. Louis Department of Public Health, set up the rotation so students called patients scheduled to come for a follow-up visit after a recent hospitalization. Patients were picked for the students ahead of time by Dr. Guyton who determined which patients would fit the criteria for a TOC intervention. In contrast to Dr. Guyton’s ambulatory care site, Dr. Steven Hebel’s long-term care site at Corum Health Services, Inc. had students perform medication reconciliation using a standardized form. The form compared patient medication lists from different settings (home, doctor’s office and hospital discharge) and different computer systems (the skilled nursing facility and Corum pharmacy). If the students identified any medication discrepancies, omissions, and/ or duplications they had to assess the patient’s risk for hospital readmission and adverse events. Another preceptor, Dr. Andrew Crannage, created an “IPPE collaboration” between the other three TOC preceptors at his health system site, Mercy Hospital St. Louis. He set the rotation up as a shared experience where the students would spend time with each preceptor performing a specific TOC task each day they were scheduled. Tasks included an orientation day, discharge education day, home medication reconciliation day, and a day where students rounded with a pharmacist and health care team. Finally, Dr. Joshua Boudeman, a pharmacist at the solid organ transplant and oncology specialty Walgreens at SSM St. Louis University Hospital, had his students perform medication reconciliation for the solid organ transplant and oncology patients preparing for discharge. Students built patient profiles for new oncology referrals that the pharmacy received, including their medication list. This list was either obtained from the patient or, preferably, provided by the prescriber's office and confirmed by the patient.

Wrap Up

Having an effective TOC process in place is crucial to improving health outcomes for patients. Pharmacists are a vital component of the TOC team, and pharmacy schools should begin integrating care transitions into the experiential curriculum.  Adoption of these experiences could lead to improved student education on TOC and positive TOC outcomes at rotation sites.

References

1. Brantley A, Rossi D, Barnes-Warren S, et al. Bridging gaps in care: Implementation of a pharmacist-led transitions-of-care program. Am J Health Syst Pharm. 2018;75(suppl 1):S1-S5.
2. Patel S, Nguyen P, Bachler M, et al. Implementation of post-discharge follow-up telephone calls at a comprehensive cancer center. Am J Health Syst Pharm. 2017;74(11 supplement 2):S42-S46. 
3. Walker P, Berstein S, Jones J, et al. Impact of a Pharmacist-Facilitated Hospital Discharge Program: A Quasi-Experimental Study. Arch Intern Med. 2009;169(21):2003-2010. 
4. Dudas V, Bookwalter T, Kerr K, et al. The Impact of Follow-up Telephone Calls to Patients After Hospitalization. Am J Med. 2001;111(9):26S-30S.
5. Walker P, Jones J, and Mason N. An Advanced Pharmacy Practice Experience in Transitional Care. Am J Pharm Educ. 2010;74(2):20.

Authors:  Elizabeth F. Englin, PharmD, BCPS and Heather Taylor, PharmD, BCPS
Clinical Assistant Professors - UMKC School of Pharmacy

Since the inception of the Hospital Readmission Reduction Program (HRRP) by the Centers for Medicare and Medicaid Services (CMS) in 2011, implementation and expansion of pharmacy – led transitions of care (TOC) services has become a focus for many institutions and clinics.¹ The positive impact of pharmacy – led TOC services has been well documented in the literature through landmark trials such as the Medications at Transitions and Clinical Handoffs (MATCH) study and Project Re – Engineered Discharge (ProjectRED).^2,3 Examples of pharmacy – led TOC services include medication history collection, medication reconciliation, comprehensive medication review, disease state education and medication counseling. One barrier to implementation of successful pharmacy – led TOC services is staffing resources.⁴ In order to implement or expand pharmacy – led TOC services, there is an increased need for additional pharmacy personnel or adjustment of current workflows.⁴ One method to overcome this barrier is the utilization of pharmacy residents and students to provide pharmacy – led TOC services.⁵ Involving pharmacy residents and students in performing TOC services provides valuable learning opportunities for them, while also benefitting the institution and improving patient care. Under appropriate supervision, pharmacy residents and students can help expand TOC services and reach more patients by serving as practice extenders at less or no additional cost to the institution.⁶ Data demonstrate student pharmacist involvement increased the number of patients receiving pharmacy-led TOC services from 10 patients per day to 15-20 patients per day.⁵

Incorporating pharmacy learners into TOC practices requires strong patient – centered care skills. Student pharmacists and pharmacy residents are equipped with the tools necessary to provide these services as they are instilled throughout their pharmacy school curricula. In 2014, the Joint Commission of Pharmacy Practitioners (JCPP) established the Pharmacists’ Patient Care Process (PPCP).⁷ The five step PPCP outlines a universal approach to patient - centered care with the underlying principles of collaboration, communication and documentation.⁷ The five steps of the PPCP are: collect, assess, plan, implement and follow – up including monitoring and evaluation.⁷ The ultimate goal of the PPCP is to provide a standardized approach to patient care for pharmacists to apply regardless of pharmacy setting or direct patient care activities.⁷ The Accreditation Council for Pharmacy Education (ACPE) incorporated the PPCP into the 2016 accreditation standards for pharmacy schools and colleges.⁸ Standard 10.8 states that schools and colleges of pharmacy should “prepare students to provide patient – centered collaborative care as described in the Pharmacists’ Patient Care Process model endorsed by the Joint Commission of Pharmacy Practitioners.”⁸ As a result, student pharmacists and new pharmacy graduates are equipped with the skills and knowledge to deliver patient – centered care according to the PPCP.

The American Pharmacists Association (APhA) recently published a guidance document titled: Applying the Pharmacists’ Patient Care Process to Care Transitions Services.⁹ In this document, they highlight the many components of TOC services and map them to the PPCP.⁹ Aligning TOC services with the PPCP allows institutions to adopt a standardized approach to the delivery of pharmacy-led TOC services. This also serves as a great method to train pharmacy residents and students to deliver TOC services. Medication management is a crucial component of TOC in which pharmacists in all practice settings play an important role. Studies show that the risk and incidence of medication errors increases during TOC and pharmacist involvement in the TOC process helps avoid preventable medication errors. Many services that pharmacists currently provide in a variety of practice settings are components of TOC. Recognizing these services as elements of TOC and involving pharmacy learners in advancing these services are great steps to providing optimal patient care. As pharmacists, we have an obligation to help safely and effectively manage our patient’s medications during TOC in every pharmacy practice setting, including hospital, community, ambulatory care, long-term care, along with many others. We have a great opportunity to collaborate with pharmacist colleagues in other practice settings to achieve this common goal.

If your institution has a residency program, a student intern program, or serves as a rotation site for Introductory/Advanced Pharmacy Practice Experience (IPPE/APPE) students, we encourage you to identify opportunities to involve them in developing or expanding pharmacy-led TOC services. Through delivering these services, pharmacy learners will increase their knowledge and skills by engaging in direct patient care while also adding a valuable contribution to the pharmacy department. Are you ready to reap the countless benefits of involving pharmacy learners in TOC today?  

References:

1. CMS: Hospital Readmissions Reduction Program (HRRP). Centers for Medicare & Medicaid Services. https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/Readmissions-Reduction-Program.html. Updated 27 September 2018. Accessed 26 April 2019.
2. MATCH: Gleason KM, McDaniel MR, Feinglass J, et al. Results of the Medications at Transitions and Clinical Handoffs (MATCH) study: an analysis of medication reconciliation errors and risk factors at hospital admission. J Gen Intern Med. 2010; 25(5):441-447. doi: 10.1007/s11606-010-1256-6
3. ProjectRed: Jack BW, Chetty VK, Anthony D, et al. A Reengineered Hospital Discharge Program to Decrease Rehospitalization: A Randomized Trial. Ann Intern Med. 2009; 150(3):178-187. doi: 10.7326/0003-4819-150-3-200902030-00007
4. APhA-ASP: ASHP – APhA Medication Management in Care Transitions Best Practices. https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/quality-improvement/learn-about-quality-improvement-medication-management-care-transitions.ashx. Published February 2013. Accessed 8 May 2019.
5. Walker PC, Tucker Jones JN, Mason NA. An advanced pharmacy practice experience in transitional care. Am J Pharm Educ. 2010; 74(2): article 20.
6. Eltaki SM, Singh-Franco D, Leon DJ, et al. Allocation of faculty and curricular time to the teaching of transitions of care concepts by colleges of pharmacy. Curr Pharm Teach Learn. 2018; 10 (6): 701-711. doi: 10.1016/j.cptl.2018.03.014
7. PPCP:  Joint Commission of Pharmacy Practitioners. Pharmacists’ Patient Care Process. May 29, 2014. Available at: https://jcpp.net/wp-content/uploads/2016/03/PatientCareProcess-with-supporting-organizations.pdf.
8. Stds 2016: Accreditation council for pharmacy education. Accreditation standards and key elements for the professional program in pharmacy leading to the doctor of pharmacy degree. https://www.acpe-accredit.org/pdf/Standards2016FINAL.pdf. Published February 2, 2015. Accessed 8 May 2019.
9. American Pharmacists Association. Applying the Pharmacists’ Patient Care Process to Care Transitions Services. February 2019

Authors:  Emily Shor, PharmD and Alex Meyr, PharmD
PGY1 Pharmacy Residents, SSM Health St. Mary’s Hospital – St. Louis

According to a report released by the Center for Disease Control and Prevention, over 100 million adults in the United States currently live with diabetes or prediabetes.¹ Notably, various antidiabetic agents, such as insulin and secretagogues, are commonly associated with hypoglycemic events in the inpatient setting. Controlling both hyperglycemia and hypoglycemia is important in hospitalized patients and is associated with increased cost, length of stay, morbidity, and mortality.² Association of hypoglycemia with mortality has resulted in changes in clinical guidelines which make recommendations regarding glycemic control.³

The 2019 American Diabetes Association guidelines defines level 1 hypoglycemia as a blood glucose < 70 mg/dL but > 54 mg/dL. A blood glucose of < 70 mg/dl is considered clinically important regardless of severity of hypoglycemia symptoms. Level 2 hypoglycemia is defined as blood glucose < 54 mg/dL and is associated with neuroglycopenic symptoms and requires action to resolve the hypoglycemic event.³  

A retrospective review of hypoglycemic events (blood glucose < 50 mg/dL) in diabetes patients at SSM St. Mary’s Hospital St. Louis between June 2014 and October 2015 assessed a total 539 hypoglycemic events to identify the incidence of preventable recurrent hypoglycemic events before and after a collaboration between pharmacy and certified diabetic educators. This review determined that 7.5% of events that were reported pre-collaboration were preventable while 3.7% of events that occurred post-collaboration were preventable. Although this finding was not a statistically significant difference, it represents a nearly 50% reduction in events. The collaboration facilitated communication with the treatment team and thus therapeutic modification in an effort to prevent inpatient hypoglycemia. Through this project, SSM St. Mary’s Hospital pharmacy team developed a monitoring spreadsheet that allows for pharmacists to monitor hypoglycemia events and track interventions.

Since its development, the hypoglycemia monitoring spreadsheet has proven to be a useful tool that helps pharmacists identify potential causes for hypoglycemia as well as opportunities to prevent subsequent hypoglycemic events. Pharmacists run a report of any hypoglycemic events, defined by a blood glucose less than 50 mg/dL, which have occurred at St. Mary’s Hospital each day and then document the details regarding that event. Through this monitoring form, pharmacists intervene by contacting and communicating with providers to adjust the insulin regimen as well as determine if an event is considered preventable. These preventable events prove to be teaching moments for the entire pharmacy team to attempt to prevent these events from occurring repeatedly. At the end of each month, the list of hypoglycemic events is reviewed by the Medication Event Reporting Team (MERT), which consists of two pharmacy residents, two clinical pharmacy specialists, and pharmacy management. At these meetings, the nature of each event is discussed and whether or not they are truly preventable. Events considered preventable are reported so that other members of the healthcare team (including those specifically involved with the event) can have an opportunity to learn from the event and make necessary adjustments going forward. Additionally, the discussions during MERT meetings are presented to the rest of the pharmacy staff during weekly meetings as a means to further educate pharmacists about preventing hypoglycemic events (ideally aiming to have pharmacists take closer looks at insulin orders and not hesitating to clarify orders with physicians before verifying).

Although the hypoglycemia monitoring spreadsheet has been helpful in educating healthcare members about preventing events, there are still gaps in the monitoring form that have made it difficult for the MERT team and other pharmacists to truly learn from certain events. As a result, a new hypoglycemia monitoring spreadsheet was developed this year to help address some of these issues. Specifically, the old spreadsheet required pharmacists to document each specific event, even if it happened to the same person. This made it difficult to understand the full course of a patient’s hospital visit and determine if the multiple events a patient had were related (especially if the events were dispersed throughout the spreadsheet). Additionally, the original spreadsheet did not require pharmacists to input all of the necessary information needed to accurately assess the etiology and severity of a particular event. This resulted in significant variability among reports submitted by different pharmacists. There was a column that allowed pharmacists to provide a brief description of the event, but most pharmacists were not taking the time to document a full report of the event consistently.

The new hypoglycemic monitoring spreadsheet incorporates more columns in an effort to help pharmacists input more specific information regarding the event so the reported details are consistent and allow for easier interpretation by the MERT team. Furthermore, several drop down options were added to the spreadsheet to help make it convenient for pharmacists to document the information (i.e. drop down tabs for diet, type of insulin regimen, hypoglycemia management strategies). Additionally, the new spreadsheet included a section regarding recurrent events. This gives pharmacists an opportunity to simply add information to the same patient row as opposed to creating an entire new row and repetitive information if a different pharmacist had documented the event previously. By making this change, the MERT team was able to get a better understanding of the nature of various events and determine what specific factors contributed.

During the initial phases of implementing the new hypoglycemia spreadsheet, the pharmacists working with the spreadsheet most frequently identified a few barriers. Specifically, some pharmacists felt overwhelmed with the new form because it included several more columns than they were used to seeing. At a quick glance, the spreadsheet seemed like it would be more work and require more information to be documented. However, after some education and practice opportunities, pharmacists quickly realized that the process does not take much longer (some felt that it was quicker), and it allows for more detailed information to be provided.

Oftentimes, pharmacists find it challenging to identify the true cause of the hypoglycemic event. Additional research continues at SSM Health St. Mary’s Hospital to identify particular risk factors for hypoglycemic events. A recent review of hypoglycemic events between January 1, 2017 and June 1, 2017 found that almost half of the hypoglycemic events had documented PO intake and insulin administration mismatch. Additionally, patients’ home basal insulin dose was rarely decreased until a hypoglycemic event occurred. Based on the results of this review, pharmacists may consider recommending a reduction in home basal insulin doses by 20-30% or not exceed 0.3 units/kg for initial basal insulin doses inpatient.

The new hypoglycemia monitoring form has been implemented for over three months now, and the MERT team has already identified improvements in the monitoring process and the way in which pharmacists go about addressing insulin orders. Specifically, by inputting the required information in the spreadsheet, pharmacists seem to be more able and willing to provide a detailed description of a particular event. As a result, the MERT team is able to have more thorough discussions regarding events. This has led to more conversations among pharmacists and has helped make staff more vigilant with insulin orders. With more time implementing this new spreadsheet, data could be collected to see if there have been any reductions in the number of hypoglycemic events.

References:

1. Centers for Disease Control and Prevention. 2017. “New CDC Report: More Than 100 Million American Have Diabetes or Prediabetes.” Last modified July 18, 2017. Accessed May 10, 2019. https://www.cdc.gov/media/releases/2017/p0718-diabetesreport.html.
2. Hulkower RD, Pollack RM, Zonszein J. Understanding hypoglycemia in hospitalized patients. Diabetes Manag (Lond). 2014;4(2):165-176.
3. Glycemic targets: standards of medical care in diabetes—2019. Diabetes Care. 2019;42(Suppl 1):S61-S70.

Authors:  Andrea Prince, PharmD and Michelle Ndiulor, PharmD
PGY-2 Ambulatory Care Pharmacy Residents

Mentor:  Joshua Holland, PharmD, BCPP
Psychiatry Pharmacy Specialist
CoxHealth – Springfield, MO

Program Number:  2019-05-08
Approval Dates:  June 5, 2019 – December 4, 2019
Approved Contact Hours: One (1) CE(s) per LIVE session.

Learning Objectives:

1. Review the mechanism of action and indication of antipsychotics
2. Discuss advantages and disadvantages of long-acting injectable antipsychotics
3. Identify the appropriate place in therapy for long-acting injectable antipsychotics in psychiatric conditions
4. Identify various long-acting injectable antipsychotic agents available in the United States
5. Explain the dosing, proper administration of long-acting injectable antipsychotics and how to address missed and late doses

Introduction

Schizophrenia and bipolar disorder are chronic disease states and complex disorders in which antipsychotics are utilized for treatment. Oral antipsychotics are known to have a high rate of poor adherence, which can result in relapse for the patient. Poor adherence is associated with mood relapses; increased risk for hospitalization and emergency room visits; and increased employee costs due to absenteeism, disability, and worker’s compensation. Some of the reasons for poor adherence may include side effects, poor efficacy, cognitive deficits, complexity of regimens, medication access, and an unstable living environment.¹ Long-acting injectable antipsychotics (LAI APs) have shown similar efficacy and safety to oral antipsychotics and can be a treatment option for patients with adherence issues.

Overview of Antipsychotics

The use of antipsychotic agents in mental health disorders began around 1951 with chlorpromazine^2,3. Prior to this period, chlorpromazine was used in patients due to its potential anesthetic effects during surgery. Psychiatrists during the time noticed its sedative effects and began using the medication in their patient populations^2,3. Following this period, several oral first-generation or “typical” antipsychotic agents were introduced into the United States market for treatment of mental health disorders such as schizophrenia and bipolar disorder. Along with the effective mechanism of action that this class of medications brought came several adverse effects including extrapyramidal symptoms. In 1990, introduction of clozapine into the US market initiated the use of oral second-generation or “atypical” antipsychotics agents³. These agents showed a reduced potential for causing extrapyramidal symptoms.

In between the development of the various oral first- and second-generation antipsychotics, the first LAI AP was developed in 1966 by ER Squibb & Sons Ltd in the United Kingdom^2,4. Fluphenazine enanthate appeared to show some potential advantages over oral antipsychotic agents including ensured contact with a provider and ease of administration. However, the medication was met with a great deal of adversity due to psychiatrists seeing it as a ‘threatening’ formulation for patients^2,4.

With time, long-acting injectable antipsychotics made their way up treatment ladders for mental health conditions as prescribers and patients noticed its efficacy, tolerability, and simplified regimen. Currently there are several long-acting injectable antipsychotic agents available in the United States and other countries around the world^2,4.

Mechanism of Action

Typical Antipsychotics⁵

The primary action of first-generation antipsychotics (FGA) is its pharmacological activity on the D2 (dopamine) receptor. This class of medication acts as an antagonist to the receptor, which is responsible for its antipsychotic effects. Unfortunately, this mechanism is also responsible for many of its various side effects. Neurolepsis results from D2 receptor antagonism. Patients that present with neurolepsis will appear apathetic and will lack motivation. Other adverse effects associated with the class’ D2 receptor antagonism include extrapyramidal symptoms (EPS) and hyperprolactinemia. Other actions of this class of medication include muscarinic cholinergic receptor antagonism, histamine receptor antagonism, and alpha-1 adrenergic receptor antagonism. Orthostatic hypotension may be seen with alpha-1 adrenergic receptor antagonism while side effects such as urinary retention and dry mouth may be seen due to anticholinergic effects.

Atypical Antipsychotics⁵

Atypical antipsychotics still have dopamine receptor blockade but also have serotonin-activity (5HT2-A antagonism). Having this second action leads to antipsychotic effects in addition to lower EPS and hyperprolactinemia risk through partial serotonin (5HT-1A) & D2 receptor agonism. Second generation antipsychotics (SGA) bind to dopamine receptors transiently and rapidly dissociate from receptors allowing dopamine to bind receptors. This is thought to be the reason why risk of extrapyramidal symptoms and hyperprolactinemia are lessened. Furthermore, some atypical antipsychotics exhibit serotonin agonism leading to increased release of dopamine and decreased release of glutamate which can potentially improve the side effect profile.

2014 National Institute for Health and Care Excellence (NICE) Guideline Recommendations for Long-Acting Antipsychotic Use in Schizophrenia Treatment⁶

Currently, the 2014 NICE guidelines recommend the consideration of a depot/long-acting injectable antipsychotic as maintenance therapy. In patients living with conditions such as psychosis or schizophrenia, LAI antipsychotics may be considered after an acute episode or when there is a desire to avoid intentional/non-intentional non-adherence. Oral antipsychotics are recommended during acute episodes alongside cognitive behavioral therapy.

The decision on which antipsychotic agent to use should be one that involves both the patient and/or caregiver and the healthcare professional. Furthermore, a discussion with the patient should include the likely benefits and potential side effects associated with the medication being initiated. Likely benefits to discuss with the patient would include less frequent administration potentially leading to improved adherence and potential for reduced relapse frequencies and rehospitalization rates⁷.  Furthermore, discussion of the potential side effects would include²:

• Metabolic (including diabetes and weight gain)
• Extrapyramidal symptoms (including dyskinesia, dystonia, and akathisia)
• Cardiovascular (including prolonged QT interval)
• Hormonal side effects (including hyperprolactinemia)

2014 NICE Guideline Recommendations for Long-Acting Antipsychotic Use in Bipolar Disorder Treatment⁸

For treatment of bipolar disorder, the 2014 NICE guidelines recommend the use of oral antipsychotic agents including haloperidol, quetiapine, olanzapine, or risperidone. Even, though the guidelines do not explicitly state the use of long-acting injectable antipsychotic agents, long-acting injectable antipsychotic agents are used in practice for bipolar disorder management.

According to the guidelines, it is recommended that before starting an antipsychotic agent, the patient’s weight, pulse, blood pressure, blood lipid profile, and fasting blood glucose or glycosylated hemoglobin A1c be measured and recorded. An electrocardiogram may also be necessary in the case that the patient has cardiovascular disease, has a family history of cardiovascular disease, is being admitted as an inpatient, or if it is specified with the specific antipsychotic being used².  Monitoring recommendations for patients receiving antipsychotic treatment are listed in Table 1 below.

Table 1: Monitoring Recommendations for Patients Receiving Antipsychotic Treatment⁹

Place in Therapy: Long-Acting Injectable Antipsychotics

Adherence issues have been of growing concern. Despite having oral first and second-generation antipsychotics available for use, adherence to this formulation is lacking¹⁰. Some factors involved in nonadherence to antipsychotic therapy include lack of provider awareness of non-adherence, irregular daily routines, and complexity of the patient’s medication regimen. Evidence has shown that non-adherence rates of patients living with schizophrenia ranges from around 40 to 60% of all patients^11-13. Furthermore, various studies have shown an association between non-adherence and increased rates of relapse, re-hospitalizations, worsening long-term prognosis, increased dependence on families, increased dependence on the healthcare system, and worsened functionality^14-18. Long-acting injectable antipsychotics have exhibited efficacy, safety, and a more simplified medication regimen compared to some oral options⁴. Therefore, the use of long-acting injectables may be considered for use in this patient population.

Ideal Candidates⁷

Guidelines and literature suggest that ideal candidates for long-acting injectable antipsychotics include patients with recent-onset schizophrenia and individuals with risk factors for medication non-adherence. These risk factors include the following:

Advantages/Disadvantages of Long-Acting Injectable Antipsychotics⁷

When compared to oral antipsychotics, there are a number of potential advantages of long-acting injectable antipsychotics. One of the main advantages of LAIs APs compared to oral APs is there being no need for daily administration. Additionally with LAIs, there is less risk of intentional or unintentional overdose due to the guaranteed administration of the LAI and transparency of adherence. Benefits also include more consistent bioavailability and a more predictable correlation between dosage and plasma levels.  Moreover, when patients stop taking their medication, the plasma levels of the LAI decrease more slowly as compared to oral formulations. This gives the healthcare professionals time to intervene and reduce the probability of rebound symptoms and abrupt relapses.

One of the main disadvantages associated with LAI APs is the increased time it takes to achieve steady state levels and less flexibility of dose adjustments due to the long acting nature of the formulation. With injectable medications, there is the potential for injection-site reactions as well as pain at the injection site, which can be irritating to the patient. Depending on the patient’s lifestyle and socioeconomic factors, they may not be able to make frequent visits to clinics or pharmacies for administration due to job constraints, lack of or limited transportation, and/or work schedule. Lastly, the LAI APs are more expensive than the oral APs and may additionally require prior authorizations which can delay their use.

Overview of Long-Acting Injectable Antipsychotics Available in the United States

All the LAI APs have product specific dosing and dosing intervals. Additionally, some products require a trial of the oral formulation as well as an overlap period of oral and LAI formulations. Selecting an optimal LAI AP should be patient-centered and various practical considerations should be discussed. All of the LAI APs require administration by a healthcare professional. The side effect profile of the LAIs generally follows the known side effect profiles of the oral formulation. Pharmacokinetics of the LAIs varies among the different agents and is summarized below in Table 2. The advantages of the FGAs are cost and a lower metabolic side effect profile when compared to LAI SGAs. The disadvantages include a higher risk of EPS and greater interpatient variability regarding pharmacokinetics. Table 3 summarizes the clinical features of the LAI APs.

First-Generation LAI Aps^19-27

Fluphenazine decanoate is indicated for treatment of psychotic disorders. Tolerability with oral fluphenazine should be established prior to initiation of injection. The drug vehicle for the injection is sesame oil thus close attention to the patient’s allergy profile is warranted. Initially, it is dosed at one to two-week intervals. Once steady state is reached, the dosing interval may be lengthened to four to six weeks.

Haloperidol decanoate is used for the treatment of schizophrenia. Tolerability with oral haloperidol should be established prior to use and overlap with oral haloperidol can be tapered and discontinued following the second or third injection. The vehicle for the injection is sesame oil similar to fluphenazine decanoate.

Second-Generation LAI Aps^19-27

Abilify Maintena® (aripiprazole monohydrate) is indicated for the treatment of schizophrenia and maintenance of bipolar 1 disorder.  The drug vehicle is microparticles in water. Abilify Maintena® requires the patient to establish tolerability with 14 days of oral therapy and also requires a 14-day overlap of oral therapy. There are two types of kits one of which is a prefilled dual chamber syringe and the other contains vials of lyophilized powder which require reconstitution.

Aristada® (aripiprazole lauroxil) has an FDA-labeled indication for the treatment of schizophrenia. Tolerability should be established with oral aripiprazole prior to initiation treatment with Aristada®. Overlap with oral aripiprazole for 21 days is necessary with the first injection unless using Aristada Initio®. Aristada Initio® is a one-time injection that can be given on day 1 with a single 30mg dose of oral aripiprazole in addition to the first Aristada dose. When using Aristada Initio®, the 21 day oral aripiprazole overlap is not necessary. Aristada® is supplied as an off-white aqueous suspension in single-use pre-filled syringes.

Zyprexa Relprevv® (olanzapine pamoate) is indicated for the treatment of schizophrenia. It does not require overlap with the oral formulation but does require the establishment of tolerability with oral olanzapine prior to initiation. Zyprexxa Relprevv® is supplied as a microcrystalline suspension in vials. Zyprexa Relprevv® has a small risk for post-injection delirium/sedation syndrome which limits its use. The signs and symptoms associated with the reaction include: sedation, anxiety, confusion, aggressiveness, dizziness, ataxia and extrapyramidal symptoms. After an injection, patients require monitoring for three hours by a healthcare professional. Prescribers, facilities, and pharmacies must enroll in a national registry for documentation of this adverse event.

Invega Sustenna® (paliperidone palmitate) is indicated for treatment of schizophrenia and schizoaffective disorder. It does not require overlap with oral paliperidone; however, it does require establishment of tolerability with oral paliperidone. Invega Sustenna® requires two initiation doses during the first week to rapidly attain steady-state paliperidone concentrations.

Invega Trinza® (paliperidone palmitate) is indicated for the treatment of schizophrenia. Once patients are established on Invega Sustenna® for a least a four month duration, they may transition to Invega Trinza®, which has a three-month dosing interval. It is supplied as a suspension in a pre-filled syringe which requires vigorous shaking to ensure a homogenous suspension.

Risperdal Consta® (risperidone) is used for the treatment of schizophrenia and for the long-term treatment of bipolar 1 disorder. Tolerability with oral risperidone should be established prior to use of Risperdal Consta®. Overlap with oral risperidone for three weeks is necessary to establish adequate therapeutic plasma concentrations. Risperdal Consta® is supplied as a kit that requires reconstitution of a microsphere polymer suspension using a vial, vial adapter, and pre-filled syringe with diluent.

Perseris® (risperidone) is a once monthly injection indicated for the treatment of schizophrenia in adults. Tolerability with oral risperidone should be established prior to use of Perseris®. Perseris® is supplied as pre-filled liquid syringe carrying the delivery system and a prefilled powder syringe which contains risperidone.

Conclusion

Antipsychotic agents have been used for many years for the treatment of mental health conditions such as schizophrenia and bipolar disorder. First and second-generation antipsychotics have slightly different chemical profiles leading to reduced risk of certain adverse effects in second-generation (atypical) antipsychotics. Pharmacists can utilize their drug knowledge to assist in product selection, dosing, administration, missed doses, and drug-drug interactions. Additionally, some pharmacists are able to dispense and administer LAI APs to patients thus increasing medication access to patients.

Overall, long-acting injectable antipsychotic agents have been shown to be efficacious and relatively safe for use in patients living with mental health disorders. Long-acting injectable antipsychotics may be used to aid in the improvement of medication adherence by improving patient access to medications.

Supplemental Tables:

References:

Submit for CE

Authors:  Arianne MacGillivray, PharmD and Ijeoma Onyema, PharmD
PGY-1 Pharmacy Practice Residents

Mentor:   Anthony Lucido PharmD, BCPS
PGY-1 Pharmacy Practice Residency Director
SSM Health DePaul Hospital – Bridgeton, MO

Program Number:  2019-05-09
Approval Dates:  June 5, 2019 – December 4, 2019
Approved Contact Hours: One (1) CE(s) per LIVE session.

Learning Objectives:

1. List the current antidepressants used in major depressive disorder
2. Evaluate the impact magnesium has on depressive symptoms
3. Identify the different theories regarding major depressive disorder pathophysiology
4. Explain the mechanism of action of magnesium in major depressive disorder

Introduction

Major Depressive Disorder (MDD) is a debilitating mental disorder, with approximately 17.3 million adults in the United States and 216 million people worldwide experiencing at least one major depressive episode.⁸  This disorder is characterized by at least two weeks of low mood that is often accompanied by low self-esteem, anhedonia, fatigue, and possible suicidal ideation. The pathophysiology behind major depressive disorder has been explained by multiple neurobiologic factors.

Pathophysiology

Genetics has been thought to play a role as well as stressful life events. Chronic stress has been found to lead to increased amounts of corticotrophin-releasing hormone released from the hypothalamus and subsequent increases in cortisol levels. A lack of monoamines such as norepinephrine, dopamine, and serotonin has been found in depressed patients and increases in available monoamines is the main mechanism of action of the majority of current antidepressant therapy. Dysregulation in GABA and glutaminergic processes as well as the circadian rhythm has also been associated with depression. Additionally, depressed patients have been found to have structural neurobiologic abnormalities, such a smaller hippocampus.⁷

Secondary depression can be caused by diseases and/or medications. For example, endocrine disorders such as diabetes and hypothyroidism have been associated with depression. Low levels of vitamins and minerals have also been associated. Specially, a low level of vitamin D has been found to be closely linked to depressive states. Magnesium has also been linked to depression, and will be discussed in further detail throughout the rest of this publication. Medications such as glucocorticoids, interferons, opioids, and beta blockers have been associated with depression; however, evidence relating to medication-induced depression is conflicting. There is question whether or not medications actually induce depression or if the perceived changes in mood are just related to these medications’ side effects such as fatigue, insomnia, lack of appetite, etc.

Current Therapies

There are five classes of antidepressants that are indicated for use in major depressive disorder and are currently used in practice. These include: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIS), monoamine oxidase inhibitors (MAOIs), and “other” antidepressants such as bupropion, nefazodone, trazodone, and mirtazapine. Potential common side effects of antidepressants include: GI problems, anxiety, weight gain, sexual dysfunction, and/or sedation. The potential of these medications to cause these side effects has notoriously caused significant patient concern; however, the majority of these should subside within the first few weeks of initiation. Based on these side effects, cost, duration, and potential to cause drug interactions, the 2010 American Psychiatric Association Guidelines recommend that SSRIs, SNRIs, mirtazapine, and bupropion be utilized first line. According to these guidelines, patients will generally see improvement with these medications in the first 1-2 weeks of treatment, but the medications may take up to 12 weeks to see full effect. If a patient experiences some improvement in depressive symptoms within the first few weeks of an antidepressant initiation, but moderate improvement is not achieved after 4-8 weeks at the highest tolerated dose, a different medication may be considered.¹ Nonprescription medications such as SAM-e and fish oil have been evaluated for antidepressive efficacy, but current research is inconsistent in regards to the validity and applicability of the data analyzed. 

MOA of Magnesium in Depression

The true mechanism that magnesium plays in depression is unknown; however, it likely serves as a multi-factorial contributor in the depression. This is because of its impact on many of the pathways, hormones, and neurotransmitters involved in mood regulation. In the chronic mild stress model, the levels of magnesium and cortisol have been shown to be inversely proportionate. Also, magnesium is a calcium antagonist via its voltage-dependent blockade of the N-methyl-D-aspartate (NMDA) channel. By inhibiting the influx of calcium ions, less toxic reactive oxygen species and nitric oxide radicals are produced, leading to a reduction in neuronal swelling and neuronal death. This then results in less neuronal dysfunction and improved synapse production and activity.Moreover, magnesium has some impact on the modulation of gamma-aminobutyric acid (GABA) receptors; it likely has an inhibitory effect on GABA. This action downregulates the inhibitory effect of GABA on hippocampal activity, which contributes to suppression of hippocampal kindling and adrenocorticotropic hormone release to the HPA axis, which is a frequent occurrence in depression. Magnesium has also been suggested to play a role in systemic inflammation and the production of ATP, which could validate the impact the mineral has within the chronic stress pathophysiology model of depression in future studies.

Guideline Recommendation

There are currently no guidelines that recommend the use of magnesium for major depressive disorder treatment. However, several studies have been done to confirm that there is a reduction in magnesium levels in depressed patients as well as evaluate magnesium’s effectiveness in patients with major depressive disorder.

Table 1 – Studies Evaluating Magnesium’s Impact on Depression

Summary of Clinical Evidence

The studies that have been performed to assess magnesium’s antidepressant efficacy are highly variable in methodology. Different assessment tools for determining depression were used; none of the studies assessed used the Montgomery–Åsberg Depression Rating Scale (MADRS), which is considered to many to be the gold standard for indicating depressive symptoms in research studies. This variety in assessment methods could compromise the generalizability of recommending magnesium to depressed patients. Due to the high ambiguity of the association of serum magnesium levels to depressive symptoms in these studies (as many studies in the past have shown increased, decreased, and normal levels of magnesium in depressed patients), it has been theorized that serum magnesium levels may not be the most appropriate indicators of magnesium’s impact on major depressive disorder. Specifically, the variability of magnesium levels seen in these studies have suggested that proved that not all magnesium compositions are equally absorbed into the bloodstream. Magnesium chloride, sulfate, glycinate and taurinate have been associated with higher bioavailability than magnesium oxide.¹⁸

Conclusion

Overall, more robust research and investigation into supplementation for behavioral health management is needed to truly determine magnesium’s place in depression management, specifically with larger diverse populations and different indicators used to evaluate the efficacy of magnesium in depression (i.e. tissue magnesium level as a proxy of bioavailability). While not currently recommended in any guideline for depression, magnesium supplementation could be considered for those with mild depressive disorder who are also using behavioral interventions or an oral antidepressant given future research produces more tangible data that confirms its antidepressive effects.

References

Author:  Bert McClary

A child sometimes asks a parent, “Mommy, where did I come from?”  I rarely get asked directly, “Where did MSHP come from?” but members do express an interest when they hear facts about the early days of MSHP.  I’m not one of the parents—we have three founding fathers—I’m more like one of the uncles and aunts who were there watching and helping, but I’ll try to get you interested in our history with a few anecdotes during the next year.  We will be celebrating 50 years of activity in the spring of 2020.

You’ve heard the pharmacy history of early man using plant medications, Egyptian papyrus documents, Greco-Roman scientists/healers/apothecaries, Arab apothecary shops and European separation of pharmacy and medicine.  The first hospital in the U.S. was in Philadelphia in 1751 and the first hospital pharmacist was appointed in 1752.  Hospital pharmacists in Colonial America received little pay and little recognition from the public, the health professions or the American pharmacy profession.  The use of formal medicines, development of specialized hospital pharmacy standards of practice, and development of overall practice standards for hospitals was slow. 

In the 1930s, the APhA Sub-Section on Hospital Pharmacy was founded by Harvey A.K. Whitney and other progressive hospital practitioners.  A Minimum Standard for Pharmacies in Hospitals was developed and was approved by the American College of Surgeons.  The American Society of Hospital Pharmacists (ASHP) became an autonomous affiliate of APhA in 1942 with three constitutional goals: Establishing minimum standards, providing interchange among pharmacists and encouraging new program development, and extending the economic and rational use of medication.  Results of a 1957 study by ASHP were published in the 1964 Mirror to Hospital Pharmacy, written by Francke, Latiolais, Francke and Ho.  The Mirror provided many recommendations based on six broad goals to enhance the development of hospital pharmacy.

Nationwide in the 1950s all hospitals larger than 300 beds had a full-time pharmacist, but only 39% of all hospital beds had the services of a pharmacist.  Only 3.5% of hospitals under 50 beds did.  Small rural hospitals were sometimes serviced by local community pharmacists or not at all. 

Local and area hospital pharmacy societies had been formed nationwide beginning in 1925, and some were affiliated with ASHP.  There were pockets of progress in Missouri and the Metropolitan Society of Hospital Pharmacists of St. Louis, 1942, and the Greater Kansas City Society of Hospital pharmacists, circa 1950s, were founded by groups of nuns.  Outside the two major metropolitan areas there was little progress until the late 1960s.

Hospital pharmacy services in the 1960s were primarily focused around drug distribution.  Drug distribution in hospitals with no pharmacist or minimal pharmacist staffing was by a floor stock (ward stock) system.  In facilities that had no pharmacist, nurses managed the acquisition, storing, repackaging and distribution activities.  Even in the larger hospitals, twenty-four hour pharmacist staffing was rare, and often there was little or no weekend coverage.  Sterile intravenous and irrigating solutions were prepared by the pharmacy in larger hospitals, or by the central sterile supply department.

The Missouri Board of Pharmacy had little interest in hospital pharmacy.  The BOP did not license or inspect hospitals for inpatient pharmacy services and hospitals that did not fill outpatient prescriptions generally did not maintain a BOP license. 

A few rural hospital pharmacists were active in local retail organizations and the Missouri Pharmaceutical Association. Politically active establishment retail pharmacists controlled both the MPA and BOP and were not truly interested in hospital practice issues.

There were three forward-thinking hospital pharmacy practitioners, our founding fathers, in three distinct areas of the state and in distinctly different practice settings, who sought to improve services in their local areas and began to interact with each other on a statewide level: Thomas J. Garrison, Director of Pharmacy at the small Lakeside Hospital in Kansas City; Garf Thomas, Chief Pharmacist at the University of Missouri Medical Center in Columbia; and Harvey A.K. Whitney, Jr.,  clinical pharmacy professor at St. Louis College of Pharmacy.

During the fall of 1969 Harvey organized a “Joint Committee for the Unification of Hospital Pharmacists in Missouri.”  The first “Statewide Meeting of Missouri Hospital Pharmacists” held in Columbia on February 21, 1970 attracted 54 registrants. 

In April when the Missouri Pharmaceutical Association (MPA) learned that MSHP was being organized, the MPA Executive Director made an initial effort to bring the group into the MPA, but there was little interest by MSHP leadership in affiliation at that time.  Some members of the St. Louis and Kansas City hospital pharmacist societies were opposed to affiliation of their local organizations with MSHP.

The first annual meeting of MSHP was May 16, 1970 at StLCOP.  At the successful business and dinner meeting an Enabling Resolution and the proposed Constitution and By-Laws were approved.  George Heine of St. Louis and Garf Thomas of Columbia were elected and installed as President and President-elect. The Board of Directors and appointed committees met during the year and these goals were established: 

• Minimum Standards for Hospital Pharmacy
• Unification of Pharmacists in Missouri
• Accredited Residency Program for Missouri
• Student involvement
• Continuing education

We’ve been successfully pursuing these goals for almost 50 years.

Author: Jackie Harris, PharmD, BCPS
Executive Director of MSHP R&E Foundation/St. Louis College of Pharmacy/Christian Hospital Northeast

Dr. Haleigh Stolte, a PGY1 resident at the North Kansas City Hospital, was awarded the Best Resident Project at the ICHP/MSHP Spring Meeting for her project entitled “CAM I aCUTely Change Your Mind: A Pharmacist Driven Approach to Reducing Delirium”.  Based upon the new Guidelines for Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS), management of ICU delirium should initially focus on reduction of modifiable risk factors for delirium.  Medications such as benzodiazepines, opioids, H2 receptor antagonists, corticosteroids, anticholinergics, and NSAIDS have been associated with delirium.

 A prospective observational study was developed to evaluate the effect of substitution, renal adjustment, and/or discontinuation of high-risk deliriant medications on the length of delirium before and after implementation of a pharmacist-driven medication management protocol.  This project was developed in response to an increase in the number of psychiatric consults due to delirium seen at the North Kansas City Hospital.  Secondary objectives included assessing the frequency of high-risk deliriant medication use before and after implementation of the protocol and time spent by pharmacists completing the review.  Patients were identified electronically when an acute change in mental status is documented by nursing staff using the Confusion Assessment Method for the ICU (CAM-ICU).  The alert then notifies pharmacists to substitute, discontinue, renally adjust, and document use of medications with delirious side effect profiles, as listed above, per protocol. 

Statistical analysis was performed on 65 patients pre intervention implementation, and 41 patients post intervention implementation. No statistically significant differences between groups was identified. The primary outcome of this study is length of delirium, defined as time spent with an acute mental status change. Patients in the post intervention group had reduction in length of delirium of 7.9 hours, with a correlating p-value of 0.2. Secondary outcome measures included frequency of high risk deliriant medication use and pharmacist time spent completing interventions. Medication use decreased between pre and post intervention groups, and further decreased after pharmacist intervention. On average, pharmacists documented interventions required < 15 minutes of time to complete. Exploratory measures that included length of ICU stay and mortality at discharge. Patients in the post intervention group had a length of ICU stay that was 2 days shorter than pre intervention group. Interestingly, 24.6% of patients in the pre intervention group were alive at discharge, while 82.9% of patients in the post intervention group were alive at discharge.

If you have any questions about implementing a pharmacist-driven medication management protocol for delirium, please contact Dr. Stolte at haleigh.stolte@nkch.org.    

Author: Jackie Harris, PharmD, BCPS
Executive Director of MSHP R&E Foundation/St. Louis College of Pharmacy/Christian Hospital Northeast

At the MSHP/ICHP Spring Meeting, the R&E Foundation presented Journey McCarty, Pharm.D. with the MSHP Best Practice Award for her project entitled “Implementing a Pharmacist Driven 72-hour Antimicrobial Time Out”.  The University of Missouri Health Care System implemented a pharmacist driven 72 hour antimicrobial time out in patients receiving vancomycin, ertapenem, meropenem, micafungin, or posaconazole.  The primary outcome was days of therapy per 1000 patient days.  Secondary outcomes included number and type of interventions, number and percentage of interventions accepted by physicians, time reported by pharmacist to complete antibiotic time out, and percentage of Antibiotic Time Out alerts completed.  The pharmacy workflow developed can be seen in Figure 1.  Pharmacist training was completed which included the development of a job aid, inservice trainings, a competency assessment, required completion of an online continuing education program on optimizing antimicrobial therapy, and a quality improvement check.

Figure 1. Antimicrobial Time Out Workflow

As of March 11^th, 153 antibiotic time out forms had been completed with the majority being completed for vancomycin.  Interventions were made in 36 of those forms.  The majority of the interventions made were for de-escalation of antibiotics (16/36).  Other interventions included recommending to discontinue therapy (12/36), recommending a stop date or duration added to order (5/36), dose change (2/36), and recommending to broaden therapy (2/36).  Sixty-nine percent of those recommendations were accepted by the physician.  An additional 11% of the recommendations were accepted with modifications.  For the majority of pharmacists, the form was completed within 5 minutes (79%).  The days of therapy per 1000 patient days has been lower each month for vancomycin when comparing January, February, and March of 2019 to 2018.  Additionally, the days of therapy per 1000 patient days was lower in February for ertapenem compared with February of 2018. 

This project has been well received at the University of Missouri Health Care, and can certainly be implemented at other hospitals throughout the state.  The project team continues to identify opportunities for improvement, and is making plans to add more antibiotics to the Antibiotic Time Out in the near future.  The team is working towards adding fidaxomicin, daptomycin, and amphotericin B to the Antibiotic Time Out.  If you have any questions about how Dr. McCarty implemented her project, please email her at journey.mccarty24@gmail.com.