• 17 Jul 2018 11:55 AM | Anonymous

    Saint Louis College of Pharmacy

    The 2017-18 academic year came to a close on May 12, as St. Louis College of Pharmacy celebrated the class of 2018 at its 150th Commencement. This year’s ceremony marked a milestone in the College’s history as it recognized the first graduates earning bachelor’s degrees in the College’s integrated Bachelor of Science and Doctor of Pharmacy program. With more than 400 degrees conferred, the 150th Commencement featured the largest class of graduates in the College’s history.

    With our historic Commencement behind us, we are reflecting on an exciting year that was highlighted by a wide range of recognition for the College’s faculty, facilities and programs.

    • Last fall, Amy Tiemeier, Pharm.D., BCPS, director of community partnerships, associate director of experiential education and associate professor of pharmacy practice, was named to the St. Louis Business Journal’s “40 Under 40” class of 2018 in recognition of her work in the community to combat opioid abuse.
    • In recent months, the College’s Recreation and Student Center (RAS) was the recipient of a 2017 Design Award from the American Institute of Architects (AIA) St. Louis Chapter. The AIA sponsors the awards annually to celebrate excellence in the designed environment.
    • The College’s STEM Health Science Academy was selected as an Arcus Award finalist in the Achievement in Inclusion and Talent Attraction category in recognition of its mission to equip high school students with education, on-the-job training and soft-skill development to prepare them for STEM-based careers.
    • The College was also a finalist in the BMO Harris Bank St. Louis Spirit Award category for its efforts to combat opioid abuse. Presented annually by the St. Louis Regional Chamber, the Arcus Awards recognize companies and organizations that make the St. Louis Region a more attractive place to live, work and invest.
    • This spring, the BESt Pharmacy Summer Institute was presented with a 2018 “What’s Right with the Region” award in the “Improving Racial Equality and Social Justice” category. As a collaboration between Barnes-Jewish Hospital, Express Scripts and St. Louis College of Pharmacy, the BESt program was recognized for its commitment to exposing and preparing area multicultural students for future careers in healthcare, with an emphasis on pharmacy. The “What’s Right with the Region” awards are presented annually by FOCUS St. Louis, the region’s premier leadership organization.

    During the academic year, we were also thrilled to welcome Thomas Burris, Ph.D., FAAAS, FAHA, to campus as the Alumni Endowed Professor in the College’s Center for Clinical Pharmacology and President’s Senior Research Advisor. With a research background focused on using chemical biology approaches to examine the physiological roles of nuclear hormone receptors and developing drugs targeting them for the treatment of conditions including type 2 diabetes, heart disease, cancer and Alzheimer’s disease, Burris brings the Center for Clinical Pharmacology one step closer to becoming a national research leader in pain management and personalized approaches to medication therapy. He joins pharmacists, physicians and researchers at the center who hold academic appointments at both the College and Washington University School of Medicine in St. Louis.

    This is an exciting time at St. Louis College of Pharmacy!  I invite you to visit campus soon for a first-hand look at the many wonderful things underway as the College continues its work to prepare students for expert practice and leadership in pharmacy and health professions careers.

    Sincerely,

    Bruce R. Canaday, Pharm.D., FASHP, FAPhA
    Dean of Pharmacy and Professor

    UMKC School of Pharmacy

    As usual, we have been very busy at the UMKC School of Pharmacy!  While it would be impossible here to describe all that has been going on, I would like provide a brief update on recent activities at the school.

    UMKC School of Pharmacy at MSU:  After six years of hard work by UMKC and MSU faculty and staff, as well as support from the state of Missouri and many hard-working legislators, we have come through on our promise to provide pharmacy education in Southwest Missouri.  Our first cohort of 31 students graduated from our Springfield location in May.  Prior to graduation, most of the students had secured jobs in and around Southwest Missouri.  This group of outstanding students included many who would not have been able to pack up and move to our sites in Kansas City or Columbia in order to attend pharmacy school.  Special thanks go to all who made this happen, but especially our friends and colleagues at Missouri State University.  President Clif Smart and Provost Frank Einhellig and all of the folks there who worked with us to make dreams come true.

    “APhA-ASP National Champions”.  If ESPN would cover pharmacy student competitions, then the entire country, even those outside the pharmacy world, would know the dominance of the UMKC chapter of the American Pharmacists Association-Academy of Student Pharmacists (APhA-ASP)!  This year, our chapter was once again recognized as the number one chapter in the country!  This is the second time since 2012 that our chapter has been recognized by APhA as the number one chapter, and every year in between they have been among the top seven or four chapters in the nation.  Our students are clearly having a huge impact on the health and wellness of people in our country, and especially throughout central and southwestern Missouri as well as the Kansas City area.  We are proud that they continue to bring such positive national attention to UMKC.  We also had national APhA awards provided to individual UMKC student pharmacists including:  Sara Massey (Class of 2018) received the John A. Gans Scholarship from the APhA Foundation; Sierra Woods (Class of 2019) received the APhA Good Government Student Pharmacist of the Year.

    Outstanding Faculty Advisors.  I often get asked by other deans of pharmacy around the country about the keys to the success of our student chapter of APhA-ASP, and the answer is simple:  it’s clearly the outstanding faculty advisors they have.  Special thanks go to the mentorship provided by Drs. Kelly Cochran, Kathryn Holt, Lisa Cillessen, Angela Brownfield, Sarah Cox, Heather Taylor, Andrew Bzowyckyj, and Cameron Lindsey.  All of these faculty are well-known nationally for leading our students, but we are particularly pleased that Dr. Valerie Ruehter received the APhA-ASP Outstanding Chapter Advisor Award—the top advisor in the country!

    Other National Student Awards.  Our students received many other national awards.  Marian Lyford (Class of 2018) was recognized by the United States Public Health Service with the 2018 Excellence in Public Health Pharmacy Award.  Also, Dion Tyler (Class of 2018) and his interprofessional team of health care student finished 3rd at the annual CLARION National Competition at the University of Minnesota.

    Faculty and Staff Focus on Student Success!  While we are absolutely elated that our students rake in all the national awards, the truth is their greatest accomplishment is graduation.  For that ultimate measure of student success, we are forever grateful for the hard work and dedication of our staff and faculty.  We are also proud of our student success numbers where 94.4 % of the students who entered our program in 2014 graduated on time in 2018.  While we do not yet have NAPLEX pass rates from them, we do know that for 2017 graduates—97.5 % of whom graduated on time—92% passed the NAPLEX on first sitting.

    Faculty Accolades.  Many of our faculty have received substantial accolades in the last year, far too many to list all here.  Among our clinical faculty, some of the accomplishments included:  Dr. Andy Smith was named a Fellow of the American College of Clinical Pharmacy; Dr. Heather Taylor became a Board-Certified Pharmacotherapy Specialist; Dr. Heather Lyons-Burney was named MPA Faculty Member of the Year and received the Jefferson Award, a national program started by Jacqueline Kennedy in 1972 that honors everyday heroes in our community; Dr. Paul Gubbins published a book as Editor entitled Drug Interactions in Infectious Disease: Mechanisms and Models of Drug Interactions, 4th Ed.; Dr. Maureen Knell co-authored a publication in Pain Medicine this year that is receiving significant attention locally and nationally for understanding opioid prescribing patterns; Drs. Angela Brownfield, Paul Gubbins, and Valerie Ruehter received the Award for Excellence in Scholarship in Experiential Education from the American Association of Colleges of Pharmacy; and Dr. Kendall Guthrie was elected to serve on the Board of Directors of the MPA.

    There are many other great accomplishments of our students faculty in the past year.  If you can make time to come by and see us, we’d be happy to tell you all about it.  You are all welcome to visit the school anytime at our sites in Kansas City, Columbia, and/or Springfield.  We also appreciate your assistance in identifying any students who might be interested in pursuing pharmacy careers.  Just let us know, we love to talk to anyone about our great profession! 

    Best wishes to everyone in MSHP!

    Russell B. Melchert, Ph.D.
    Dean of Pharmacy and Professor


  • 17 Jul 2018 11:26 AM | Anonymous

    Summer Tenet - Have Fun

    Aaah, summer - that long anticipated stretch of lazy, lingering days, free of responsibility and rife with possibility. It's a time to hunt for insects, master handstands, practice swimming strokes, conquer trees, explore nooks and crannies, and make new friends.

    - Darell Hammond

    While you are doing your best to stay cool from the summer heat, I hope you are able to take time for yourself and your family, enjoy some summer fun, and perhaps even a nice vacation with those you love.  Integrating fun into your life, at home and at work, is an essential part of the personal and professional balance we are all trying to find.  Take some time, chat with your co-workers, tell a joke, go get some ice cream, and enjoy the ride on this crazy journey called life!

    Summer has arrived and so has a new year for many including universities, residency programs, health systems and of course MSHP.  We started our year with our annual Strategic Planning Meeting which was held in Mid-June in Kansas City.  I am happy to report that we had a good turnout, a productive meeting, and set straightforward, measurable goals for our society this year.  Highlights include efforts to achieve full prescribing authority with recognition as mid-level providers in the state of Missouri, continued support for technician advancement initiatives ongoing in the state, increase the utility of our members’ only section of our Society website, and improve communication to the membership at large.  While fun may not be the best word to describe our experience during this meeting, there were a few laughs, everybody left with a smile on their face, and a good feeling about the plan for the year.

    Lastly, I want to update you on a new and fun opportunity that will take place on September 6-9th, 2018 in Branson, MO.  We are working with the Missouri Pharmacy Association (MPA) on a co-branded fall meeting.  This is a new effort for our organizations and we hope it is the first step in a collaborative effort that will continue into the future.  Content for the meeting will be presented by both MSHP and MPA members and will cover both community and health systems perspectives on various topics.  I encourage anyone who is interested to participate to join me for some fun in Branson this fall.  Information and registration details can be found at https://www.morx.com/conference.

    Enjoy your summer, have as much fun as you can, and get those new residents trained.  I look forward to updating you in the fall with what I hope will be early success on a few of the strategic priorities mentioned above.

    Respectfully,

    Tony Huke, PharmD, BCPS


  • 01 Jun 2018 3:12 PM | MSHP Office (Administrator)

    Immunotherapy and Management of Immune-Related Adverse Effects: A Focus on the Immune Checkpoint Inhibitors

    Authors: Mallory Crain, PharmD: PGY-2 Oncology Resident Barnes-Jewish Hospital and Sara K. Butler, PharmD, BCPS, BCOP: Barnes-Jewish Hospital

    Program Number: 2018-04-10
    Approval Dates: 6/6/18 - 9/6/18
    Approved Contact Hours: One (1) CE(s) per LIVE session.

    Objectives
    Understand the general mechanism of immune checkpoint inhibitors and specific mechanisms of action for the individual agents.

    1. Identify immune checkpoint inhibitor agents, mechanism of action, FDA-approved indications, and dosing.
    2. Recognize common immune-related adverse effects and factors that increase patient’s risk of developing immune-related adverse effects.
    3. Identify management strategies for common immune-related adverse effects including cutaneous, gastrointestinal, endocrine, and pulmonary toxicities.
    4. Recommend monitoring and supportive care measures for medications initiated to manage immune-related adverse effects.


    Background
    Immunotherapy is quickly becoming a mainstay treatment option for numerous malignancies, and multiple immunotherapy agents have been approved by the US Food and Drug Administration (FDA).  In general, immunotherapy agents work by using the immune system to fight off cancer, which can be done through various mechanisms.1 The immune checkpoint inhibitors, a specific class of immunotherapy agents, upregulate the immune system by blocking proteins that inactivate the immune system.  This class of agents can be very effective against malignancies that express these inactivating proteins.2-9 

    Immune Checkpoint Inhibitors
    The immune checkpoint inhibitors are a group of agents that target specific proteins that help control the immune response, called the immune checkpoint proteins.  There are three different checkpoint proteins that are currently targeted by available agents: cytotoxic T-lymphocte-associated-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1).  CTLA-4 and PD-1 are expressed on the surface of T-cells.  These inactivating proteins interact with CD80/CD86 and PD-L1, respectively, on tumor or antigen presenting cells.  When this interaction occurs, T-cell activation is inhibited resulting in malignant cells evading T-cell-mediated death.  Immune checkpoint inhibitors are able to block the interaction between PD-1 and PD-L1 or CTLA-4 and CD80/CD86.  When this occurs, T-cells are activated and able to fight off malignancy.2-9

    There are currently six different immune checkpoint inhibitors that are FDA approved (table 1).  The first agent to gain FDA-approval was ipilimumab, the only agent that inhibits CTLA-4.10  Following ipilimumab, two PD-1 inhibitors, pembrolizumab and nivolumab, were both approved.11,12  The newest immune checkpoint inhibitors, atezolizumab, avelumab, and durvalumab, all inhibit PD-L1.13-15  All of these agents are FDA-approved for a variety of solid malignancies and Hodgkin’s lymphoma.10-15  In addition, there is a vast amount of ongoing clinical trials evaluating the immune checkpoint inhibitors for other solid and hematologic malignancies.

    Introduction to Immune-Related Adverse Effects
    Since immune checkpoint inhibitors result in a non-tumor-specific activation of T-cells, there is potential for immune-related adverse effects to occur.  This is a result of the immune system attacking non-tumor cells, which can cause organ damage.  The immune-related adverse effects can occur in any organ system. However, the most frequent immune-related adverse effects seen in clinical practice involve the gastrointestinal (GI) tract, endocrine glands, skin, and liver.  Although infrequent, the central nervous system, cardiovascular, and pulmonary systems can also be involved.6-9,16-19  There is some evidence supporting a higher incidence of specific immune-related adverse effects depending on the location of the primary malignancy.  For instance, pneumonitis may be more common in patients with lung cancer compared to other types of malignancy.20 

    Immune-related adverse effects usually develop within the first few weeks to months of exposure to checkpoint inhibitors, but can occur at any time point, even after treatment discontinuation.  In general, prolonged treatment or higher doses have not been associated with an increased incidence of immune-related adverse effects.6-8  Ipilimumab is the exception to this since literature comparing 3 mg/kg to 10 mg/kg found increased immune-related adverse effects in the patients who received 10 mg/kg.21  In addition, patients who receive combination therapy with ipilimumab and nivolumab do have an increased frequency of immune-related adverse effects compared to monotherapy with either agent.22  There is currently conflicting evidence surrounding whether development of an immune-related adverse effect is associated with efficacy. However, patients that do not develop an immune-related adverse effect can still achieve response with immune checkpoint inhibitor therapy.8

    Depending on the mechanism of the immune checkpoint inhibitor, immune-related adverse effects can occur at different frequencies (table 2).10-15 Evidence shows that patients who receive CTLA-4 inhibitors have increased grade 3 or higher immune-related adverse effects compared to PD-1 and PD-L1 inhibitors.23 The frequency is increased further when a CTLA-4 inhibitor is used in combination with a PD-1 inhibitor.22  In addition, even though PD-1 and PD-L1 inhibitors have the same mechanism for efficacy, these agents can have different safety profiles.  This is because both PD-L1 and PD-L2 interact with PD-1 to cause T-cell inactivation.  When PD-1 is inhibited by an immune checkpoint inhibitor, both PD-L1 and PD-L2 are unable bind to PD-1.  However, when just PD-L1 is blocked, PD-L2 can still bind to PD-1.24 This is thought to result in fewer immune-related adverse effects with PD-L1 inhibitors compared to PD-1 inhibitors.

    Management of Immune-Related Adverse Effects
    The management of immune-related adverse effects is highly dependent on the organ system involved and the severity of the adverse effect.  The severity of immune-related adverse effects is graded by the common terminology criteria for adverse events (CTCAE).25 In general, for most mild immune-related adverse effects, therapy with an immune checkpoint inhibitor can usually be continued.  For moderate to severe immune-related adverse effects, therapy usually needs to be held in addition to administration of systemic corticosteroids.  There are some situations that may require administration of other immunosuppressants such as infliximab, cyclophosphamide, or mycophenolate mofetil.6-8 Since the management of immune-related adverse effects is very dependent on the specific adverse effect and severity, below are specific recommendations for management of common immune-related adverse effects encountered in clinical practice.

    Cutaneous Toxicities:
    Cutaneous toxicities are reported in 30-50% of patients who receive immune checkpoint inhibitor therapy and are the earliest immune-related toxicities to present.26 These toxicities are less frequently reported with PD-1 and PD-L1 inhibitors compared to ipilimumab, but all agents have the same incidence of grade 3 or higher toxicities around 1-3%.  Skin toxicities include rash/inflammatory dermatitis, bullous dermatoses, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS).  Since rash/inflammatory dermatitis is the most common immune-related skin toxicity, this is the only specific management recommendations included (table 3).  For grade 1 toxicities, the immune checkpoint inhibitor can be continued with topical emollients and/or corticosteroids applied for treatment.  For grade 2-4 toxicities, it is recommended to hold immune checkpoint inhibitor therapy and administer systemic corticosteroids at 1-2 mg/kg of (methyl)prednisolone or equivalent.  Topical emollients and corticosteroids along with oral antihistamines should also be given for grade 2-3 toxicities.6-9 

    Gastrointestinal (GI) Toxicities:
    GI toxicities are common immune-related adverse effects that occur with immune checkpoint inhibitor therapy.  The two main GI immune-related adverse effects are colitis and hepatitis.  Other serious GI immune-related adverse effects, such as pancreatitis, have been reported in the literature.  The incidence of these adverse effects depends on the therapy given.  In regards to colitis, 8-27% of patients may experience this adverse effect, with higher frequencies reported with dual anti-CTLA-4 and anti-PD-1 therapy and monotherapy with CTLA-4 inhibitors.  Hepatitis is much less common compared to colitis, occurring in 2-10% of patients treated with immune checkpoint inhibitor monotherapy.  Similar to colitis, the incidence increases with combination therapy up to 25-30%, with 15% of cases categorized as at least grade 3.  Colitis most often occurs within the first 5-10 weeks after immune checkpoint inhibitor initiation.  The general onset of hepatitis is similar to colitis at 6-12 weeks after immune checkpoint inhibitor initiation.9,27  Since colitis and hepatitis are both fairly common immune-related adverse effects, it is important to understand the management of each of these toxicities (tables 4 & 5). 

    For colitis, unless restricted to grade 1, therapy should be held or permanently discontinued depending on the severity/grade.  In addition, patients should receive systemic corticosteroids.  In patients that have grade 3-4 colitis, infliximab should be considered if patients have persistent symptoms despite systemic corticosteroids.  Another therapy option for colitis is vedolizumab. However, this agent should be reserved to patients who are refractory to, or have contraindications to, infliximab.6-9,28-29

    In patients who develop grade 1 hepatitis, immune checkpoint inhibitor therapy can be continued without administration of systemic corticosteroids.  Systemic corticosteroids should be administered in patients with at least grade 2 hepatitis.  If patients develop severe, grade 3-4 hepatitis, immune checkpoint inhibitor therapy should be permanently discontinued.  In addition, if patients have persistent symptoms after three days, mycophenolate mofetil can be added on to systemic corticosteroids.6-9,30  Infliximab should not be used in cases of hepatitis since there is concern for hepatic toxicity.31

    Endocrine Toxicities:
    There are a vast amount of endocrinopathies that can occur with immune checkpoint inhibitor therapy.  Some of these include hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, and diabetes.  One important step is distinguishing between primary and secondary endocrine toxicity since it is possible that patients could have an endocrinopathy not related to immune checkpoint inhibitor therapy.6-7 Overall, clinically significant endocrine toxicities related to immune checkpoint inhibitors occur in about 10% of patients.  The incidence is mostly the same among the different immune checkpoint inhibitor agents.32 

    Compared to other immune-related adverse effects, the management of endocrine toxicities differs slightly, with some of the specific management strategies reviewed below (table 6).  For most endocrinopathies, immune checkpoint inhibitors may be continued as long as the patient is asymptomatic or only has mild symptoms.  This is because most endocrine toxicities can be controlled through various supplementations and medications.6-9 An example of this is a patient with immune-related asymptomatic hypothyroidism treated with levothyroxine.  As long as patient’s hypothyroidism is controlled, the immune checkpoint inhibitor can be continued.

    Pneumonitis:
    Pneumonitis is an uncommon immune-related adverse effect, occurring in about 2.7% of patients. However, it is a very serious toxicity when it does occur.  Unlike most other immune-related adverse effects, pneumonitis is more common with PD-1 and PD-L1 inhibitors compared to CTLA-4 inhibitors, and the incidence increases with combination therapy.  In addition, the onset of pneumonitis can vary from two to 24 months after the initiation of therapy, with the median time to onset reported in the literature around three months.20,33  Since pneumonitis can be very severe, it is recommended to hold or permanently discontinue immune checkpoint inhibitor therapy depending on the grade (table 7).  For grades 2-4, patients should be started on empiric antibiotics and systemic corticosteroids.  In addition, if symptoms persist for 48 hours after systemic corticosteroids, additional immunosuppressant therapy is recommended.  There are a variety of agents that could be started at this time including infliximab, mycophenolate mofetil, intravenous immunoglobulin (IVIG), or cyclophosphamide.6-9

    Other Immune-Related Adverse Effects:
    There are numerous other immune-related adverse effects that can occur with immune checkpoint inhibitor therapy. However, for the most part, these are much less common.  In addition, all of these toxicities have fairly similar management with holding the immune checkpoint inhibitor and initiating systemic corticosteroids.  Some of the toxicities, including musculoskeletal and central nervous system toxicities that require unique management, are discussed below.  Other immune-related adverse effects seen with immune checkpoint inhibitors include nephritis, hematologic toxicities (ex. hemolytic uremic syndrome, aplastic anemia, and immune thrombocytopenia), cardiovascular toxicities (ex. myocarditis, arrhythmias, and venous thromboembolism), and ocular toxicities.6-9,16-19

    Musculoskeletal toxicities have a wide range of severity.  Myalgias and arthralgias are less severe musculoskeletal toxicities and more common after immune checkpoint inhibitor therapy, occurring in up to 40% of patients.34 Inflammatory arthritis and myositis are severe immune-related adverse effects that may require additional immunosuppression, IVIG, or plasmapheresis for severe cases.  Similar to musculoskeletal toxicities, central nervous system toxicities also range in severity from neuropathy to myasthenia gravis, Guillain-Barré syndrome, and encephalitis.  For severe cases of myasthenia gravis or Guillain-Barré syndrome, IVIG or plasmapheresis is recommended with systemic corticosteroids.  When diagnosed with encephalitis, patients should receive empiric antimicrobials, and in severe cases, high-dose systemic corticosteroids (methylprednisolone 1000 mg IV) with or without IVIG.7 

    Additional Treatment Considerations:
    One of the main management strategies of immune-related adverse effects involves holding immune checkpoint inhibitor therapy.  As clinicians, a common question that may be asked is when therapy can be restarted.  The first step is making sure the patient’s immune-related adverse effect has resolved to at least grade 1.  The next step is assessing the corticosteroid dose.  In general, most practitioners consider prednisone 10 mg (or equivalent) daily an appropriate corticosteroid dose to resume immune checkpoint inhibitor therapy.7 

    Aside from holding immune checkpoint inhibitor therapy, the other main management strategy for immune-related adverse effects is administration of systemic corticosteroids.  Systemic corticosteroids pose numerous supportive care challenges, mainly from adverse effects that require monitoring (table 8).35  In addition to monitoring of adverse effects, patients often require prophylactic medications as well, if the expected duration of systemic corticosteroids is prolonged.  Common supportive medications required include Pneumocystis jirovecii pneumonia (PJP) and GI prophylaxis with sulfamethoxazole-trimethoprim and a histamine2-receptor antagonist (H2RA) or proton pump inhibitor (PPI), respectively.7 

    A common question from patients and practitioners is if corticosteroids decrease the efficacy of immune checkpoint inhibitor therapy.  Studies have shown that patients who receive corticosteroids for treatment of immune-related adverse effects have similar objective response rates, time to treatment failure, and overall survival compared to patients who did not receive corticosteroids.36,37  Therefore, evidence supports that corticosteroids do not impact the efficacy of immune checkpoint inhibitor therapy.

    Conclusions
    The immune checkpoint inhibitors are a class of immunotherapy agents currently used in a variety of solid malignancies and Hodgkin’s lymphoma.  Their use has been rapidly increasing with numerous clinical trials currently open for various solid and hematologic malignancies.  The immune checkpoint inhibitors increase the immune system activity through blocking the inactivating checkpoint proteins located on T-cells.  This allows the immune system to attack malignant cells, but also puts patients at risk for developing immune-related adverse effects.  Management may differ depending on the exact immune-related adverse effect and severity. However, the main management strategies involve holding immune checkpoint inhibitor therapy and administering systemic corticosteroids.  Due to the increased use of immune checkpoint inhibitors, it is likely that immune-related adverse effects will become more common in clinical practice.  Early recognition of these adverse effects and recommending appropriate management and supportive care strategies are key steps for successful resolution of immune-related adverse effects. 

    Click here to download and open the Appendix

    Appendix includes tables:

    Table 1: Immunotherpy Agent Overview
    Table 2: Incidence of Immune-Related Adverse Effects
    Table 3: Management of rash/inflammatory dermatitis
    Table 4: Management of colitis
    Table 5: Management of hepatitis
    Table 6: Management of endocrine toxicities
    Table 7: Management of pneumonitis
    Table 8: Immunosuppressants used for management of immune-related adverse effects


    Click here to submit for CE Credit


    References

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    33. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2016; 35:709-17.
    34. Cappelli L, Gutierrez AK, Shah AA, et al. Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: A systematic literature review. Arthritis Care Res. 2016; 69:1751-63.
    35. Prednisone [package insert]. Columbus, OH: Roxane Laboratories, Inc.; Nov 2012.
    36. Horvat TZ, Adel NG, Dang TO, et al. Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015; 33(28):3193-98.
    37. Weber JS, Hodi FS, Wolchok JD, et al. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients with Advanced Melanoma. J Clin Oncol. 2016; 35:785-92.
    38. Mycophenolate mofetil [package insert]. South San Francisco, CA: Genetech, Inc.; Jul 2015.
    39. Vedolizumab [package insert]. Deerfield, IL: Takeda Pharmaceuticals, Inc.; Feb 2018.
    40. Cyclophosphamide [package insert]. Deerfield, IL: Baxter Healthcare Corporation; May 2013.


  • 25 May 2018 2:36 PM | MSHP Office (Administrator)

    The changes in sepsis guidelines: How do they shape our current practice?

    Authors: Paige Hagen, PharmD: PGY-1 Resident SSM Health St. Clare Hospital and Christopher K. Carter, PharmD, BCCCP: SSM Health St. Clare Hospital

    Program Number: 2018-04-09
    Approval Dates: 6/6/18 - 9/6/18
    Approved Contact Hours: One (1) CE(s) per LIVE session.

    Learning Objectives

    1. Recognize where early goal directed therapy came from and when it was incorporated into the Surviving Sepsis Campaign guidelines.
    2. Identify the trio of trials that largely impacted the 6-hour resuscitation bundle from the 2012 to 2016 guidelines.
    3. Apply the findings from the trio of trials to current medical practice.


    Sepsis’ Impact and Importance
    Even with advances in medicine, sepsis remains difficult to define and is associated with high mortality rates. Sepsis accounts for roughly 31.5 million cases annually, resulting in 5.3 million deaths. Patients who survive are at higher risk for long-term physical, cognitive, and psychosocial morbidity, and have an increased mortality rate for up to two years after an event.1   

    In addition to high mortality rates, sepsis poses a significant burden to our healthcare system due to the cost of treatment. In the United States, sepsis is the number one highest cost of hospitalizations, averaging roughly $24 billion dollars for treatment annually. The average hospital stay costs about $18,400, but depends on when sepsis was detected. If detected early on in the emergency department, it costs about $3,000. If not detected until after admission, the cost of treatment can be as much as $32,000. Additionally, patients with sepsis experience a length of stay that is 75% longer than patients with other disease states. Furthermore, sepsis is the number one cost of readmissions with roughly 62% of patients re-admitted within 30 days. 2 

    With the high mortality rates and the significant cost burden to our healthcare system, it is important to constantly re-evaluate and re-define the approach to the treatment of sepsis and septic shock. 

    Timeline of Trials for Early Goal Directed Therapy (EGDT)
    In 2001, Rivers et al. published striking evidence from their trial looking at early goal directed therapy (EGDT) for the treatment of severe sepsis and septic shock. EGDT involves the measurement of central venous oxygen saturation, central venous pressure, and mean arterial pressure through central venous and arterial catheterization. According to the protocol, patients are administered crystalloid or colloid fluids, vasoactive agents, red blood cell transfusions, and/or inotropic agents in order to meet each monitoring parameter and achieve an optimal balance between oxygen demand and oxygen delivery. This trial was the first attempt at showing benefit from EGDT with the purpose of determining whether EGDT before admission to the intensive care unit (ICU) effectively reduced the incidence of multi-organ dysfunction, mortality, and the use of health care resources among patients with severe sepsis or septic shock.  When looking at in-hospital mortality rates, the study found benefit in the EGDT group versus the usual care group (30.5 % vs. 46.5%). Additionally, it found that those who received EGDT at the earliest stages of sepsis and septic shock experience significant short-term and long-term benefits, such as early identification and treatment of patients at high risk for cardiovascular collapse and for early intervention to help restore the balance between oxygen delivery and oxygen demand to the vital organs.3

    In 2004, EGDT was incorporated into the Surviving Sepsis Campaign guidelines’ three and six hour treatment bundles.

    Since 2014, there has been a rapid influx of sepsis literature, with the publication of three large trials and updated definitions. The trio of trials was aimed at reproducing the findings by Rivers et al. and to better determine the generalizability of these results.

    Protocolized Care for Early Septic Shock (ProCESS)4 was published in May of 2014. It was conducted across the United States and randomly assigned patients with septic shock to one of three groups for six hours of resuscitation: protocol based EGDT, which mimicked the protocol from Rivers et al.; protocol based standard therapy that did not require the placement of a central venous catheter (CVC), administration of inotropes, or blood transfusions; and usual care. The primary endpoint looked at 60-day in-hospital mortality. As a result when comparing EGDT to protocolized standard therapy to usual care, no significant difference was found in mortality rates (21% vs 18.2 % vs 18.9%). However, the protocol-based care groups resulted in increased use of central venous catheterization, IV fluids, vasoactive agents, and blood transfusions.

    The Australasian Resuscitation in Sepsis Evaluation (ARISE)5 was published in October 2014 as the second trial aiming to determine if EGDT, as compared with usual care, would decrease 90-day all-cause mortality among patients presenting to the emergency department (ED) with early septic shock in diverse health care settings. This trial was conducted in 51 tertiary care and non-tertiary care metropolitan and rural hospitals across Australia and New Zealand, with several sites in Finland, Hong Kong, and the Republic of Ireland. Patients presenting to the ED with early septic shock were randomly assigned to EGDT or usual care. For the studied primary endpoint of all-cause mortality within 90 days after randomization, no significant difference between the EGDT and usual care groups was found (18.6% vs 18.8%).  There were also no differences in 28 day or in-hospital mortality, duration of organ support, or length of hospital stay.

    Protocolized Management in Sepsis (ProMISe)6 rounded out the trio of trials with its publication in April of 2015. Its aim was to determine if the 6-hour EGDT resuscitation protocol was superior, in terms of clinical and cost-effectiveness measures, to usual care in patient presenting with early septic shock to National Health Service emergency departments in England. When studying the primary endpoint of all-cause mortality at 90-days, there was no significant difference among those receiving 6 hours of EGDT compared to usual care (29.5 % vs 29.2%). The EGDT group had increased used of central venous catheters, IV fluids, vasoactive drugs, and red-cell transfusion as a result of the treatment protocol. Additionally, ProMISe found that continuous monitoring with ScvO2 and strict protocolization did not show an improvement in overall outcomes.

    Finally, in May of 2015, a meta-analysis was published comparing the results of the trio of trials in addition to past trials that used EGDT.7 Eleven trials were reviewed to address the question of whether EGDT, compared with other resuscitation strategies, was associated with a survival benefit. The study’s primary outcome was mortality in patients presenting to the ED with septic shock at 28 days, 90 days, and hospital discharge.  The results found no difference between EGDT and usual care (23.2% vs 22.4%). Additionally, EGDT was associated with an increased rate of admission to the ICU and increased the utilization of resources.

    It is important to take a step back and analyze these results as a whole. Some may ask, “why is it that Rivers et al. found ground breaking evidence with EGDT in lowering mortality rates, yet the trio of trials and meta-analysis found no difference in mortality outcomes and no benefit of this specific protocol?” One explanation for these results may stem from the improvement of “usual care” from 2001 to 2014. Detection and treatment of sepsis and septic shock has improved dramatically over the years. To this day, usual care is centered on the fundamentals of the Rivers et al. protocol which includes fluid resuscitation, blood cultures, and early initiation of broad-spectrum antibiotics. The only difference is that “usual care” today is not using the parts of EGDT that are extraneous in most patients like inotropes, blood transfusions, and central lines.

    Updated Sepsis Definition
    In February of 2016, there was an update to the definitions of sepsis and septic shock titled “The Third International Consensus Definitions of Sepsis and Septic Shock (Sepsis-3).”8 The definitions had last been revised in 2001 and the aim of the authoring task group was to provide practitioners with more robust criteria to diagnose patients with sepsis and identify patients with a suspected infection that would likely progress to a life-threatening state. From the review and updates, Sepsis-3 found four key findings.

    First, the previous definition focused excessively on the inflammatory process, which portrayed a misleading model that sepsis follows a continuum from sepsis to severe sepsis to septic shock. Additionally, Sepsis-3 determined that the systemic inflammatory response syndrome (SIRS) criteria lacked specificity and sensitivity and are present in many hospitalized patients. This likely has then led to an over-diagnosis of sepsis. It was also thought that SIRS criteria do not indicate a dysregulated, life-threatening response as was intended by the 2001 definition. The taskforce therefore defined sepsis as a “life- threatening organ dysfunction caused by a dysregulated host response to infection.” This new definition helps to emphasize the importance of urgent recognition and the severity of mortality with a septic presentation.

    Secondly, Sepsis-3 found that there were multiple definitions in use for sepsis, septic shock, and organ dysfunction, which lead to discrepancies in reported incidence and observed mortality. As a result, organ dysfunction was redefined as an increase in the SOFA score of ≥ two points.  This assumes that patient’s baseline SOFA score should be zero, unless the patient has pre-existing organ dysfunction. Of note, an increase in SOFA score ≥ two points is associated with in-hospital mortality of greater than 10%.

    Furthermore, Sepsis-3 determined that the term “severe sepsis” is redundant since sepsis is now further defined as life-threatening organ dysfunction and eliminated this distinction  Septic shock was also further defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. It is clinically identified by a vasopressor requirement to maintain a mean arterial pressure (MAP) ≥65 mmHg and a serum lactate > two mmol/L (>18 mg/dL) in the absence of hypovolemia. Patients with septic shock are associated with in-hospital mortality rates of > 40%.

    Finally, Sepsis-3 introduced the QuickSOFA (qSOFA) score that provides simple criteria to identify patients with suspected infection who are likely to have poor outcomes. It can be performed quicker than the SOFA score, as it does not require invasive testing and can be reassessed repeatedly. It is advised that the qSOFA be used to prompt physicians to further investigate for organ dysfunction, initiate therapy as appropriate, and to increase patient monitoring. With the updated definitions and clinical criteria, Sepsis-3 can facilitate earlier recognition and timely management for patients with sepsis or those at risk of developing sepsis.

    Surviving Sepsis Campaign’s Response to Sepsis-3
    In response to the updated Sepsis-3 definitions and the new evidence from the aforementioned trials, the Surviving Sepsis Campaign published new guidelines in 2016. 9,10 These guidelines specifically updated the six-hour sepsis treatment bundle by removing the requirement of a CVC to monitor central venous pressure (CVP) and central venous oxygen saturation (ScvO2) in all patients with septic shock who received timely antibiotics and fluid resuscitation.


    SEP-1 Core Measure
    In response to the updated definition and sepsis guidelines, it is important to take into account CMS’ introduction of SEP-1, the sepsis core measure. SEP-1 was implemented October 1, 2015 and uses the 2001 sepsis definition that uses SIRS criteria for sepsis, severe sepsis, and septic shock recognition. The core measure does support bundle compliance as stated in the most recent Surviving Sepsis Campaign guidelines (2016). In order to receive reimbursement from CMS, all measures outlined by SEP-1 must be met. It is important to note that over-diagnosis of sepsis may occur under this core measure due to the use of the 2001 definition instead of the updated definition.  This should be considered at an entity level when determining what resources will be required to ensure CMS compliance.


    Effect on Current Medical Practice
    Rivers et al. originally found striking evidence in lowering sepsis mortality rates using EGDT. From there, EGDT was incorporated into the Surviving Sepsis Campaign Guidelines in 2004. When a trio of trials attempted to recreate the finding by Rivers et. al., EGDT was not substantiated or associated with a lower rate of mortality. They also discovered that strict monitoring and measurement of CVP and ScvO2 did not improve mortality outcomes.

    Following the publication of ProCESS, ARISE, and ProMISe, the 2001 definition of sepsis was updated with the publication of Sepsis-3. The aim of Sepsis-3 was to update the definition of sepsis and provide greater consistency and clarity for diagnosing sepsis. Additionally Sepsis-3 introduced the QuickSOFA score, allowing for quick recognition of patients with a suspected infection that would likely result in poor outcomes.

    From the trial results and the publication of Sepsis-3, the Surviving Sepsis Campaign Guidelines updated the six-hour bundle, removing the requirement for CVP and ScvO2.. Eliminating these requirement will help to decrease the healthcare resource utilization costs and lower rates of ICU admissions.

    Even with the rapid influx of sepsis literature, CMS’ SEP-1 core measure still uses the 2001 definition that uses SIRS criteria for sepsis, severe sepsis, and septic shock recognition. With this, over-diagnosis of sepsis may occur across entities to ensure CMS compliance.

    In summary, there has been great advancements in sepsis literature since 2001, reshaping our current practices. Even with all of the new discoveries, I believe that the EGDT fundamentals outlined by Rivers et al. for early resuscitation in sepsis and septic shock remain unchanged. The fundamentals are as important today as they were in 2001 which include fluid resuscitation, blood cultures, and early initiation of broad-spectrum antibiotics.

    Click here to submit for CE Credit

    References

    1. Raith EP, Udy AA, Bailey M, McGloughlin S, MacIsaac C, Bellomo R, Pilcher DV, for the Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcomes and Resource Evaluation (CORE). Prognostic Accuracy of the SOFA Score, SIRS Criteria, and qSOFA Score for In-Hospital Mortality Among Adults With Suspected Infection Admitted to the Intensive Care Unit. JAMA. 2017; 317(3):290–300.
    2. Sepsis Alliance. (2016). Sepsis fact sheet. Retrieved from http://www.sepsis.org/downloads/2016_sepsis_facts_media.pdf.
    3. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, Early Goal-Directed Therapy Collaborative Group (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377.
    4. The ProCESS Investigators (2014) A randomised trial of protocol-based care for early septic shock. N Engl J Med 370:1683–1693.
    5. The ARISE Investigators and the ANZICS Clinical Trials Group (2014) Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371:1496–1506.
    6. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RG, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM, ProMISe Trial Investigators (2015) Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 372(14):1301–1311.
    7. Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med 2015; 41: 1549–1560.
    8. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-810.
    9. Dellinger RP, Schorr CA, Levy MM. A users’ guide to the 2016 Surviving Sepsis Guidelines. Intensive Care Medicine. 2017; 43(3):299-303.
    10. Rhodes A, Evans LE, Alhazzani W, et al: Surviving Sepsis Campaign: International Guidelines for the Management of Sepsis and Septic Shock: 2016. Intensive Care Med 2017 Jan 18.


  • 23 May 2018 2:02 PM | MSHP Office (Administrator)

    Author: Sundus Awan, PharmD: UMKC School of Pharmacy Class of 2018 
    Preceptor: Dominick Salvatore, PharmD, BCPS: UMKC School of Pharmacy at MU

    In January 2018, the Center for Disease Control (CDC) released a statement on urinary tract infections (UTI’s) to help distinguish the type of infection. According to the CDC, UTI’s are the fourth most common type of healthcare-associated infection, making up more than 12% of the infections reported by acute care hospitals.1 The most common microorganisms associated with UTI’s are Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and other Enterococcus species.2

    The Infectious Disease Society of America (IDSA) defines asymptomatic bacteriuria as an isolation of a specified amount of bacteria in an adequate urine sample obtained from a person who does not display signs or symptoms of a UTI. 3 The specified quantitative criteria is at least 100,000 colony-forming units per mL (cfu/ml) of urine in a voided midstream clean-catch specimen and at least 100 cfu/ml of urine from a catheterized specimen.3 The CDC provides a beneficial flow chart which can assist providers in determining the type of urinary tract infection a patient possesses.1

    Asymptomatic bacteriuria occurs more commonly in women than in men, with a strong association to sexual activity in younger women. It is rare to find in young men, but the prevalence in men increases after the age of 60 years. Patients with comorbid conditions, such as diabetes, were found to have a higher prevalence of asymptomatic bacteriuria. Patients with short-term indwelling catheters were found to acquire bacteriuria at a rate of 2-7% per day.3

    The treatment of asymptomatic bacteriuria is dependent on the patient population. Premenopausal, non-pregnant women with asymptomatic bacteriuria typically clear their bacteriuria spontaneously.4 The IDSA states that women with asymptomatic bacteriuria are more likely to have subsequent episodes. However, the treatment of asymptomatic bacteriuria does not prevent or decrease the frequency of future episodes. Because of this, the IDSA does not recommend screening for, or treating, asymptomatic bacteriuria in this patient population.4 Similarly, the IDSA does not recommend screening for, or treating, asymptomatic bacteriuria in women with diabetes, older patients, patients with spinal cord injuries, or patients with indwelling urethral catheters.4

    Patients who should be screened and treated for asymptomatic bacteriuria are women who are pregnant and patients who are undergoing urologic procedures.3 Pregnant women who have asymptomatic bacteriuria are more likely to deliver premature or low birthweight infants and have an increased risk of developing pyelonephritis.4 It has been shown that antimicrobial therapy for asymptomatic bacteriuria in pregnant patients can improve fetal outcomes.4 The IDSA recommends treatment for pregnant women who have asymptomatic bacteriuria with three to seven days of appropriate antimicrobial therapy, such as nitrofurantoin.3,4

    The CDC states that most healthcare associated UTI’s occur due to urologic instrumentation.1 Patients undergoing urologic procedures, especially transurethral resection of the prostate, should be screened and treated for asymptomatic bacteriuria.3 Ideally, antibiotic therapy should be initiated either the night before or immediately before the procedure to prevent bacteremia and sepsis.3 Additionally, the antimicrobial therapy should not be continued beyond the procedure, unless an indwelling catheter remains after the procedure.3 For patients who are immunocompromised, such as transplant patients, IDSA currently does not make a recommendation for the screening or treatment of asymptomatic bacteriuria, due to the need for further research.3

    In a study done at a community teaching hospital, the overtreatment of asymptomatic bacteriuria in hospitalized patients was assessed to determine the total costs of inappropriate treatment and if the implementation of an educational intervention program was effective in reducing the overtreatment of asymptomatic bacteriuria. The study had three phases: a retrospective pre-intervention phase, the implementation of an educational intervention program, and a prospective post-intervention phase. The educational intervention included a seminar in which six clinical vignettes were presented and guideline recommendations were discussed. It also included pocket cards emphasizing the IDSA guidelines on diagnosis and treatment of asymptomatic bacteriuria. Lastly, the intervention included a letter sent to the hospital attending physicians emphasizing the IDSA guidelines and the importance of minimizing inappropriate treatment of asymptomatic bacteriuria.5

    During the pre-intervention phase, 47% of patients were inappropriately treated for asymptomatic bacteriuria with a total cost of overtreatment being $1200. In the post-intervention analysis, 15% of patients were inappropriately treated for asymptomatic bacteriuria with a total cost of overtreatment being $600. There was a significant decrease in the proportion of inappropriately treated patients (p=0.036) between the pre- and post-intervention phases. Of note, it was also found that there were fewer urine specimens collected in the post-intervention phase (p < 0.001).5 These findings support the implementation of an educational program aimed at reducing the overtreatment of asymptomatic bacteriuria.

    In summary, if a non-pregnant patient does not show any signs or symptoms of a UTI, but microbial organisms are present in at least two adequate urine samples, the patient would be classified as having asymptomatic bacteriuria.  Pharmacologic treatment is not indicated, in order to prevent the recurrence of subsequent episodes and the development of antimicrobial resistance. However, if symptoms are present, then the patient should be treated according to the IDSA guidelines on treatment of symptomatic UTI’s. Implementation of education programs in hospitals and health-systems may be a beneficial way to reduce the overtreatment of asymptomatic bacteriuria.

    References:

    1. Center for Disease Control. Urinary tract infection--catheter-associated urinary tract infection and non-catheter-associated urinary tract infection and other urinary system infection events. Jan 2018.
    2. Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010. Infect Control Hosp Epidemiol 2013; 34(1): 1-14.
    3. Nicolle LE, Bradley S, Colgan R, Rice JC, et al. Infectious Disease Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005; 40:643-654.
    4. Colgan R, Nicolle LE, McGlone A, and Hooton TM. Asymptomatic bacteriuria in adults. Am Fam Phys 2006; 74(6): 985-990.
    5. Chowdhury F, Sarkar K, Branche A, Kim J, et al. Preventing the inappropriate treatment of asymptomatic bacteriuria at a community teaching hospital. J of Comm Hosp Internal Med Pers 2012; 2: 1-6.


  • 23 May 2018 1:57 PM | MSHP Office (Administrator)

    Authors: Bradley Erich, PharmD Candidate 2019: UMKC School of Pharmacy and Jeremy Hampton, PharmD, BCPS: UMKC School of Pharmacy

    With the opioid epidemic claiming more than 91 lives per day in the United States,1 and with three out of five drug overdoses including opioids,2 the use of naloxone as an opioid reversal agent in overdose patients is likely to increase dramatically. Naloxone hydrochloride is a competitive antagonist of the mu opioid receptor and is intended to displace receptor-bound opioids.7 In the setting of overdose, this dose-dependent antagonism can facilitate the reversal of opioid-induced respiratory depression, sedation, and hypotension. Although signs and symptoms of an opioid overdose include unusual sleepiness, altered mental status, and decreased responsiveness to painful stimuli (e.g., sternal rub and pinpoint pupils), these symptoms alone do not warrant the administration of naloxone.  However, if these symptoms are accompanied by respiratory depression (decreased respiratory rate or oxygen saturation), then naloxone should be administered expeditiously. When administered either intravenously (IV) or intranasally (IN), naloxone has an onset of action of approximately two minutes and an average duration of approximately 45 minutes.7 It is imperative that patients be monitored for a duration that is commensurate with the pharmacokinetics of the substance ingested, as the clinical effects of opioids will often exceed the duration of naloxone, making re-sedation a potential concern.  Because respiratory depression is considered a medical emergency and should be managed immediately, emergency responders may keep naloxone either on their person or in their vehicles. Concern has been raised, however, as to whether storing the drug in a hot environment (e.g., in a police car during summer), will lead to loss of potency. Because protocols allowing first-responders to carry naloxone is a relatively new phenomenon, a paucity of information is available regarding temperature excursions and best practice for drug storage in the field. This review will aim to offer guidance regarding these concerns.

    Police officers and emergency responders carry a large amount of equipment that can weigh up to 20-30 pounds, on average. With a fully loaded equipment belt or pack, it can be cumbersome to carry any additional equipment, even an item as small as a naloxone syringe or canister. Due in part to the increasing opioid-induced morbidity, emergency responders and police officers carry naloxone for emergency situations in their vehicles, where they are readily available upon arrival to a possible overdose scene. This raises the question: Is it appropriate to store naloxone in a vehicle for extended periods of time? In addition, what temperature ranges are appropriate for naloxone to be stored in? In the heat of the summer, and in the cold of the winter, temperatures inside of a vehicle can range from less than 0° Fahrenheit to greater than 100° Fahrenheit, depending on the outside temperature and the time the vehicle has spent unattended.

    According to the manufacturer of Narcan® Nasal Spray (Adapt Pharma, oral communication, January 2018)3, the recommended storage temperature is 59° - 77° Fahrenheit, with excursions permitted of no greater than 24 hours at 39°- 104° Fahrenheit. The manufacturer recommends that the product not be frozen, refrigerated, or exposed to light for prolonged periods. The stability of Narcan® Nasal Spray is based on the product being removed from its original blister pack packaging. According to the manufacturer of Evzio® (naloxone for injection) (Kaleo, Inc, oral communication, January 2018)4, the recommended storage is 59° - 77° Fahrenheit, with brief excursions permitted between 39° - 104° Fahrenheit. Although studies have not yet been conducted to determine potency following exposure to extreme temperatures, the manufacturer notes that potency may be negatively impacted when exposed to temperatures below 39° or above 104° Fahrenheit. The product should be stored in the outer case provided, it should not be frozen or refrigerated, and the solution in the auto-injector should always be checked for discoloration or particulate matter prior to administration. If discoloration or particulate matter is observed, the product should not be administered.

    Immediate availability of naloxone for emergency situations is vital for first responders and emergency staff, whether that supply is carried with them or stored in their vehicle. However, consideration should also be given to maintaining the drug’s stability and potency. The manufacturers of Narcan ® Nasal Spray and Evzio ® Auto-Injector both have recommendations that their products may have excursions (including time in emergency vehicles) between 39° - 104° Fahrenheit.3,4 Adapt Pharma recommends excursions do not last any longer than 24 hours for Narcan® Nasal Spray,3 and although Kaleo Inc. (Evzio® Auto-Injector) provides no information regarding an excursion window, they recommend checking the solution for discoloration or particulate matter prior to administration.4

    The symptoms of opioid intoxication/overdose are largely dependent on factors such as type, amount, potency of the substance(s) ingested, the presence of co-ingestants, and the degree of opioid tolerance (or naivety) of the patient.  For example, the synthetic opioid carfentanil will produce a profound state of sedation and respiratory depression which is resistant to “standard” doses of naloxone (0.04 mg to 0.4 mg), and reports of doses in excess of 10 mg naloxone have been required to reverse the respiratory depressant effects10, whereas morphine-induced respiratory depression may be reversed with as little as 0.04 mg of naloxone.10

    With the high variability of severity and type of symptoms based on each person and the type of substance they ingested, the question arises: How much naloxone is needed to reverse the opioid overdose?

    According to the American Heart Association, naloxone is a recommended component of the pulseless arrest treatment algorithm in a patient that is suspected of an acute opioid overdose. The recommended starting dose is 2 mg IN, or 0.4 mg IM. Reversal of respiratory depression should be considered the clinical endpoint, and doses should be repeated every 2-3 minutes until this effect is elicited, using caution to avoid precipitating withdrawal symptoms. Additionally, continuous monitoring of the patient until advanced help arrives is imperative, paying careful attention to respiratory rate, level of awareness, and pulse.  If the respiratory rate drops below 8 breaths per minute, it is advisable to administer additional doses of naloxone as necessary.8

    For patients who have used a longer acting or synthetic product such as methadone, fentanyl, or carfentanil, a continuous infusion of naloxone may be considered in order to sustain the reversal effects. The infusion rate should be calculated based on the initial dose required to reverse respiratory depression. Following the IM/IN/IV bolus dose, initiate the infusion at a rate of two-thirds of the initial effective naloxone bolus per hour, titrating as necessary to ensure proper patient response and to prevent withdrawal symptoms, if possible.7 For example, if 2 mg of IV naloxone is required for initial reversal of respiratory depression, the initial infusion rate for naloxone should be 1.3 mg/hour and may be titrated every 5-10 minutes as necessary to maintain a respiratory rate greater than eight breaths per minute.

    According to the CDC, the mortality rate associated with synthetic opioid overdoses from tramadol, fentanyl, and carfentanil has increased by 72.2% from 2014 – 2015, with increases noted across all demographics and regions in the United States.5 This increase in mortality directly correlates to an increase in the illicit manufacture of fentanyl and fentanyl analogs, including acetylfentanyl, beta-hydroxythiofentanyl, butyryl fentanyl, AH-7921, thiafentanil, U-47700, furanyl fentanyl, and 4-fluoroisobutyryl fentanyl. These analogs are extremely potent, precipitate significant respiratory depression, and are associated with high naloxone dose requirements.10

    In summary, opioid overdoses and deaths related to opioids continue to rise in the United States, and show no bounds to demographics, age, region, or socioeconomic status. Vigilance and immediate support from emergency personnel is imperative to serve and save patients from potentially fatal overdoses of opioids. Due to the increase in opioid-related morbidity and mortality, many first responders now carry naloxone so that it may be rapidly administered to patients with a suspected opioid overdose.  A concern related to this practice involves the storage of naloxone syringes in the cab of responders’ vehicles, thereby subjecting the drug to extreme temperatures and raising the question as to whether loss of potency is a concern and, if so, what storage practices should be followed.  Although information is sparse regarding temperature excursions for naloxone, manufacturers have stated that “brief” excursions in temperatures of up to 104-degrees Fahrenheit have been noted without subsequent loss of potency.  To minimize the risk of potency loss, it is recommended that if naloxone is to be stored in first responder vehicles, the drug should be stored in such a way that it is sequestered from direct heat, i.e., storage in a glove compartment, console, or small cooler may be recommended.

    References:

    1. Centers for Disease Control and Prevention. Opioid Overdose. https://www.cdc.gov/drugoverdose/data/index.html. Published July 18, 2017. Accessed January 8, 2018.
    2. Centers for Disease Control and Prevention. Opioid Overdose. https://www.cdc.gov/drugoverdose/epidemic/index.html. Published August 30, 2017. Accessed January 8, 2018.
    3. NARCAN ® NASAL SPRAY [package insert]. Adapt Pharma; 2015.
    4. EVZIO Auto-Injector for Intramuscular or Subcutaneous Use [package insert]. Kaleo, Inc.; 2014.
    5. Centers for Disease Control and Prevention. Opioid Overdose. https://www.cdc.gov/drugoverdose/data/fentanyl.html. Published December 16, 2016. Accessed January 9, 2018.
    6. Naloxone - Medical Countermeasures Database - CHEMM. U.S. National Library of Medicine. https://chemm.nlm.nih.gov/countermeasure_naloxone.htm#other. Updated September 29, 2017. Accessed January 9, 2018.
    7. Naloxone. Lexicomp. Lexi-Drugs [database online]. Saint Louis, MO: Wolters Klewer Health, Inc; December 2017. Accessed January 9, 2018.
    8. Highlights. CPR & First Aid Emergency Cardiovascular Care. https://eccguidelines.heart.org/index.php/circulation/cpr-ecc-guidelines-2/part-10-special-circumstances-of-resuscitation/highlights-introduction/highlights/. Updated 2015. Accessed January 9, 2018.
    9. Armenian P, Vo KT, Barr-Walker J, Lynch KL. Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review. Neuropharmacology. 2017. doi:10.1016/j.neuropharm.2017.10.016.
  • 23 May 2018 1:36 PM | MSHP Office (Administrator)

    Authors: Brandon Reynolds, PharmD: UMKC School of Pharmacy Class of 2018 and  Kerra Cissne, PharmD: PGY-2 Pharmacy Resident at Truman Medical Center

    Introduction:

    Ketamine was first described as an anesthetic and “chemical derivative” of phencyclidine (PCP) in 1965 by the American Society for Clinical Pharmacology and Therapeutics.1 Ketamine, like PCP, has the capability of inducing a state of dissociative anesthesia as well as producing a strong analgesic and amnestic effect.2,3 Unlike PCP, ketamine demonstrates a shorter duration of action and less pronounced psychotomimetic effects than its parent drug, vastly improving its clinical properties as an anesthetic.4 In contrast to other medications employed for analgesia and procedural sedation, ketamine preserves respiratory function and hemodynamic stability.5 In the emergency department, ketamine has several uses, including acute pain management, procedural sedation, limb reduction, and anesthesia in patients with diminished or worsening respiratory drive.6

    Pharmacology:        

    Ketamine has multiple mechanisms of action. The most studied mechanism is the drug’s ability to block glutamate receptors, such as the N-methyl-D-aspartate (NMDA) receptor and the non-NMDA glutamate receptors.4 Although there are several other proposed mechanisms related to analgesia such as µ-opioid receptor agonism,7 NMDA receptor antagonism is expected to induce the characteristic properties of ketamine use such as amnesia, analgesia, and psychosensory effects.4 Interestingly, the dissociative anesthesia induced by ketamine is proposed to be caused by a disconnect between the thalamo-neocortical and limbic systems, which may also be associated with the emergence phenomenon8 afflicting an estimated 23% of patients that do not receive adjunctive benzodiazepines.8,9 This phenomenon, however, is still relatively poorly understood and is described in a heterogeneous manner throughout the literature.

    Literature Analysis:

    Subanesthetic analgesia: A prospective, randomized, double-dummy trial of IV ketamine use for subdissociative analgesia in the emergency department (ED) was published in the American Journal of Emergency Medicine in August 2017 by Motov et al12

    • Power: set and met at 80%, requiring 24 patients per group. Alpha set at 0.05.
    • Comparison: ketamine 0.3 mg/kg via IV push (over 5 minutes) or by IV infusion over 15 minutes compounded in a 100 mL 0.9% sodium chloride bag.
    • Primary outcome measure: overall rates of adverse effects as measured on the SERSDA scale (Side Effects Rating Scale for Dissociative Anesthetics).
    • Exclusion criteria was significant for excluding patients weighing <46 kg or >115 kg.
    • Result: among the SERDSA list of possible adverse effects, 91.7% of patients in the IV push group experienced feelings of unreality, while 54.2% of patients in the slow IV infusion group experienced this effect (p=0.008).

    Procedural sedation and analgesia: Ferguson I et al 14 published the POKER study in the Annals of Emergency Medicine in 2016. POKER is the largest randomized, double-blind, prospective clinical trial to date comparing propofol to ketofol, a 1:1 mixture of ketamine and propofol, for procedural sedation in adults

    • This trial set and met power at 90%, requiring 263 patients per group. Alpha was set at 0.05.
    • The primary outcome was the occurrence of an adverse respiratory event that required physician intervention.
    • The only statistically significant differences between groups was hypotension as determined by a systolic blood pressure less than 90 mmHg being recorded in 7% of patients in the propofol group compared with 1% in the ketofol group (p=0.0001).
    • The researchers deemed this result to not be clinically significant as patients that experienced hypotension did not require further intervention after administration of a fluid bolus.

    Dissociative sedation for excited delirium: A prospective, single-center, observational study evaluated different treatment modalities for emergency department patients with excited delirium, a condition is characterized by violent outbursts oftentimes due to acute psychosis or intoxication15

    • Patients were placed in one of five groups: ketamine, midazolam, lorazepam, haloperidol, or a combination of a benzodiazepine and haloperidol.
    • Power was set but not met at 80%, requiring 17 patients per group. Alpha was set at 0.05.
    • The primary outcome was the time required to reach adequate sedation (defined as an agitation score of ≤2: a patient that at most is “mildly” aroused).
    • Patients receiving ketamine were significantly younger than those receiving other medications (p=0.033).
    • Due to the observational nature of the study, groups did not receive a standard dose of any medication used. The average ketamine dose was 0.87 mg/kg IV or 2.97 mg/kg IM, and the midazolam dosage was on average 3.08 mg IV and 2.25 mg IM. These dosages are lower than the published dosage ranges for these medications.15
    • There were statistically significantly more patients that were no longer aroused in the ketamine group than in the other medication groups at 5, 10, and 15 mins (p=0.001, <0.001, and 0.032 respectively).


    Conclusions:

    Ketamine has a multitude of uses and beneficial effects due to its unique pharmacology, and it harbors significant advantages over current mainstream therapies. It is an opioid-sparing pain-relieving agent6, it preserves respiratory drive while facilitating painful procedures13,14, and can very rapidly dissociate a patient experiencing excited delirium.15,16 Of note, ketamine does have drawbacks, including an increase in nausea and vomiting as well as the risk of emergence phenomenon in higher dosages.17 Research continues to be published on the use of ketamine in several situations, as evidenced by the recent surge of literature for esketamine, the active S-enantiomer of ketamine, for treatment of major depressive disorder with an imminent suicide risk.18 With new research and the overarching threat of opioid addiction in the United States, ketamine may present itself as an old drug with new tricks. 

    References:

    1. Domino E, Chodoff P, and Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965; 6:279-91
    2. Priestley S, Taylor J, McAdam C, and Francis P. Ketamine sedation for children in the emergency department. Emergency Med. 2001; 13:82-90
    3. World Health Organization. Ketamine update review report. Switzerland 2014
    4. Mion G and Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci & Therapeutics. 2013; 370-380
    5. Ahern T, Herring A, Miller S, and Frazee B. Low-dose ketamine infusion for emergency department patients with severe pain. Pain Med. 2015; 16(7):1402-1409
    6. Ketalar® [package insert]. Par Pharmaceutical, Inc., Chestnut Ridge, NY; Updated May 5, 2017
    7. Sleigh J, Harvey M, Voss L, and Denny B. Ketamine – more mechanisms of action than just NMDA blockade. Trends in Anesth and Crit Care. 2014; 4(2-3):76-81
    8. Corssen G. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg. 1966; 45(1):29-40
    9. White P, Way W and Trevor A. Ketamine-its pharmacology and therapeutic uses. Anesth. 1982; 56(2):119-136
    10. American College of Emergency Physicians. PREP sub-dissociative ketamine for analgesia. 2017. Available from: https://www.acep.org/Clinical---Practice-Management/Sub-dissociative-Dose-Ketamine-for-Analgesia/#sm.00000ywtftjttyd4py5ihwzksxnh9
    11. Kurdi M, Theerth K, and Deva R. Ketamine: current applications in anesthesia, pain, and critical care. Anesth Essays Res. 2014; 8(3):283-290
    12. Motov S, Mai M, Pushkar I, Likourezos A, Drapkin J, et al. A prospective randomized, double-dummy trial comparing IV push low dose ketamine to short infusion of low dose ketamine for treatment of pain the ED. Am J Emerg. Med. 2017; 35(8):1095-1100
    13. Godwin S, Burton J, Gerardo C, Hatten B, Mace S, Silvers S, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg. Med. 2014;63(2):247-258
    14. Ferguson I, Bell A, Treston G, New L, Ding M, and Holdgate A. Propofol or ketofol for procedural sedation and analgesia in emergency medicine – the POKER study: a randomized double-blind clinical trial. Ann Emerg. Med. 2016; 68(5):574-582
    15. Green S, Roback M, Kennedy R, and Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011; 57(5):449-461
    16. Riddell J, Tran A, Bengiamin R, Hendey G, and Armenian P. Ketamine as a first-line treatment for severely agitated emergency department patients. Am J Emerg. Med. 2017; 35:1000-1004
    17. Gao M, Rejaei D, and Liu H. Ketamine use in current practice. Acta Pharmacol Sin. 2016; 37(7):865-872
    18. Johnson & Johnson. Esketamine receives breakthrough therapy designation from U.S. Food and Drug Administration for major depressive disorder with imminent risk for suicide. N.J., 2016
  • 23 May 2018 1:29 PM | MSHP Office (Administrator)

    Authors: Michael Scott, PharmD Candidate 2019: UMKC School of Pharmacy and Jeremy Hampton, PharmD, BCPS: UMKC School of Pharmacy

    Bolus dose vasopressors, also referred to as push-dose pressors (PDPs), have become a popular topic of discussion within the practice of Emergency Medicine and pre-hospital care. PDPs are so named because as the name implies they are not administered as an IV infusion, but as a volume of 0.5 to 2mL pushed slowly via syringe. There is controversy regarding appropriate use of PDPs due to the lack of published literature evaluating their safety and efficacy. This article will provide an overview of which drugs may be used as PDPs in the emergency department (ED), indications for use, safety issues regarding their use and how to mitigate those issues, general instructions for preparation, and an overview of the few retrospective studies that have analyzed their use in the ED.

    Medications used as PDPs include epinephrine, phenylephrine, and ephedrine. These have been administered as bolus doses for years by anesthesiologists in operating rooms, but recently this practice has gained favor in the ED due to their utility in preventing cardiac arrest. Epinephrine and phenylephrine are the drugs of choice in the ED due to their quick onset of action and short duration of action. Ephedrine, while utilized frequently in operating rooms, does not confer much utility in the ED due to its slower onset and longer duration of action. Both epinephrine and phenylephrine can be useful depending on the presentation of the patient. Epinephrine, having both alpha and beta adrenergic activity, will provide vasoconstriction as well as positive inotropic and chronotropic effects to produce a temporary increase in cardiac output and blood pressure. Phenylephrine, being an alpha agonist, will provide a pure vasopressor response with no further elevation in heart rate. Phenylephrine also has the potential to decrease heart rate due to the parasympathetic reflex following vasoconstriction.

    A controversial issue in regard to PDPs is whether it is appropriate to utilize this administration method rather than conventionally administered vasopressors. Proponents argue that PDPs are more appropriate for short term use as a temporizing measure to increase blood pressure in patients with transient hypotension, such as in the setting of post-intubation hypotension, procedural sedation, traumatic brain injury, post-cardiac arrest with return of spontaneous circulation, or as a bridge to vasopressor infusion while the infusion is being prepared or a central line is being placed.1 However, the use of PDPs should not supplant continuous infusion vasopressors in patients requiring long-term blood pressure management, e.g., as in septic shock.

    Care should be exercised during administration of PDPs. The Journal of Critical Care compiled published reports on local tissue injury and extravasation occurring during vasopressor administration through peripheral intravenous and central venous catheters. They identified 318 events resulting from peripheral infusion and seven resulting from central infusion, indicating a higher risk of adverse events due to peripheral administration. Two-hundred four of the peripheral events were local tissue injury events, which included skin necrosis, tissue necrosis, and gangrene. The majority of these events were caused by norepinephrine and dopamine, with six events being caused by phenylephrine and six from epinephrine. There were 114 extravasation events due to peripheral infusion, with the majority being caused by norepinephrine and dopamine. Eleven extravasation events were caused by epinephrine and none were caused by phenylephrine. When local tissue injury was attributable to peripheral administration, the catheter site was located distal to the antecubital or popliteal fossa in 85.3% of events. The average duration of infusion before tissue injury occurred was 55.9 hours with a median of 24 hours. Of the 114 extravasation events, 52 reported infusion sites and 75% of those infusion sites were distal to the antecubital or popliteal fossa.8

    Based on these data, it is possible that the incidence of adverse events may be reduced if the administration site is located at or proximal to the antecubital or popliteal fossa. While there is an inherent risk of local tissue injury with the peripheral administration of vasopressors, PDPs do not carry the increased risk associated with prolonged infusion duration due to their method of administration. The data also suggests that there is less risk of local tissue injury and extravasation with phenylephrine and epinephrine as compared to alternative vasopressor options. Furthermore, phenylephrine is approved for both intramuscular and subcutaneous administration making extravasation of little concern, and the dose used for push dose epinephrine has the same epinephrine concentration as lidocaine with epinephrine (1:100,000), which does not pose a risk for extravasation.1

    One of the main safety concerns regarding PDPs is the high risk of dosage administration errors. Due to the manipulations and calculations required to prepare the appropriate dilution, the process of preparing these medications is error prone. As such, it is highly recommended that prefilled syringes be used whenever available. These syringes are typically acquired via outsourced sterile compounding facilities. However, if commercially prepared dilutions are unavailable, it is imperative that the provider use caution in preparing doses and to have dilutions double-checked by other providers in order to minimize the risk of error.

    • Bolus dose phenylephrine is typically prepared by adding 10mg (10mg/mL vial) of phenylephrine to a 100mL bag of normal saline, and then drawing the solution into a 10mL syringe, resulting in a 100 mcg/mL dilution. 
    • Bolus-dose epinephrine is typically prepared by combining 0.1mg epinephrine (1mL of a 1mg/10mL syringe) and 9mL of normal saline into a 10mL syringe, resulting in a 10 mcg/mL dilution.

    Following this process of dilution, phenylephrine is typically administered in aliquots of 0.5-2mL (50-200mcg), and epinephrine in aliquots of 0.5-2mL (5-20mcg). These should be administered via slow IV-push over 30-60 seconds every 1-5 minutes based on patient response. Due to the risk of administration errors, it is recommended that individual doses be transferred to empty 3mL syringes via the use of tip-to-tip luer lock transfer adaptors (if available).

    To date, there have only been two studies published evaluating the effectiveness of PDPs in the ED, and both were retrospective studies of phenylephrine. Panchal et al5 evaluated 20 patients receiving phenylephrine during the peri-intubation period, which they defined as 30 minutes prior to and post intubation. When phenylephrine was administered during the peri-intubation period, systolic and diastolic blood pressure significantly increased with no change in heart rate. The authors noted that there was not a systematic pattern used for administering bolus dose phenylephrine, and concluded that although hemodynamics were improved, nonsystematic use may lead to inadvertent negative side effects. Schwartz et al6 reviewed the use of bolus dose phenylephrine for acute hypotension in 73 patients in the ED. Their primary objective was to report the frequency of patients initiated on a continuous vasopressor infusion within 30 minutes of phenylephrine administration. They found that 46.5% of these patients had a continuous vasopressor infusion initiated within 30 minutes of phenylephrine administration. As a secondary objective, Schwartz et al assessed the impact of early preload expansion with intravenous fluids on the initiation of continuous vasopressor infusions. They found that only 34.2% of patients were adequately fluid challenged prior to vasopressor administration, and that receiving adequate fluid challenge was associated with fewer doses of phenylephrine.6

    Holden et al2 provides an in depth summary of safety recommendations for the use of PDPs in the ED based on current safe medication practice guidelines, as well as instructions for preparing and labeling the medications. Some of these recommendations include the official approval of bolus dose vasopressors by the organization prior to their use, consensus on who can order and administer PDPs, establishment of a common name for the practice to avoid confusion, and education of all members of the healthcare team involved in their use. They also recommend specifying indications for use, compounding instructions, providing easily accessible storage of the medications and all associated supplies, readily available medication information, and having a thorough documentation process for their utilization. Online videos with demonstrations on proper dilution of PDPs have been developed by the Emergency and Critical Care physician, Scott Weingart, and may be found online at www.EMCrit.org.4

    While there is currently a paucity of data regarding outcomes following PDP administration, it is a reasonable assertion that they may see increased use in the ED due to their ability to mitigate hypotensive episodes. There are significant risks and safety concerns that accompany the use of PDPs, and these risks are highest when there is not a standardized plan to be followed for their use. If PDPs are to be utilized, a systems-based approach that includes adequate training pertaining to accurate dilution and administration is necessary. If the proper policies and procedures are in place and there is ample communication amongst the healthcare team, it is possible that this administration method can be used safely and effectively to save lives in the ED. 

    References:

    1. Weingart S. Push-dose pressors for immediate blood pressure control. Clinical and Experimental Emergency Medicine. 2015; 2(2):131-132. doi:10.15441/ceem.15.010.
    2. Holden D, Ramich J, Timm E, Pauze D, Lesar T. Safety Considerations and Guideline-Based Safe Use Recommendations for “Bolus-Dose” Vasopressors in the Emergency Department. Annals of Emergency Medicine.  2018; 71(1):83-92.
    3. Weingart S. EMCrit Podcast 205 – Push-Dose Pressors Update. EMCrit Blog. Published on August 7, 2017. Available at: https://emcrit.org/racc/push-dose-pressor-update/. Accessed February 10, 2018.
    4. Weingart S. EMCrit Podcast 6 – Push-Dose Pressors. EMCrit Blog. Published on July 10, 2009. Available at: https://emcrit.org/racc/bolus-dose-pressors/. Accessed March 20, 2018.
    5. Panchal AR, Satyanarayan A, Bahadir JD, Hays D, Mosier J. Efficacy of bolus-dose phenylephrine for peri-intubation hypotension. J Emerg Med. 2015; 49:488-494.
    6. Schwartz MB, Ferreira JA, Aaronson PM. The impact of push-dose phenylephrine use on subsequent preload expansion in the ED setting. Am J Emerg Med. 2016; 34:2419-2422.
    7. Cole, JB.  Bolus-Dose Vasopressors in the Emergency Department: First, Do No Harm; Second, More Evidence Is Needed. Annals of Emergency Medicine. 2018; 71(1):93-95.
    8. Loubani OM. Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. Journal of Critical Care. 2015; 30(3):653.e9-17.


  • 23 May 2018 12:51 PM | MSHP Office (Administrator)

    Kansas City VA Medical Center Diffusion of Excellence Project
    Author: Sarah Cook, PharmD: Clinical Pharmacist at SSM Health St. Joseph’s Hospital – St. Charles

    The Kansas City VA (KCVA) has implemented a practice model that allows pharmacists to practice at the top of their scope in the primary care setting, resulting in increased utilization of pharmacists, offloading of primary care provider appointments, and improved patient outcomes.  Kyleigh Gould, PharmD, BCPS is the Associate Chief of Clinical Pharmacy Services at KCVA Medical Center and was instrumental in the implementation of this practice at her site.  She has graciously participated in an interview to share the work she is doing at the KCVA with MSHP members.  If you have any questions regarding the topic, please sent them to Sarah.Cook@ssmhealth.com and they will be forwarded on to Dr. Gould. 


    Please describe the program you started at your institution.

    In 2015, the Under Secretary for Veteran Affairs, Dr. David Shulkin, recognized that individual Veteran Affairs (VA) institutions had successful and innovative practices, but they weren’t being effectively implemented throughout the system nationwide. As a result, the Diffusion of Excellence (DOE) program was created to improve standardization across the VA system by identifying best practices and finding frontline champions to adopt and replicate them at other VA sites. Dr. Ellina Seckel, on behalf of the William S. Middleton Memorial Veterans Hospital in Madison, WI, submitted a project titled: “Increasing Access to Primary Care with Pharmacist Providers,” which was selected as one of 13 Gold Status practices. The results of the project showed when Patient Aligned Care Team (PACT) Clinical Pharmacy Specialists (CPS) were fully optimized in their roles, PACT CPS can offload 27% of primary care provider (PCP) appointments. In addition, implementation of pharmacist driven new patient medication intake appointments prior to the initial primary care provider appointment saved primary care providers 20 minutes on average for every new patient. Team satisfaction and communication improved, and 4 additional pharmacist resources were approved locally. Since 2016, Dr. Seckel and the Pharmacy Benefits Management (PBM) Clinical Pharmacy Practice Office (CPPO) have continued to implement this Gold Status practice at VA medical centers across the country.

     

    In October of 2016, The Kansas City VA (KCVA) pharmacy leadership team requested a visit from the DOE consultative visit team to review the CPS role at the time and potential opportunities for implementation of the DOE Gold Status practice. KCVA proceeded with implementation of the DOE model in the recommended phased approach; beginning with one pharmacist and then implementing to the broader pharmacist team over several months.  Based on the clinic location I was practicing at, I was the phase one pharmacist that led the DOE roll-out at KCVA. However, all PACT CPS’s were involved with the successful roll-out at KCVA.  Implementation occurred in a multimodal approach:

    • Aligning each CPS to designated PAC-Teams in the appropriate ratio of 1 CPS to 3 PAC-Teams. The PAC-Team consists of a medical support assistance (MSA), licensed practical nurse (LPN), registered nurse and primary care provider.
    • An educational campaign to outline disease states CPS can help manage. Education was provided to Veterans and team members.
    • CPS participating in weekly PAC-Team meetings/huddles to focus on team-based population management initiatives and day-to-day needs.
    • CPS performing new patient medication intake visits to help streamline initial PCP visits.

    How do you (pharmacists) in your program provide care to patients and ensure safe and effective medication therapy?  

    Within the VA system, a PACT CPS is an advanced practice provider who has a practice -area based scope of practice to independently evaluate patients, prescribe medications and order labs, imaging and consults as necessary for Veteran care post-diagnostically. CPS’s provide comprehensive medication management to improve medication use and clinical outcomes.  CPS’s have scheduled appointments of multiple modalities such as face-to-face, telephone, and virtual telemedicine. CPS’s improve access in multiple practice areas by providing comprehensive medication management to improve medication use and clinical outcomes, which creates opportunity for other providers to see more urgent/acute patients.

    What services have you determined to be essential to support your programs?

    Prior to the DOE roll-out, the KCVA PACT CPS’s did not have support for ancillary functions such as scheduling appointments and performing vital sign checks. As the role of the CPS evolved to be an additional provider on the team and the number of Veterans cared for by the CPS increased, it was necessary to establish the same ancillary support for the CPS as the primary care provider. Through leadership and frontline staff collaboration, the KVCA PACT CPS’s have successfully gained ancillary support for scheduling, patient check-in’s, and care coordination with the RN care manager.

    How did you gain support of hospital administrators, physicians, and nursing to implement your program?

    Gaining support was a widespread approach. While the DOE consultative visit team was on-site much of their time was spent meeting with hospital leadership, front-line supervisors and front-line team members explaining the benefits of the Gold status practice and how rolling out at KCVA could benefit our facility. Additionally, the DOE team discussed the individual needs of KCVA and how to put our touch on the project which resulted in tracking pharmacists’ involvement on the PAC-Team and specific Healthcare Effectiveness Data and Information Set (HEDIS) measures: A1C >9 %, diabetics with blood pressure above goal and patients with atherosclerotic cardiovascular disease not on statins. 

    After the consultative team visit, pharmacy leadership scheduled weekly internal calls with primary care leadership, front-line supervisors and PACT CPS to review progress, overcome barriers and ensure continued momentum for the project. I met with the front-line MSAs and LPNs several times to ensure consistent support. In addition, weekly team meetings helped to improve communications and relationships with the team and focused on population management initiatives to proactively engage high-risk patients into care.

     

    What are key barriers that needed to be overcome to start your program?

    The main barrier was the need for consistent ancillary support and clinic space to allow the CPS to spend 75-85% of time in direct patient care performing comprehensive medication management services. Scheduling support and patient-check-in support helps to streamline CPS patient visits and improve CPS efficiency. We worked with the clinic managers to gain dedicated space within the clinic to perform patient care visits.

    Pharmacy leadership also worked hard to off-load operational pharmacy tasks to the appropriate member within the pharmacy department to ensure the PACT CPS is consistently working at the top of their scope. Through consistent education, redirection and strong leadership support we have been able to work through these barriers. 

    What are some key considerations to gain employee acceptance and buy-in for your program?

    Consistent and positive communication regarding the program and showing the benefits are important. Tracking outcomes helped to show each member that their support has helped to prove the programs benefits.

    What benefits have you been able to show with your program?

    For the three PACTs involved with the phase one roll out, we tracked outcomes on the following HEDIS measures: A1C >9 %, diabetics with blood pressure above goal and patients with atherosclerotic cardiovascular disease not on statins. For all three teams, all three HEDIS measures improved! This was a true testament of each team member working together. This project successfully helped define and optimize the role of the CPS on the team and show the positive impact of embedding the CPS into the team. During the roll-out, Dr. Geetha Kamath, a primary care providers involved in the initial phase reported to pharmacy leadership, “I would like to update you and provide feedback on the significant positive impact made by this project in improving quality of care to our patients. Patients on our panel have closer follow-up and med reconciliation and chronic disease management with our pharmacist Kyleigh Gould’s active participation and involvement in medication management. I would definitely recommend this be continued on an ongoing basis/permanently as part of PACT team”. We have successfully spread this model throughout all the KCVA primary care clinics and are excited to continue to be a key member of the PACT.

    What are lessons learned while implementing your program that you would like to share with other pharmacists?

    Culture change is hard and takes time, but through positive interactions, collaboration, transparency and teamwork, it is doable and well worth the effort!

    The MSHP Newsletter Committee would like to thank Dr. Gould for being willing to share the pharmacy practice at KCVA that is allowing pharmacists to practice at the top of their scope!  Finally, if you have a best practice which you feel others in the state would benefit from reading about, please contact me – Sarah Cook, Vice Chair of the MSHP Newsletter Committee – at Sarah.Cook@ssmhealth.com. 


  • 23 May 2018 12:30 PM | MSHP Office (Administrator)

    Author: Barb Kasper, PharmD, BCACP

    MSHP Newsletter Committee Chair/UMKC School of Pharmacy at MU

    The MSHP/KCHP Spring Meeting took place May 4-5th, 2018 at the Embassy Suites in Olathe, KS. 220 pharmacists, students, and technicians from both societies were in attendance. The meeting featured 61 faculty presenters, who delivered a total of 24 presentations for pharmacists, three presentations for students, and four presentations for technicians. Pharmacists were able to earn up to nine hours of continuing education and technicians were able to earn up to four hours.

    The ASHP keynote speaker was Tim Brown, PharmD, BCACP, FASHP from the Cleveland Clinic. He delivered a compelling presentation about pharmacist burnout. 55 posters were presented by students, residents, technicians, and professionals. Additionally, 26 companies and organizations participated in the exhibit hall.

    The annual R&E Foundation fundraisers were very successful. A social event was held on May 4th at Stone Pillar Winery and raised $2700. Additionally, a total of 13 baskets were donated for the R&E Silent Auction and raised $725.

    The 2018-2019 MSHP Board of Directors were inducted on May 4th. A number of awards were presented between the MSHP Best Practice Awards Breakfast and MSHP Awards Lunch on May 5th. Additionally, the newly inducted MSHP President, Tony Huke, delivered his inaugural presidential address at the MSHP Awards Lunch. Congratulations to the new officers and award winners!

    Best Practice Award Winner: Shelby Semanski, PharmD
    Best Residency Project Award Winner
    : Alexandria Stringberg, PharmD

    Best Orginal Poster: Damon Bartel Pabst, RPh
    Best Student Poster: Caitlynn Tabaka, PharmD Candidte 2019
    Best Resident Poster: Perry Carrington, PharmD

    Pharmacist of the Year: Joanna Hatfield, PharmD
    Preceptor of the Year: Laura Challen, PharmD
    Volunteer of the Year: Barb Kasper, PharmD
    Garrison Award: Greg Teal, PharmD

    The meeting was a tremendous success and could not have happened without the extensive planning efforts of the MSHP/KCHP Education and Programming Committees, MSHP/KCHP Board of Directors, Q&A Business Solutions, and many other volunteers. A huge thanks to those who gave their time to ensure the meeting was carried out so well.

    Please save the date for the 2019 MSHP/ICHP Spring Meeting at the Gateway Center in Collinsville, IL: March 29-30th.


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