Author: Bert McClary
A child sometimes asks a parent, “Mommy, where did I come from?” I rarely get asked directly, “Where did MSHP come from?” but members do express an interest when they hear facts about the early days of MSHP. I’m not one of the parents—we have three founding fathers—I’m more like one of the uncles and aunts who were there watching and helping, but I’ll try to get you interested in our history with a few anecdotes during the next year. We will be celebrating 50 years of activity in the spring of 2020.
You’ve heard the pharmacy history of early man using plant medications, Egyptian papyrus documents, Greco-Roman scientists/healers/apothecaries, Arab apothecary shops and European separation of pharmacy and medicine. The first hospital in the U.S. was in Philadelphia in 1751 and the first hospital pharmacist was appointed in 1752. Hospital pharmacists in Colonial America received little pay and little recognition from the public, the health professions or the American pharmacy profession. The use of formal medicines, development of specialized hospital pharmacy standards of practice, and development of overall practice standards for hospitals was slow.
In the 1930s, the APhA Sub-Section on Hospital Pharmacy was founded by Harvey A.K. Whitney and other progressive hospital practitioners. A Minimum Standard for Pharmacies in Hospitals was developed and was approved by the American College of Surgeons. The American Society of Hospital Pharmacists (ASHP) became an autonomous affiliate of APhA in 1942 with three constitutional goals: Establishing minimum standards, providing interchange among pharmacists and encouraging new program development, and extending the economic and rational use of medication. Results of a 1957 study by ASHP were published in the 1964 Mirror to Hospital Pharmacy, written by Francke, Latiolais, Francke and Ho. The Mirror provided many recommendations based on six broad goals to enhance the development of hospital pharmacy.
Nationwide in the 1950s all hospitals larger than 300 beds had a full-time pharmacist, but only 39% of all hospital beds had the services of a pharmacist. Only 3.5% of hospitals under 50 beds did. Small rural hospitals were sometimes serviced by local community pharmacists or not at all.
Local and area hospital pharmacy societies had been formed nationwide beginning in 1925, and some were affiliated with ASHP. There were pockets of progress in Missouri and the Metropolitan Society of Hospital Pharmacists of St. Louis, 1942, and the Greater Kansas City Society of Hospital pharmacists, circa 1950s, were founded by groups of nuns. Outside the two major metropolitan areas there was little progress until the late 1960s.
Hospital pharmacy services in the 1960s were primarily focused around drug distribution. Drug distribution in hospitals with no pharmacist or minimal pharmacist staffing was by a floor stock (ward stock) system. In facilities that had no pharmacist, nurses managed the acquisition, storing, repackaging and distribution activities. Even in the larger hospitals, twenty-four hour pharmacist staffing was rare, and often there was little or no weekend coverage. Sterile intravenous and irrigating solutions were prepared by the pharmacy in larger hospitals, or by the central sterile supply department.
The Missouri Board of Pharmacy had little interest in hospital pharmacy. The BOP did not license or inspect hospitals for inpatient pharmacy services and hospitals that did not fill outpatient prescriptions generally did not maintain a BOP license.
A few rural hospital pharmacists were active in local retail organizations and the Missouri Pharmaceutical Association. Politically active establishment retail pharmacists controlled both the MPA and BOP and were not truly interested in hospital practice issues.
There were three forward-thinking hospital pharmacy practitioners, our founding fathers, in three distinct areas of the state and in distinctly different practice settings, who sought to improve services in their local areas and began to interact with each other on a statewide level: Thomas J. Garrison, Director of Pharmacy at the small Lakeside Hospital in Kansas City; Garf Thomas, Chief Pharmacist at the University of Missouri Medical Center in Columbia; and Harvey A.K. Whitney, Jr., clinical pharmacy professor at St. Louis College of Pharmacy.
During the fall of 1969 Harvey organized a “Joint Committee for the Unification of Hospital Pharmacists in Missouri.” The first “Statewide Meeting of Missouri Hospital Pharmacists” held in Columbia on February 21, 1970 attracted 54 registrants.
In April when the Missouri Pharmaceutical Association (MPA) learned that MSHP was being organized, the MPA Executive Director made an initial effort to bring the group into the MPA, but there was little interest by MSHP leadership in affiliation at that time. Some members of the St. Louis and Kansas City hospital pharmacist societies were opposed to affiliation of their local organizations with MSHP.
The first annual meeting of MSHP was May 16, 1970 at StLCOP. At the successful business and dinner meeting an Enabling Resolution and the proposed Constitution and By-Laws were approved. George Heine of St. Louis and Garf Thomas of Columbia were elected and installed as President and President-elect. The Board of Directors and appointed committees met during the year and these goals were established:
We’ve been successfully pursuing these goals for almost 50 years.
Author: Jackie Harris, PharmD, BCPSExecutive Director of MSHP R&E Foundation/St. Louis College of Pharmacy/Christian Hospital Northeast
Dr. Haleigh Stolte, a PGY1 resident at the North Kansas City Hospital, was awarded the Best Resident Project at the ICHP/MSHP Spring Meeting for her project entitled “CAM I aCUTely Change Your Mind: A Pharmacist Driven Approach to Reducing Delirium”. Based upon the new Guidelines for Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS), management of ICU delirium should initially focus on reduction of modifiable risk factors for delirium. Medications such as benzodiazepines, opioids, H2 receptor antagonists, corticosteroids, anticholinergics, and NSAIDS have been associated with delirium.
A prospective observational study was developed to evaluate the effect of substitution, renal adjustment, and/or discontinuation of high-risk deliriant medications on the length of delirium before and after implementation of a pharmacist-driven medication management protocol. This project was developed in response to an increase in the number of psychiatric consults due to delirium seen at the North Kansas City Hospital. Secondary objectives included assessing the frequency of high-risk deliriant medication use before and after implementation of the protocol and time spent by pharmacists completing the review. Patients were identified electronically when an acute change in mental status is documented by nursing staff using the Confusion Assessment Method for the ICU (CAM-ICU). The alert then notifies pharmacists to substitute, discontinue, renally adjust, and document use of medications with delirious side effect profiles, as listed above, per protocol.
Statistical analysis was performed on 65 patients pre intervention implementation, and 41 patients post intervention implementation. No statistically significant differences between groups was identified. The primary outcome of this study is length of delirium, defined as time spent with an acute mental status change. Patients in the post intervention group had reduction in length of delirium of 7.9 hours, with a correlating p-value of 0.2. Secondary outcome measures included frequency of high risk deliriant medication use and pharmacist time spent completing interventions. Medication use decreased between pre and post intervention groups, and further decreased after pharmacist intervention. On average, pharmacists documented interventions required < 15 minutes of time to complete. Exploratory measures that included length of ICU stay and mortality at discharge. Patients in the post intervention group had a length of ICU stay that was 2 days shorter than pre intervention group. Interestingly, 24.6% of patients in the pre intervention group were alive at discharge, while 82.9% of patients in the post intervention group were alive at discharge.
If you have any questions about implementing a pharmacist-driven medication management protocol for delirium, please contact Dr. Stolte at firstname.lastname@example.org.
Author: Jackie Harris, PharmD, BCPSExecutive Director of MSHP R&E Foundation/St. Louis College of Pharmacy/Christian Hospital Northeast
At the MSHP/ICHP Spring Meeting, the R&E Foundation presented Journey McCarty, Pharm.D. with the MSHP Best Practice Award for her project entitled “Implementing a Pharmacist Driven 72-hour Antimicrobial Time Out”. The University of Missouri Health Care System implemented a pharmacist driven 72 hour antimicrobial time out in patients receiving vancomycin, ertapenem, meropenem, micafungin, or posaconazole. The primary outcome was days of therapy per 1000 patient days. Secondary outcomes included number and type of interventions, number and percentage of interventions accepted by physicians, time reported by pharmacist to complete antibiotic time out, and percentage of Antibiotic Time Out alerts completed. The pharmacy workflow developed can be seen in Figure 1. Pharmacist training was completed which included the development of a job aid, inservice trainings, a competency assessment, required completion of an online continuing education program on optimizing antimicrobial therapy, and a quality improvement check.
As of March 11th, 153 antibiotic time out forms had been completed with the majority being completed for vancomycin. Interventions were made in 36 of those forms. The majority of the interventions made were for de-escalation of antibiotics (16/36). Other interventions included recommending to discontinue therapy (12/36), recommending a stop date or duration added to order (5/36), dose change (2/36), and recommending to broaden therapy (2/36). Sixty-nine percent of those recommendations were accepted by the physician. An additional 11% of the recommendations were accepted with modifications. For the majority of pharmacists, the form was completed within 5 minutes (79%). The days of therapy per 1000 patient days has been lower each month for vancomycin when comparing January, February, and March of 2019 to 2018. Additionally, the days of therapy per 1000 patient days was lower in February for ertapenem compared with February of 2018.
This project has been well received at the University of Missouri Health Care, and can certainly be implemented at other hospitals throughout the state. The project team continues to identify opportunities for improvement, and is making plans to add more antibiotics to the Antibiotic Time Out in the near future. The team is working towards adding fidaxomicin, daptomycin, and amphotericin B to the Antibiotic Time Out. If you have any questions about how Dr. McCarty implemented her project, please email her at email@example.com.
Authors: Danielle Moses, PharmD, BCPP; Clinical Pharmacy Specialist – PsychiatryAnthony Lucido, PharmD, BCPS, Pharmacy Clinical Coordinator/PGY1 Residency Program Director
SSM Health DePaul Hospital – St. Louis, MO
Long-acting Injectable (LAI) medications have seen an increase in the variety of options and use in recent years, particularly in the psychiatric population. LAIs have become a mainstay of treatment for patients suffering from chronic illnesses such as schizophrenia and bipolar disorder, with a growing role in substance use disorders.1 While injectable therapy is a promising treatment avenue to promote compliance and improved quality of life, many barriers to patient access still exist. The complicated dosing paired with an administration route that requires a healthcare provider results in deficits in transitions of care and reduced utilization in this patient population. SSM Health DePaul Hospital in St. Louis recognized an opportunity to improve the care of this patient population by establishing an outpatient Long-Acting Injection Clinic. Clinical pharmacists and pharmacy residents collaborated with other healthcare providers to design and launch the LAI Clinic which has resulted in significant improvements in the quality of care for patients.
The goals of the LAI Clinic are to improve patient access to providers; remove patient barriers in coverage, including cost through insurance optimization and charity; and remove the financial burden to the hospital by reducing costs and increasing revenue. The LAI Clinic employs several innovative strategies including: LAI antipsychotic per pharmacy protocol for inpatients; complimentary transport to and from the clinic, group or individual therapy, and a fresh meal; pharmacy benefit specialist dedicated to the LAI Clinic, ensuring coverage of medications or facilitating enrollment in patient assistance programs; access to a psychiatrist if needed; and a collaborative practice agreement between the psychiatrist and the clinical pharmacist to facilitate additional capacity and rapid growth of the clinic. The services provided to patients by the LAI clinic are detailed in the appendix in figure 1.
Significance of the LAI Clinic to the Health-System
SSM Health DePaul Hospital has 125 acute inpatient behavioral health beds and SSM Health is the largest provider of acute psychiatric care in the St. Louis metropolitan area. In 2017, the hospital had 5010 acute inpatient psychiatric admissions and 3487 unavailable psychiatric beds. LAI medications represent a significant portion of care with 680 patients discharged on a psychiatric LAI medication in 2017.
The genesis of the LAI Clinic began in spring 2017 with the hiring of a psychiatric clinical pharmacy specialist (CPS) for the inpatient units as part of the hospital's residency program. In the early weeks of establishing a practice, the psychiatric CPS observed that patients who had received LAI antipsychotics were often not achieving the rates of increased compliance and decreased readmission noted in the data. The CPS hypothesized that the LAI’s benefits were not realized in this population due to avoidable lapses in care, specifically at discharge, rather than the efficacy of the agents themselves. A PGY1 resident chose to complete a retrospective review on the appropriateness of LAI antipsychotic dosing, including discharge prescriptions, and its correlation to readmission rates. Early results of the resident project's data created compelling evidence to implement a protocol allowing pharmacists to dose LAI antipsychotics for inpatients, including oral bridging therapy and discharge prescriptions.
As a result of the LAI per pharmacy protocol, the psychiatric CPS and inpatient pharmacists became more involved with LAI discharge prescriptions. Several gaps in the transition of care for these patients were found: patients unable to meet required copays/coinsurance, discharge prescription for LAI not generated, suboptimal insurance benefit coverage due to lack of prior authorization for LAIs, lack of availability of psychiatrist visit for additional refills and follow-up after discharge, and inability to follow up at a site that provides injections due to lack of transportation or patient knowledge of sites to administer the injection. The psychiatric CPS championed the establishment of a hospital LAI Clinic to pharmacy leadership. The key outcome of the clinic was to create a clear care pathway that would support medication adherence for patients discharged from the psychiatric unit on LAIs.
Pharmacy leadership presented the concept to hospital administration and the premise moved forward as a Lean project in December 2017. The timeline for the LAI clinic is detailed in the appendix in figure 2. The LAI Clinic steering team consisting of representatives from inpatient pharmacy, outpatient pharmacy, business development, psychiatric nursing leaders, social work, and hospital administrators was formed and began work on the LAI Clinic as an A3 project. The steering team used Lean A3 methodology which vetted the concept by examining the current and future states, identifying gaps, and developing possible solutions. Early barriers identified included lack of resources/space, personnel, psychiatrist provider, and workflows for the LAI Clinic.
In January 2018, the steering team moved to a 2P event (Preparation/Process) which consisted of frontline staff and experts, including ambulatory care pharmacists, pharmacy benefit specialists (job title is pharmacy concierge), psychiatric clinic nurse, and social workers. The 2P solved gaps of space, people, and workflows. Space which was utilized for outpatient psychiatric group sessions was able to be modified to allow for storage and administration of medication. A psychiatric nurse working in the outpatient psychiatric program had inpatient experience and was able to administer the injections. Workflows which included changes to the EHR for referrals and billing were made.
In 2018, the LAI Clinic steering team recruited a psychiatrist (part-time) for the patients at the clinic in addition to his inpatient and office practice. The LAI Clinic began as a pilot in January 2018 with a small number of patients. The Clinic consistently grew at a rate of approximately 20 patients per month, and by May the psychiatrist provider was at patient capacity. The LAI Clinic steering team initiated a rapid improvement event (RIE) which used plan-study-do-act (PSDA) methodology to increase the capacity of the Clinic. The RIE team consisted of psychiatric CPS, pharmacy benefit specialist, inpatient social worker, LAI Clinic nurse, director of the outpatient pharmacy, and Intensive Outpatient Program team leader, with ad hoc specialties such as business development and revenue integrity. The primary outcome of the RIE was the development of a pro forma to appropriately staff the rapidly growing clinic. This led to the addition of a dedicated pharmacy benefit specialist to the clinic and increased pharmacist FTEs which included a collaborative practice agreement between psychiatric CPS and LAI Clinic psychiatrist.
The primary route of patient access for the Clinic is internal referral within the SSM Health system. At DePaul Hospital, the psychiatric CPS educates every patient continuing or initiated on an LAI antipsychotic and schedules them an appointment at the clinic that will print on their discharge instructions after their hospital stay. For other hospitals in the region within the SSM Health system, the psychiatric CPS runs a report to determine which patients were discharged with an LAI. The psychiatric CPS, LAI Clinic nurse, and pharmacy benefit specialist call patients, determine their coverage, and assess their needs and desires to attend the clinic. In May, the LAI Clinic began to accept external referrals after requests from other providers in the community.
The day prior to a patient's appointment, the nurse calls to provide a reminder and confirm plans for transportation. She then registers the patient, orders lunch and transportation (if necessary), and requests the LAIs to be filled via the outpatient pharmacy. All injections are delivered to the Clinic by 9:30 am the day of scheduled appointments. When patients arrive, they sign in and are escorted to group therapy (or individual therapy if requested) by the LAI Clinic therapist. After group, lunch is served. During lunch, the individual patients are seen by the LAI Clinic physician or psychiatric CPS for assessment and medication changes if necessary. The patient then sees the nurse for an assessment, including vitals, and injection administration. Patients are observed for reactions and given appointment cards as a reminder of the next injection administration date. Patients are then transported home. Any injections of patients that did not show for their appointment are returned to the outpatient pharmacy by the pharmacy benefit specialist.
Demonstration of Improvements
The improvements to the hospital by the LAI Clinic were intended to enhance patient-centered transition of care and sustainment of mental health. The LAI clinic has also produced a self-sustaining financial benefit. Prior to the LAI Clinic, patients receiving discharge injections did not have a consistent care pathway and suffered many disruptions in therapy from hospitalization to discharge. This is a well-known barrier to LAI use in the psychiatric patient population.2 Suboptimal prescribing patterns for patients’ LAIs at discharge in the hospital were confirmed by the hospital's PGY1 pharmacy resident research which showed 38% of a representative sample of discharge prescriptions had incorrect dosing with gaps in oral overlap, titration of the LAI, or lack of prescriptions generated for discharge. A further examination of 68 patients in 2017 showed 89 potentially avoidable readmissions due to errors in LAI discharge orders or lack of follow up care.
The financial benefits of the LAI Clinic were achieved through decreased spend on non-reimbursable medications in both inpatient psychiatric wards and outpatient infusion centers as well as increased revenue through the outpatient pharmacy. Increased revenue through the outpatient pharmacy amplifies the program's financial benefit through the hospital's participation in the federal 340B program as a disproportionate share hospital. The outpatient margin (revenue less charity expense and operating costs) on the LAI Clinic patients was positive in January and increased in June. The margin at the hospital is amplified by the 340B program, but the program is viable without 340B. The LAI Clinic patient volume and prescription volume are detailed in table 3 of the appendix.
The LAI Clinic provides additional operational benefits for the health-system. During the RIE, the team reviewed the accounts for LAI patients at the hospital's infusion center. The team found 246 patients who were receiving LAIs at the infusion center over a 12 month period for a net financial loss. This was due to various insurers requiring the long acting injection to be billed under the pharmacy benefit rather than medical to receive coverage. The infusion center is a hospital department with medications supplied by the inpatient pharmacy. The hospital infusion center does not fill any medications through the outpatient pharmacy and therefore the patient's pharmacy benefit was not used. Transferring these patients to the LAI Clinic affords the opportunity to use the pharmacy benefit and achieve reimbursement. The result was a double win with decreased write-offs by the infusion center and increased revenue for the LAI Clinic through the outpatient pharmacy. Additional financial benefits to the hospital include decreased inpatient spending on LAI medications. This is achieved by coordination with psychiatric CPS and the LAI Clinic. The psychiatric CPS estimates approximately $85,000 in drug expenditure was saved from January to May 2018.
The primary problem the LAI Clinic was founded to improve was the access of LAIs for the hospital’s psychiatric patient population. This was achieved as demonstrated by the rapid enrollment of patients and positive acceptance in the community. The LAI Clinic started with 4 patients in January and by July had a total of 126 active patients. Another metric to measure the success of the LAI Clinic's objective of increasing patient access is through the improved coverage and charity care. The pharmacy benefit specialist is able to obtain coverage for the majority of the patients (June, ~80%) by completing prior authorizations (PAs) for commercial plans and Medicaid if needed or enrolling the patient in patient assistance programs (PAPs). The remaining patients' prescriptions, approximately 20% in June, are filled through a charity fund from positive margin from the LAI Clinic.
The LAI Clinic results in demonstrable improvements in the care of patients by affording better access and coverage of LAI treatments. The impact of the program was immediately noticed by the friends and family of these patients who provided many testimonials to the hospital and local news. To date, the Clinic has enabled at least 12 patients to reenter the workforce who previously could not maintain a job due to their debilitating illness; a young female has returned to school to complete her masters level education in psychology; an elderly male who could not form coherent sentences at his first visit now laughs with staff about his relationship with his 7 siblings; a middle aged woman who could not break the cycle of addiction is now sober and in a solid relationship, something she notes she did not ever expect to attain. Countless success stories led a local TV affiliate to interview a patient's family, psychiatric CPS, and hospital personnel about the LAI Clinic in June 2018. This was subsequently picked up by the AP wire and published in national news services.
AHRQ Statistical Brief in October 2017 by Fingar and colleagues estimated patients with schizophrenia and related diagnoses had a 30-day readmission rate of 22.9%, the highest single disease for 30-day readmissions.3 As of December 2018, follow up retention rate for the Clinic was 89%. For those patients retained who have been attending the Clinic at least 6 months, they have experienced a 74% decrease in SSM admissions from 6 months prior to their start date to 6 months after, and 81% of these patients experienced zero readmissions within that 6 month period.
Significance to the Profession
The Long-Acting Injection Clinic demonstrates its significance to the profession by advancing the responsibility of pharmacists as prescribing authorities both in the inpatient and ambulatory care settings in psychiatry. The development of this clinic has led to an increased value of pharmacists within the hospital’s system, as hospital administration has recognized the importance of pharmacist utilization for appropriate dosing, transitions of care, and provider status. The expertise of the pharmacist in multidisciplinary teams has shown decreased costs for the hospital, improved patient quality of care, increased patient access to care, and generation of revenue that would otherwise be overlooked.
The LAI antipsychotic per pharmacy protocol is an established agreement between the psychiatric CPS, an alternate psychiatric residency preceptor, PGY1 residents, and the four primary psychiatrists that service the inpatient psychiatry beds. The EHR pharmacy specialist worked with the psychiatric CPS to create an order allowing psychiatrists to input the LAI antipsychotic of choice and its indication for use. Once the psychiatrist signs the order, all legal requirements of the protocol are associated and the order populates in the verification queue. The pharmacist or resident then performs clinical assessment and places the order for the LAI and its oral counterpart in addition to creating applicable discharge orders in EHR.
Due to the extreme variability in oral overlap, injectable/oral dosing after a break in therapy, and patient access to injectable medications post-hospital stay, one of the hospital's 2017-18 PGY1 residents found that a significant portion of patients receiving LAIs within the system were dosed inappropriately and did not receive proper follow-up care. Under the LAI antipsychotic per pharmacy protocol, pharmacists are able to prescribe appropriate doses and durations of the LAI antipsychotic and its oral counterpart based on various patient factors, such as: symptomatic control on current oral dose, date of last administration of injection (if applicable), renal and hepatic function, and insurance coverage. Being an integral part of the patient's care during the hospital stay, the pharmacist is then able to educate the patient on their antipsychotic and schedule an appointment with the LAI Clinic for maintenance care.
The evolution of the LAI Clinic has led to the significant advancement of pharmacy practice within the field of psychiatry. Due to the lack of outpatient psychiatric care in the region, attaining an appointment with a provider post-hospital stay can take between 120 and 180 days. As most discharge prescriptions do not contain refills, this gap in care feeds the readmission cycle of many psychiatric patients as they often relapse shortly after medication discontinuation. The need for pharmacist involvement into the ambulatory care setting in psychiatry with provider capacity is indisputable. From the relationship built between the LAI Clinic psychiatrist and psychiatric CPS on the inpatient setting via treatment team discussions, treatment recommendations by the pharmacist, and dosing of long-acting injectable antipsychotics through the inpatient protocol, a collaborative practice agreement between the provider and pharmacist was a natural response to the rapid influx of patients to the clinic. At its inception, the collaborative practice agreement allowed psychiatric CPS to initiate, modify, or switch long-acting injectable therapy for the indication provided by the psychiatrist and treat any associated adverse effects with such treatment. The agreement quickly expanded to allow the psychiatric CPS to initiate, modify, or switch treatment for any mental health diagnosis provided by the psychiatrist (e.g., depression) and treat any associated adverse effects. This has further broadened hospital administration and physician perspective of pharmacists as clinical providers within the hospital.
Utilization of pharmacist expertise in the creation, implementation, and expansion of the LAI Clinic has proven to be imperative in meeting its initial goals. The unique knowledge and skill set of the pharmacist has allowed an increase in the availability of care in the community, ensured medications are utilized and received in the most cost-effective manner, and provided assurance that patients are maintaining optimum mental health with the least amount of adverse effects possible via appropriate pharmacotherapy choices and dosing strategies.
Author: Cecylee Lewis, PharmD Candidate 2019University of Missouri – Kansas City School of Pharmacy at MU
Mentor: Austin Campbell, PharmD, BCPPUniversity of Missouri Hospital/Missouri Psychiatric Center
Mental illness is both prevalent and debilitating among adolescents and adults in the United States. Suicidal ideation has been increasing in recent years and with more attention in the social media spotlight1,2. In 2016, suicide was the 10th leading cause of death in the United States, consisting of 44,965 deaths or 1.6% of deaths overall3. Depression is the leading cause of disability in the United States affecting 6.7% of the population which is roughly 16.1 million adults aged 18 years or older4. Treatments for depression and suicidal ideation have evolved over the years and include psychotherapy and various medications. However, a major limitation of these treatment options is a delayed onset of action. New and novel medications have been a major topic of interest in mental health and should be investigated to provide alternative options for those who have failed standard therapy. Over the past decade, ketamine has been increasingly discussed as a useful tool in the management of treatment resistant depression (TRD) and eminent suicidal ideation (SI), and upon recent revelations esketamine seems to provide clinical benefit.
What is Ketamine?
Ketamine is a noncompetitive, glutamate N-methyl-D-aspartate (NMDA) receptor antagonist approved for general anesthesia, typically given intravenously. It has been known for its hallucinogenic and dissociative effects, which have resulted in misuse and potential abuse as a street drug. However, ketamine is a promising prospect in treatment resistant major depression and suicidal ideation5. When used for these disorders, the onset of action for ketamine is very rapid (within hours) as compared to the standard therapies which can take weeks to months to reach full effect. Currently ketamine is not FDA approved for depression or suicidal ideation, but has been used off-label in various clinical trials and inpatient settings6. Ketamine infusions are being used nationally and more recently here in Missouri at Missouri Psychiatric Center (MUPC) since November 2018, with very positive results.
Typical dosing for anesthesia ranges from 0.5-2mg/kg, but according to the manufacturer’s labeling, can have a max dose of 4.5mg/kg7. The most common dosing of intravenous ketamine for TRD and SI is 0.5mg/kg over 40 minutes. This dosing has been established through numerous trials which have determined it to be the optimal dose for response while minimizing potential side effects. Vidal et al8 conducted a recent study at Geneva University Hospitals with a new rapid intravenous ketamine injection of 0.5mg/kg over 1 minute. The adverse events were similar in nature to the 40 minute infusion, suggesting that this approach could be just as safe and with comparable efficacy. Although no long-term dosing regimen has been established, the amount of infusions needed for remission remains undetermined. Some studies have suggested that two infusions per week for up to six weeks have positive results5,9. Continuation or addition of antidepressants have not been well studied or established to maintain remission in patients treated with ketamine. This gray area of whether to add or keep antidepressant medications is up to the provider of whom is conducting the treatment.
A recent breakthrough treatment that has been backed through the FDA advisory board is esketamine. It was voted through by a wide margin; 14 yes votes, 2 no, and 1 abstention10. This backing happened on February 12th, 2019 after a new drug application (NDA) was submitted by Janssen in September 2018. It is an intranasal inhalation of esketamine (Spravato), the S enantiomer and more potent form of ketamine, which is patient administered under medical supervision. Proposed adult dose of esketamine is 28-56mg with each administration and can be titrated to 84mg by week two10. Most common side effects included increased blood pressure, dizziness, and dissociation within the first two hours of administration. As of March 5th, 2019, Spavato (esketamine), in conjunction with an oral antidepressant, has been approved for treatment resistant depression. The FDA states that is must be administered in a certified doctor’s or clinical office and will include a REMS program for safe use11.
Author: Ashley Wellen, PharmD, PGY1 Community Pharmacy ResidentMentor: Michelle Jeon, PharmD, BCACP, Assistant Professor of Pharmacy Practice/Clinical Pharmacist - St. Louis College of Pharmacy/Walgreens Co.
Migraine is a disease that affects over 36 million Americans. The disabling disease affects almost three times as many women as men.1 Patients with episodic migraine may experience a few migraine days per month, and those with chronic migraine spend 15 or more days per month with debilitating pain and neurologic symptoms.2
A study published in 2018 that aimed to describe the prevalence of migraine in adults also described the socioeconomic burden of the disease.3 According to results, the following groups had a statistically significant higher burden of severe headache or migraine:
Migraine headache etiology and pathophysiology are not completely understood. The pain and associated symptoms a patient experiences are believed to occur through a combination of mechanisms including neural suppression and activation of subcortical structures of the trigeminal system. The activation of trigeminal sensory nerves leads to the release of vasoactive neuropeptides including calcitonin gene-related peptide (CGRP), neurokinin A, and substance P. The vasodilation caused by these neuropeptides leads to neurogenic inflammation. Continued nerve conduction relays information to the cortical pain centers and continued afferent input maintains the headache.4,5,6
Impact on Quality of Life
Individuals with migraine experience attacks that may last for several hours to days. Migraines can severely negatively affect quality of life for patients. Affected patients may not be able to participate in daily activities, engage with family and friends, or perform at work. Sunlight, smells, and weather may trigger, amplify and exaggerate symptoms of a migraine.
The Migraine Impact report published by Eli Lily presented data regarding the social burden associated with migraine headaches7. Findings included:
Migraine headaches have a significant impact on quality of life and overall well-being of those who are affected by the disease.
Prevention with Pharmacologic Agents
According to the American Academy of Neurology, about 38% of those with migraines need preventative therapy; however, only 3-13% use it.8 Migraine prevention is indicated for those patients with frequent or long lasting migraines; contraindications, adverse effects, failure, or overuse of acute therapies; or those with uncommon migraines. Goals of preventative therapy include reducing attack frequency, severity, and duration; improving responsiveness to treatment of acute attacks, improving function and reducing disability, and preventing progression of episodic to chronic migraines. The overall goal is to improve the patient’s quality of life from the debilitating disease.8,9
Preventative medications currently recommended by the American Academy of Neurology include agents from pharmacologic classes such as beta-blockers, antidepressants, antiepileptics, NSAIDs, and calcium channel blockers. Table 1 includes agents with labeled indications for migraine prevention. Other agents such as atenolol, amitriptyline, venlafaxine, verapamil, and NSAIDs, are commonly used off-label. Many of these agents have limited efficacy in migraine prevention as well as limited use in special populations. The agents with the highest level of evidence of use are described in Table 1 below. 8,9
Agents with Labeled Indications for Migraine Prevention
CGRP Antagonists for Migraine Prevention
AIMOVIG™ (erenumab), AJOVY™ (fremanezumab), and EMGALITY™ (galcanezumab) are CGRP antagonists that were approved by the FDA in 2018 for preventative migraine therapy. This is the first medication class primarily designed to prevent migraines.
MECHANISM CGRP antagonists are monoclonal antibodies that exert their action by blocking the action of CGRP ligands at the CGRP receptors. CGRP ligands have been discovered in high concentration in patients who experience migraine. By inhibiting ligand action at the CGRP receptor, the subsequent vasodilation and neuro inflammation that lead to migraine headache and pain are inhibited. Both AJOVY™ and EMGALITY™ bind to CGRP ligands and prevent their action at CGRP receptors. AIMOVIG™ has a slightly different mechanism, as it binds with high-affinity to the CGRP receptors and antagonizes their function.10
CLINICAL CONSIDERATIONS All CGRP antagonists are administered via subcutaneous injection. Most agents are administered monthly with the option of AJOVY™, which can be dosed every 3 months. Each pen is available as a standard dose; some regimens may require 2 to 3 consecutive injections to achieve the prescribed dose (Table 2). Hypersensitivity remains the only contraindication for all agents. Patients may continue to use triptans as acute therapy for migraine headaches as no drug interactions exist with CGRP antagonists.
* Administration of higher doses will require 2-3 consecutive subcutaneous injections.
EFFICACY All three agents were compared to placebo when determining efficacy in episodic and chronic migraine prevention. Outcomes of interest include reduction in number of migraine days per month (MMD), and achievement of a 50% reduction or more from baseline in mean migraine days (>/= 50% MMD responders). A statistically significant difference was found in all studies for all agents and their outcomes of reduction of MMD and >/= 50% MMD responders compared to placebo. Tables 3, 4, and 5 below list the trials for each CGRP antagonist and the previously mentioned outcomes.11-18
Table 3AIMOVIG™ (ERENUMAB)
Table 4EMGALITY™ (GALCANEZUMAB)
Table 5AJOVY™ (FREMANENZUMAB)
IMMUNOGENICITY Development of antibodies to the biologic agents was reported in clinical trials. Although the data did not demonstrate a significant impact on product efficacy, there is little data to make definitive conclusions at this point.
ADVERSE REACTIONS All agents have similarly shown to cause minimal adverse reactions. Those that occurred in 3% or more of patients were injection site reactions and constipation.
MONITORING Number of migraine days per month should be monitored to determine efficacy of the three agents. No safety-related monitoring is required.
SPECIAL POPULATIONS Data on efficacy and safety of these agents is limited for use in pregnant, lactating, or pediatric patients. Data is also limited regarding use in elderly; therefore, it is currently recommended to start with low doses in the elderly.
THERAPEUTIC POTENTIAL Currently, these therapies may be considered an alternative to the guideline recommended agents as no trials have compared CGRP antagonists to first line therapy options for migraine prevention. One study including AIMOVIG™ (erenumab) demonstrated its efficacy after patients had failed to experience improvement on at least 2 – 4 other agents.19 Although these agents are the first class to target pathophysiology specific to migraine headaches and are effective with minimal adverse effects, their cost hinders the decision to recommend CGRP antagonists as 1st line preventative treatment options. The subcutaneous route of administration also presents a disadvantage, however, pipeline oral CGRP antagonists are being evaluated in clinical trials.20 As several novel agents have offered new potential for more effective management of migraine, therapeutic options for the prevention of severe disease will likely continue to expand.
Author: Gloria Grice, PharmD, BCPSDirector, Office of Experiential Education, St. Louis College of Pharmacy
It's Friday, the last day of a rotation, and I get a phone call that starts with “I’m so sorry to bother you, but I need some advice about my current student”. The preceptor proceeds to describe how the student has not met any of the deadlines for the rotation, has been late multiple times, absent a handful of times for various reasons, and was caught sleeping during a meeting, all the while seemingly disengaged from the rotation in general. A recipe for disaster.
What I love about this phone call is that the preceptor reached out for advice. All too often, I learn about challenging student situations well after the student finished the rotation; or that same student goes on to a later rotation, continuing the same behavior and that preceptor is befuddled at how the last preceptor didn’t address these things and wonders “is it only happening on my rotation?”. What I wish about this phone call is that I received it weeks ago. As preceptors, if you involve your Office of Experiential Education early in a difficult student situation, they are more likely to be able to help both you and the student have a positive outcome.
In my experience, difficult student situations can be classified into one of four categories: knowledge deficits, communication deficiencies, professionalism issues, or health-related. This is supported by the literature that suggests the most common rotation performance deficits are professionalism, time management, communication, punctuality, work ethic, organization, and knowledge deficits.1-3 Each of these types of difficult student situations has nuances that should be handled differently, but in general, the recipe for managing these difficult student situations can be summarized with four main ingredients:
The first ingredient is expectations. Whenever a student is not meeting your expectations, first check that your expectations are fair. Often, new preceptors have high and sometimes unattainable goals for students since they themselves have probably just recently finished clinical post-graduate training. Even seasoned preceptors can sometimes create an ambitious calendar of activities and projects for a student with an excessive amount of work to be done during the rotation hours and beyond. It’s best to limit assignments/projects to the quantity that the school recommends since they have taken into consideration a reasonable load of work for students. It’s also important to remember that many students have multiple ‘outside of rotation’ demands. And while clerkship learning is their top priority, it isn’t their only priority. Several students must work during the week for financial stability for themselves or their family; those with families have a whole host of additional evening family obligations (e.g. Bobby’s soccer practice and Jane’s dance recital); and several are also studying for a second degree, such as an MBA or MPH. Having said all this, we do not want preceptors to make the learning a “rotation-lite” for students with competing demands. Rather, understanding that they exist will ensure that the expectations for learning and performance are reasonable. In some student situations, a more focused performance improvement plan can be created and implemented between the student and the preceptor with specific goals for the week so that the expectations can be “chunked” to allow for students to work on things at a slower pace and to ensure the student is continually progressing.4 These can often be developed with the assistance of your Office of Experiential Education
In addition to being reasonable, the expectations should be clear. Students could be not meeting your expectation because they don’t fully understand what it is or confuse it with expectations from their prior preceptor (it’s not easy to have a new boss every 4-5 weeks). The easiest way to make your expectations clear are: 1) have a rotation syllabus that is specific to you and your site that outlines goals, expectations, a calendar for the rotation, and maybe even samples of work you expect; 2) have a very thorough and detailed orientation where you can review everything verbally; 3) utilize the four preceptor roles well, particularly the modeling role so the students can visually see what is expected; and 4) routinely review the expectations at the first sight of a student not meeting them.5-7
The second ingredient is having timely, productive, and caring conversations. Trust me, I know having these hard conversations isn’t enjoyable. If you haven’t read the book “Crucial Conversations”, I would suggest that as a must read for anyone who is a preceptor (or even if you aren’t).8 This book helps prepare individuals for having tough conversations when the stakes and emotions are high. There is an art to having these conversations and it begins with trying to understand the other person, making the conversation safe, sharing what you are observing, and establishing mutual goals moving forward. There are many dangerous things we can do without having these conversations such as making up our own story about why the student is performing poorly, or assuming the student will change behavior as the rotation advances, or giving up too early on improving the behavior. There are also many dangerous things we can do if we have these conversations poorly. Knowing ourselves and how we handle conflict is the backbone of these conversations; focusing on wanting to see the student succeed is the heart of it. Communication is key!
The third ingredient is knowing when and whom to refer the student to. Many times, students that are displaying professionalism issues and even academic concerns can have underlying personal issues. “Lazy” or “poor performance” could be from social stressors affecting home life (which affects professional life), or diagnosed/undiagnosed mental health or other health conditions.4,9 As a preceptor, you are at the front lines mentoring and coaching students and can be the first to recognize a potential personal issue that could be contributing to their performance. The best thing to do is to talk to the student and ask them questions about how they are doing outside of the rotation. Good questions to ask are “how would you say your home life is?” or “how are things at home?” or even “what stressors do you deal with day to day? And have those increased lately?”. I usually start by asking permission to ask these more personal questions. I’ve noticed that students are usually grateful that someone took the time to ask them about their situation versus just pointing out all the ways in which they are not meeting expectation. Depending on what information they share, you can refer them to many of the campus resources including the Counseling Center, Student Affairs personnel, or even the Life Crisis Hotline. When in doubt, let the student know that you are concerned for them and will be reaching out to the Office of Experiential Education for additional support services for the student. It could also be that the student does not have any personal circumstances impacting them, but the referral to the Office of Experiential Education and the Counseling Center can emphasize coping skills and resiliency messaging as well as reiterate the urgency of the situation for them to begin taking the rotation more seriously if they want to be successful.
The final ingredient is remembering to document everything. This can be done in a separate file, and/or in the student’s evaluation. Without very specific written examples of the concerning behavior, it will be more challenging later for the student to reflect back on the justification for their poor performance, or for the school to uphold a preceptor’s evaluation if a student files a grade appeal, or for a subsequent preceptor to look back and identify if the student has been struggling with the same issues across multiple rotations (this depends on whether your school has an open portfolio for preceptor evaluations). Additionally, students process things by seeing them written versus hearing it verbally. With very difficult student situations that require lots of documentation, we also advise to document how the verbal conversations went and documentation of the multiple opportunities that were given to the student to improve the behavior/issue. Don’t forget to document positive areas of performance as well! As the age old saying holds true, “it didn’t happen if it wasn’t documented”.
In summary, we know it isn’t easy to take time out of your day to teach, mentor, and coach the next generation of pharmacists on top of the expectations of you as the pharmacist. The tag line for the Preceptor’s Handbook for Pharmacists by Cuellar and Ginsburg (which, by the way, every preceptor should own and is full of precepting nuggets of wisdom) is “Being a preceptor is hard work”.10 We say that precepting should be a win-win where students win from hands-on learning experience and preceptors win from having students participate in delivering patient care. When any one situation begins to take over the majority of your time and the win-win feels less and less like anyone is winning, it takes a major toll on preceptors. Using these four ingredients, a dash of patience, and help from your sous-chefs (Office of Experiential Education) will make for the best possible outcome for you and for students.
Authors: Brandon Reynolds, PharmD, PGY1 Pharmacy Practice ResidentDalena Vo, PharmD, PGY2 Critical Care Pharmacy ResidentMentor: Erin Pender, PharmD, BCPS, BCCCPTruman Medical Centers - Kansas City, MO
Program Number: 2019-03-01Approval Dates: April 1, 2019 - October 1, 2019Approved Contact Hours: One (1) CE(s) per LIVE session.
Shock is a broad term encompassing a disease state characterized by systemic hypoperfusion and organ dysfunction with multiple underlying etiologies. It is a particularly dangerous condition, carrying a mortality rate of at least 25%.1 Well understood shock modalities include cardiogenic, distributive, hypovolemic, and obstructive, with distributive being the most common. 2 Table 1 outlines common causes for each shock subset. Although the term shock has been in the literature for decades, diagnosis and treatment of the condition, especially septic shock, has undergone several revisions.
In distributive (vasodilatory) shock, a leaky vasculature leads to low systemic vascular resistance and hypotension in the presence of preserved cardiac function. Treatment consists of fluid resuscitation with the addition of vasopressors for fluid-refractory shock. The goal of vasopressors in this situation is to cause vasoconstriction and thereby increase systemic vascular resistance. In contrast, cardiogenic shock involves decreased cardiac output due to diminished work of the heart. Positive inotropes can be utilized in this setting to increase contractility of the heart and subsequently improve blood pressure. Obstructive and hypovolemic shock rarely require vasopressors as the underlying mechanism should be identified and treated accordingly.
In order to better understand why certain vasopressors are preferred in the guidelines, it is essential that pharmacists stay up-to-date on current literature. Therefore, this article will focus on mechanisms of action and place in therapy for vasopressors, as well as current evidence and role of the new vasopressor, angiotensin II.
Adrenergic Receptors and Vasopressors
The five main receptor targets for vasoactive agents include alpha1, beta1, beta2, dopamine, and vasopressin. Alpha1 receptors are mostly located on vascular smooth muscle with stimulation producing vasoconstriction. Beta1 receptors can be found on myocardial cells and activation of these receptors causes increased chronotropy (heart rate) and inotropy (contractility) of the heart. Beta2 stimulation on vascular smooth muscle causes vasodilation. Activation of dopaminergic receptors on the kidneys, heart, and splanchnic vasculature results in vasodilation of renal and mesenteric beds. Lastly, two different subtypes of vasopressin receptors can produce either vasoconstriction of vascular smooth muscle or increased water reabsorption through agonism of V1 or V2 receptors, respectively.3
Norepinephrine is an endogenous catecholamine with potent alpha adrenergic agonist activity and mild beta adrenergic activity. Therefore, most of the effects of norepinephrine are on mean arterial pressure with less pronounced increases in cardiac output and stroke volume.4 Epinephrine is another endogenous catecholamine with affinity for both alpha and beta receptors. However, stimulation of these receptors are dose dependent. At lower doses, beta adrenergic effects are more pronounced, but as infusion rates increase (>0.1 mcg/kg/min), alpha adrenergic effects become predominant.3,5 Similar to epinephrine, pharmacologic effects of dopamine are dose dependent. Low doses of dopamine (<5 mcg/kg/min) are considered “renal protective” as activation of dopaminergic receptors produce splanchnic and renal vasodilation with subsequent increase in urine output and renal blood flow.5 However, studies have failed to show any clinical benefit in preventing renal failure and current sepsis guidelines recommend against initiating low dose dopamine for this purpose.6 Moderate doses of dopamine (5-10 mcg/kg/min) have inotropic effects and high doses of dopamine (>10 mcg/kg/min) have more vasoconstriction.5
Vasopressin’s ability to increase blood pressure stems from inhibition of nitric oxide production and direct constriction of vascular smooth muscle. Vasopressin-modulated increase in vascular sensitivity to catecholamines may further potentiate its pressor activity.3 Next, phenylephrine is the only vasopressor that selectively stimulates alpha1 receptors. Although it has no effect on beta receptors and heart rate, reflex tachycardia can develop with rapid changes in blood pressure.3 It should be noted that initiating phenylephrine in patients with already diminished myocardial function may have deleterious effects on cardiac output due to increasing systemic vascular resistance and further increasing demand of the heart. Lastly, the newest vasopressor, angiotensin II, acts on a completely different pathway from the adrenergic and vasopressin systems. Activation of this third system, the renin-angiotensin-aldosterone system (RAAS), through administration of angiotensin II produces potent vasoconstriction of arterioles and increases in blood pressure. Table 2 summarizes mechanisms of action for each vasopressor.
Table 2: Summary of adrenergic receptors and vasopressors
Angiotensin II hasn’t had a strong evidence base for inclusion in practice guidelines due to a lack of clinical data. As such, many clinicians have chosen not to consider angiotensin II as a therapeutic option, instead favoring treatments with well-documented data such as the other agents listed in Table 2. Considering the high mortality burden of vasodilatory shock and the adverse effects that are associated with the commonly used vasopressors, the use of angiotensin II has increased in popularity. In an effort to further explore the use of angiotensin II as a treatment option, researchers prepared a high-quality trial known as Angiotensin-II for the Treatment of Vasodilatory Shock (ATHOS-3).
Primary Literature for Angiotensin II (ATHOS-3)
The Angiotensin-II for the Treatment of Vasodilatory Shock (ATHOS-3) trial was published in the New England Journal of Medicine in 2017. This trial was a prospective, multi-center, double-blind, randomized controlled study which enrolled 321 patients with vasodilatory shock. Vasodilatory shock was defined as a cardiac index of >2.3 L/min/m2 or a central venous oxygen saturation of >70% with a central venous pressure of >8 mmHg, and a mean arterial pressure (MAP) between 55 and 70 mmHg. To be included, patients had to be ≥18 years of age with vasodilatory shock despite at least 25 mL/kg of fluid resuscitation and receiving at least 0.2 mcg of norepinephrine/kg/min or the equivalent dose of another vasopressor for at least 6 hours but less than 48 hours. Patients were excluded if they had burns covering >20% of their body surface area, acute coronary syndrome, bronchospasm, liver failure, mesenteric ischemia, active bleeding, abdominal aortic aneurysm, or an absolute neutrophil count <1000/mm3 or who were receiving venoarterial extracorporeal membrane oxygenation or treatment with high-dose glucocorticoids. Included patients were randomized to receive either angiotensin II or placebo in addition to the standard of care vasopressor. There were no significant differences between groups at randomization. The primary outcome measure of this trial was MAP response by the 3rd hour after initiation of treatment or placebo. Patients were considered to have met the primary outcome measure if by hour 3 their MAP was 75 mmHg or greater or their MAP increased by at least 10 mmHg. Secondary outcome measures included the mean change in cardiovascular Sequential Organ Failure Assessment (SOFA) score at hour 48 and the overall change in SOFA score at hour 48. Alpha was predefined as 0.05, and power was set and met at 90% for the primary outcome measure. A sample size of 150 patients was required in each group to determine superiority of angiotensin II over placebo.7
The study group initiated treatment at a rate equivalent to 20 ng of angiotensin II/kg/min which was titratable up to 200 ng/kg/min for the first 3 hours. During this time, standard-of-care vasopressors could not be adjusted unless for safety reasons. Between 3 hours 15 minutes and 48 hours, angioteninsin II or placebo and other vasopressors could both be adjusted to maintain a target MAP between 65 and 75 mm Hg. The study drug or placebo was then discontinued at hour 48 after completion of a tapering protocol. If the background vasopressor required an increase of 0.1 mcg of norepinephrine/kg/min or the equivalent or if the patient decompensated, the study drug could be restarted for up to 7 days so long as it had not been off for >3 hours prior.7
At hour 3, there were statistically more patients in the angiotensin II group that met the primary outcome measure (69.9% vs 23.4%, p<0.001; odds ratio [OR] 7.95; 95% confidence interval [CI] 4.76 to 13.3). Cardiovascular SOFA scores were statistically lower in the angiotensin II group than in placebo (-1.75 vs -1.28 respectively, p=0.01). The mean change in SOFA score between groups was not statistically significant (p=0.49). Mean change in norepinephrine-equivalent dosage from baseline to hour 3 was statistically significant (-0.03 ± 0.1 vs. 0.03 ± 0.23, p <0.001). Angiotensin II did not improve all-cause mortality over placebo at day 7 (29% vs 35% respectively; hazard ratio [HR] 0.78; 95% CI 0.53-1.16) or at day 28 (46% vs. 54% respectively; HR 0.78; 95% CI 0.57-1.07).7 There were no significant differences in adverse events between groups reported in the study, however, FDA labeling for angiotensin II warns of increased incidence of arterial and venous thromboembolic events compared to placebo-treated patients (13% vs. 5% respectively).8 Results of the study are summarized in Table 3.
Table 3: ATHOS-3 Trial Endpoints
Overall, for patients in vasodilatory (distributive) shock refractory to ≥25 mL/kg of fluid resuscitation and ≥0.2 mcg/kg/minute of norepinephrine or the equivalent dose of another vasopressor, addition of angiotensin II significantly increased MAP and decreased vasopressor requirements within 3 hours of initiation. In patients that received angiotensin II, the cardiovascular subsection of their SOFA score also decreased by hour 48, driven by the aforementioned decrease in vasopressor requirements. Angiotensin II did not decrease all-cause mortality at day 7 or day 28, although these mortality results were not powered to detect a difference.7
Places in Therapy
There are several published studies comparing norepinephrine to dopamine or epinephrine. One such study (SOAP-II) found no difference in 28-day mortality, but a higher incidence of arrhythmias in the dopamine group.9 Similar results have been demonstrated with trials comparing norepinephrine to epinephrine.10,11 Therefore, norepinephrine is currently recommended as the first line vasopressor in septic shock refractory to fluid resuscitation and epinephrine can be initiated in addition to norepinephrine to further increase MAP.6 Dopamine or vasopressin may also be used in septic shock. However, dopamine should only be initiated in patients at low risk of tachyarrhythmias due to the results from the SOAP-II trial. Furthermore, guidelines recommend initiating vasopressin in addition to norepinephrine to further increase MAP or to decrease norepinephrine dosage.9 In contrast to vasopressin, phenylephrine has limited use in septic shock and is not recommended in the guidelines. However, one advantage of phenylephrine is that it comes manufactured as a “push dose” and is often utilized in operating rooms for transient hypotension to avoid running a vasopressor infusion. Lastly, current data does not support the use of angiotensin II as first line therapy for septic shock. Based on the ATHOS-3 study, angiotensin II may be used in addition to norepinephrine in refractory shock similar to epinephrine or vasopressin.
There are three main systems that current vasopressors act on: the adrenergic, vasopressin, and renin-angiotensin-aldosterone system. Norepinephrine, epinephrine, phenylephrine, dopamine, and vasopressin have all been extensively studied. Common reasons for initiating these vasopressors include septic shock, anaphylactic reactions, or during advanced cardiac life support (ACLS). Angiotensin II is a novel vasopressor that acts on the renin-angiotensin-aldosterone system, a mechanism not previously utilized by the aforementioned vasopressors. The ATHOS-3 study supports the use of angiotensin II as an addition to norepinephrine for vasodilatory shock to reduce vasopressor requirements, increase MAP, and reduce the cardiovascular SOFA score, making angiotensin II a strong consideration for this subset of patients.
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Author: Sarah Cox, PharmD, MS. MSHP Public Policy Chair/Assistant Professor, UMKC School of Pharmacy at MU
The General Assembly Kicked off its 100th year on January 9, 2019 and will close its session at 6pm on May 17, 2019. Since the kickoff, lawmakers have been entrenched in the policy process in which a bill becomes a law. And this year, a number of bills have been introduced in both the house and senate that would impact pharmacy and the care of our patients. In this article, we list the pharmacy-related bills and walk through how a bill becomes a law.
2019 Pharmacy-Related Bills
Each of these bills have been introduced in their respective chamber. Click here to look up these bills and see where they are in the policy process.
How a Bill Becomes a Law
Step 1. Bill introduction, first and second read:
Step 2. Committee and Public Hearing:
Step 3. Perfection:
Step 4. Third reading and final passage:
Step 5. “Truly Agreed To and Finally Passed” and Governor signature
Step 6. Becoming a Law
Authors: Robin Yang, PharmD and Sophia Huynh, PharmDMentors: Tyson Lotz, PharmD, MBA and Melissa Mays, PharmD
SSM Health St. Clare Hospital – Fenton, MO
Program Number:Approval Dates:
Approved Contact Hours: One (1) CE(s) per LIVE session.
IntroductionAspergillus is a common mold that lives in the environment. A majority of healthy people inhale Aspergillus spores daily without contracting illness.1 Since aspergillosis is not a reportable infection in the United States through the Centers of Disease for Disease Control and Prevention, the exact prevalence is unknown.2 Invasive aspergillosis (IA) is relatively uncommon and represents an infectious burden on immunocompromised patients that can be a major cause of mortality. IA has been found to be the most common fungal infection among stem cell transplant patients and the second-most common among patients with a history of solid organ transplantation from prospective surveillance.3-4 A large prospective study found that one-year survival for patients with invasive aspergillosis was 25% in stem cell transplant patients and 59% in solid organ transplant patients, respectively.3-4
Clinical Manifestations and Diagnosis5IA primarily involves the sinopulmonary tract, as inhalation is the most common portal of entry and transmission. The onset of clinical presentation may range from days to weeks with symptoms including facial swelling, nose bleeds, fever, cough, and dyspnea. Invasion of the vasculature may manifest effects such as chest pain or hemoptysis. As IA clinical manifestations are nonspecific, it remains difficult to diagnose; thus, utilization of appropriate diagnostic tools is crucial.
Diagnostic ToolsThe chest computed tomography (CT) scan is recommended in suspected invasive pulmonary aspergillosis regardless of other chest radiograph results due to its much higher sensitivity in lesion identification. Typical features of invasive pulmonary aspergillosis on CT imaging include nodules, consolidative lesions, wedge-shaped infarcts, and the characteristic feature includes a “halo sign.” The “halo sign” is particularly seen in neutropenic patients and is defined as a nodule greater than 1 centimeter in diameter surrounded by ground-glass opacity. Upon recognition of a halo sign, treatment initiation is warranted as it has demonstrated improvement in clinical response.
Bronchoalveolar lavage (BAL) is an alternative in patients with suspicion of invasive pulmonary aspergillosis and remains a cornerstone diagnostic test for microbiological identification in diffuse interstitial or alveolar lung infiltrates. Cells and other components from bronchial and alveolar spaces are obtained in this relatively safe and well tolerated procedure. However, due to being an invasive procedure, it requires patient consent, sufficient patient respiratory capacity, and no major bleeding diathesis that precludes BAL. Therapy should be initiated if findings return with high suspicion of aspergillosis.
Blood or respiratory fluid cultures can be obtained to aid in the diagnosis of aspergillosis infections. It is a common practice to obtain cultures during suspected infection and any growth can further support treatment. Standard and special fungal stains should be performed simultaneously with fungal-specific media during suspected fungal infection. Aspergillus spp. typically grows on most media in approximately 2-5 days. Therefore, incubation period should be at least 5 days. Despite this, culture yield is low and a negative culture does not definitively exclude the diagnosis of IA.
Galactomannan assay is recommended as an accurate marker to diagnose IA when used in certain patient populations including hematologic malignancy or hematopoietic stem cell transplant. Studies have demonstrated good sensitivity at approximately 70%. It can be obtained from blood or bronchoalveolar lavage. However, galactomannan is not recommended to be routinely used in solid organ transplant patients or those with chronic granulomatous disease. Studies have shown galactomannan sensitivity in non-neutropenic patients appears to be lower in other groups and decreases to approximately 20% in solid organ transplant patients.
Polymerase chain reaction (PCR) has been highly debated for its clinical utility in diagnosing IA. Due to limited supporting evidence, recommendations to use PCR routinely cannot be made. IDSA recommends clinicians utilize PCR assays only in conjunction with other diagnostic tools and interpret results accordingly, maintaining awareness of the methodologies and performance characteristics of the specific assay used.
Risk Factors5-6Patient populations at risk for IA include those with prolonged neutropenia, recipients of allogeneic hematopoietic stem-cell or solid organ transplant, acquired immunodeficiency syndrome, chronic granulomatous disease, recipients of immunosuppression agents, defective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, coexisting conditions such as diabetes and malnutrition, recipients of high doses of glucocorticoids, and pre-existing structural lung disease (emphysema, previous cavitary tuberculosis, etc.).
Management of Invasive Aspergillosis5Non-pharmacological Prevention: Adult RecommendationsHigh-risk patients are recommended to reduce mold exposure, such as avoidance of gardening, spreading compost, or exposure to construction.
Treatment: Adult Recommendations (Algorithm 1)IDSA guidelines strongly recommend early initiation of the primary treatment with voriconazole as soon as infection is suspected rather than delaying therapy. Treatment duration should encompass a minimum of 6 to 12 weeks, depending on infection severity. Alternative therapies include liposomal/lipid complex Amphotericin B and isavuconazole. Table 1 in the supplementary appendix provides direct comparisons between each antifungal medication, routes of administration, and common adverse effects. Table 2 in the supplementary appendix summarizes dosing, renal dose adjustments, and hepatic dose adjustments between each antifungal agent.
TriazolesTriazoles are preferred agents for treatment and prevention in patients with or at risk for IA.
Voriconazole has become the primary drug of choice for invasive aspergillosis based on a pivotal randomized, unblinded, controlled trial that compared patients who received voriconazole and amphotericin B deoxycholate for primary therapy of invasive aspergillosis. In this trial, voriconazole demonstrated superior antifungal efficacy through improved survival benefit in patients at week 12 and significantly fewer adverse events.7Since that pivotal trial, the results of multiple cohort studies further support voriconazole compared with other intravenous therapies.
Isavuconazole serves as an alternative primary agent as supported by the results of a phase III, randomized-controlled, non-inferiority trial that compared isavuconazole with voriconazole for suspected mold disease. Isavuconazole demonstrated to be noninferior to voriconazole in efficacy and was well tolerated compared to voriconazole with fewer adverse events during the study.8 However, there is limited data that exists outside of this single study which led to Food and Drug Administration (FDA) approval in 2015 and the cost is also significantly higher as compared to voriconazole.
Posaconazole and itraconazole are considered for salvage therapy. Itraconazole does not exist in an intravenous formulation and capsules require a low gastric pH for absorption. The suspension formulation shows favorable absorption, but has a higher association with gastrointestinal side effects. Posaconazole has primarily only been studied in prophylaxis and steady-state levels may not be achieved for up to a week, limiting its use.
Triazole antifungals have proven to be difficult to initiate in patients with pertinent drug-drug interactions with their other required medications. Clinical judgement should be used to evaluate patients on a case by case basis and establish appropriate monitoring parameters for those who continue concomitant therapy.
EchinocandinsEchinocandins include caspofungin, micafungin, and anidulafungin.
These agents have extensive half-lives, which provides ease with once-daily dosing. This class distributes well into all major organ sites except the eye and does not require renal dose adjustment. However, echinocandins are only available as parenteral administration. Anidulafungin is not approved by the FDA for IA and caspofungin is significantly more expensive than micafungin making micafungin a desirable choice from this class.
Echinocandins can be used in combination with other antifungal agents. For salvage therapy, the use of monotherapy or combination therapy is appropriate. However, the IDSA recommends against routine use as monotherapy for invasive aspergillosis due to limited data. The use of echinocandins in combination therapy provides a multimodal approach with differing mechanisms of action.
Additionally, combination therapy is supported by a study comparing therapy with voriconazole plus anidulafungin versus voriconazole alone in a subgroup of patients with hematologic malignancies and hematopoietic cell transplantation diagnosed with invasive aspergillosis did not demonstrate statistical significance, but showed a trend towards increased 6 week survival.9 While there are no strong recommendations regarding combination therapy, the safety and tolerability of echinocandins supports it as a reasonable option to initiate as add-on therapy in severe or refractory disease.
Amphotericin BAmphotericin B is an appropriate option for initial and salvage therapy of aspergillus infections when a triazole cannot be administered. Currently, two amphotericin formulations, deoxycholate and liposomal derivatives, exist. The deoxycholate formulation should only be reserved for use when alternative agents are unavailable due to its higher risk of adverse effects as compared to the liposomal and lipid complex formulations. Amphotericin B shows activity against most Aspergillus species. Common adverse effects include infusion-related reactions such as fever, rigors, hypotension and may require premedications for alleviation.10
Summary of Evidence5