By: Annalisa Torres, PharmD Candidate 2021; St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy in St. Louis
Mentor: Paul Juang, PharmD, BCPS, BCCP, FASHP, FCCM; Professor, Department of Pharmacy Practice, St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy in St. Louis
SARS-CoV-2 and COVID-19
As 2019 drew to a close, the world saw the emergence of a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease known as Coronavirus disease 2019 (COVID-19). This highly pathogenic coronavirus was originally identified in Wuhan, China and would eventually spread to the rest of the global population resulting in a modern worldwide pandemic. The increased morbidity and mortality associated with COVID-19 resulted in the need for both the rapid manufacturing and global distribution of a safe and effective vaccine that is unparalleled.1 Due to its highly infectious nature that has resulted in numerous mortalities along with the global economic impact, understanding how SARS-CoV-2 enters the cell is an important factor in vaccine development.2
Like its predecessor, severe acute respiratory syndrome coronavirus (SARS-CoV), which resulted in the 2003 SARS outbreak, SARS-CoV-2, is a betacornoavirus that gains entry into the host cell via a spike protein (S2) that is present as a trimer on viral cell surfaces. A receptor binding domain for angiotensin-converting enzyme 2 (ACE2) is located on S protein resulting in the entry of both SARS-CoV and SARS-CoV-2 into the host cell. While the mechanism for entry is the same, slight variations in the receptor binding domain of SARS-CoV-2 result in a higher binding affinity for ACE2 compared to SARS-CoV.2 This mechanism has been the key area of interest related to COVID-19 vaccine development.3
Generally, it takes between 15 and 20 years before a safe and effective vaccine is available for distribution to the public.5,6 But given the need for more rapid vaccine development a public – private partnership known as Operation Warp Speed (OWS) was formed in May 2020. OWS is a partnership between the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector in order to accelerate not only vaccine development but also manufacturing and distribution, in the hopes of being able to provide at least 100 million doses by mid-2021.7
mRNA Vaccines: Moderna and Pfizer/BioNTech
A novel approach to vaccine development, messenger RNA (mRNA) based vaccines work on the notion that mRNA coded for pathogen antigen, in this case SARS-CoV-2, can not only be delivered to human cells but can then be used to produce antigen within the cell. mRNA vaccine technology synthesizes the viral protein by utilizing the human protein translational process. This method of vaccine delivery allows for a robust immune response without the introduction of live or inactivated portions of SARS-CoV-2. Due to its susceptibility to be rapidly degraded by ribonucleases, these vaccines need to be encapsulated with a lipid nanoparticle.5,6 Both Moderna in conjunction with NIAID (National Institute of Allergy and Infectious Disease) and Pfizer in conjunction with BioNTech have developed an mRNA based vaccine that encodes for spike protein found on the surface of SARS-CoV-2. 5,8,9
Adenovirus Vector Vaccines: AstraZeneca and Janssen
The vaccines currently being developed by AstraZeneca in conjunction with University of Oxford and Janssen Pharmaceuticals are known as replication-incompetent vectors. These vaccines have been engineered to express the spike protein found on SARS-CoV-2 while also disabling in vivo replication. Both vaccines are based on adenovirus vectors that deliver the spike protein to human cells. Upon entry into host cells, these vectors will allow for the expression of the spike protein, resulting in an immune response. While these vaccine types have been shown to elicit a good B and T cell response, they are somewhat affected by pre-existing vector immunity. In order to overcome this issue, vector types are either rare in humans, animal derived, or induce low immunity.5,6
Inactive Spike Protein Vaccines: Novavax and Sanofi/GlaxoSmithKline
The vaccine candidates being put forth by Novavax and Sanofi/GlaxoSmithKline utilize inactivated viral vectors to display the SARS-CoV-2 spike protein.5 The benefit of these vaccine types is that they are not only safe in immunocompromised individuals, and they have been extensively utilized in prior viral protein-based vaccines.6 NVX-CoV2373, the vaccine candidate from Novavax, includes the transmembrane domain of the wild-type SARS-CoV-2 spike (S) protein. As mentioned above, S mediates the attachment of SARS-CoV-2 to human cells.10
Table 1, comparing the current available data for the six leading COVID-19 vaccine candidates, is shown below.
Moderna. Moderna announces longer shelf life for its COVID-19 vaccine candidate at refrigerated temperatures. Moderna Web site. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-longer-shelf-life-its-covid-19-vaccine. November 16, 2020. Accessed November 17, 2020.
Word Health Organization. Draft landscape of COVID-19 candidate vaccines. Word Health Organization Web site. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines. November 12, 2020. Accessed November 17, 2020.
By: Abbey Jin, Ashley Jose, and Miriam Bisada, PharmD Candidates Class of 2021; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Yvonne Burnett, PharmD, BCIDP; Assistant Professor, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Infectious Diseases Clinical Pharmacist, Missouri Baptist Medical Center
Coronaviridae are a diverse family of single-stranded RNA viruses that typically infect mammalian and avian hosts. Structurally, coronaviridae are spherical in nature with protruding spikes on the surface, resembling clubs.1 First discovered in humans in the 1960s, the coronavirus family has since rapidly mutated to include seven different human coronaviruses (hCoV), which can be broken down into four sub-groups: alpha, beta, gamma, and delta, alpha and beta being the most common.2 Notably in the 21st century, three life-threatening coronavirus infections have emerged: Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and Coronavirus Disease 2019 (COVID-19).2
As these viruses are related, there are parallels between the three viruses and clinical disease. SARS, MERS, and COVID-19 are zoonotic diseases that have genetic origins from bats and other mammals.3 Additionally, all three are transmitted via respiratory droplets; however, MERS-CoV may also be transmitted via other bodily fluids. As these usually require close contact with respiratory droplets, they can be easily transmitted, with SARS-CoV-2 being the most easily transmitted, then SARS-CoV and MERS-CoV.3 The clinical presentations are often similar and will be compared below. While there are many similarities between the three viruses, they are distinct, and only SARS-CoV-2, causing COVID-19, has resulted in a worldwide pandemic. This review will compare clinical epidemiological features, clinical presentations and symptoms, and/or treatment recommendations between the MERS, SARS, and COVID-19 coronaviruses.
Severe Acute Respiratory Syndrome (SARS)
SARS-CoV is a beta coronavirus that was first identified in 2002 in Guangdong, China and rapidly spread to other countries/areas, including Canada, Hong Kong, Singapore, and Vietnam.3-5 The incubation period of SARS is typically between 2-10 days, with the mean time from onset of clinical symptoms to admission ranging between 3-5 days.4 According to World Health Organization (WHO), over 8000 people worldwide became infected with SARS-CoV between 2002 and 2003 and, of these, 774 died.6
Clinical Presentation and Diagnostics
SARS commonly presents with symptoms like that of influenza infection, including malaise, headache, fever, diarrhea, chills, and myalgia, similar to MERS and COVID-19.3,4 Patients may also experience dry cough or shortness of breath in the first two weeks of illness; however, rash and neurologic findings are uncommon.4 Symptoms may further progress and result in the development of pneumonia or hypoxia. Patients with SARS have also presented with biphasic infection, where initial improvement is followed by rapid deterioration with noted fever, chest infiltrates and respiratory failure.4
The primary method of diagnosis is molecular PCR testing of nasopharyngeal or oropharyngeal swabs, sputum, blood or stool samples.3,4,7 PCR testing is the most well-developed molecular technique that has been used to evaluate novel infections due to its high sensitivity, specificity and cost effectiveness.8 However, it also comes with the risk of false positive or false negative results. Serological testing, such as antibody testing, can be used to detect the presence of antibodies in the blood due to SARS-CoV infection.6 Per the Centers for Disease Control and Prevention (CDC), antibody testing is not recommended to be used as the sole basis for diagnosis of acute SARS infection; however, it may be useful for detecting exposure to the virus.9 Serologic tests may be misleading, if not used within an appropriate time of disease, antibody development may take up to 3 weeks, until then infected patients may have negative results.10 Lastly, the sensitivity of both PCR and serology testing have been found to be around 80% and close to 100%, respectively.11
To date, there are no guidelines or vaccines to direct the management or prevention of SARS. SARS management is centered around providing supportive care and minimizing infectious spread.4 The combination of ribavirin and corticosteroids have been studied for management of SARS, but were not found to be effective.4 The data surrounding corticosteroid use in SARS is conflicting. One study found methylprednisolone alone lowered oxygen requirement and rapidly resolved lung opacities, while others have reported 20-fold increase in adverse outcomes, including mortality or intensive care unit admission, with the use of corticosteroids.12,13 Convalescent plasma may also be administered in patients who continue to deteriorate, as one preliminary study observed decreased hospital length of stay and mortality in severely ill patients with SARS.14
Middle East Respiratory Syndrome (MERS)
MERS-CoV first presented to humans in 2012 in Jordan, but most cases occurred in the Kingdom of Saudi Arabia. Since then, MERS-CoV has spread to 27 countries.15 While the mortality rate due to MERS is relatively high at 34.4%, this may be due to underreported cases with mild or asymptomatic infection.16 The median incubation period is 5 days, and the median time for hospitalization since illness onset is 4 days.3 Of the three coronaviruses, MERS-CoV has the lowest reported transmission rates.3
MERS infection presents in a progressive manner where, initially, many patients may be asymptomatic or present only with mild influenza symptoms.17 Common presentations include cough, headache, fatigue, fever >38oC, and diarrhea, like SARS and COVID-19.3 Patients may progress to more severe disease, identified by worsening respiratory status, acute respiratory distress syndrome (ARDS), and multi-organ failure. Multi-organ failure and deaths occurred in 20% to 40% of infected patients.15
Like SARS, MERS can be detected via molecular and serologic tests. Molecular tests, such as PCR, diagnose active infection in patients. The MERS-CoV PCR diagnostic sensitivity and specificity were both 100%.18 Serologic testing detects patients who were infected and had an immune response by identifying antibodies to MERS-CoV; however, like SARS and COVID-19, this approach is for investigational use only and not for diagnosis. The CDC recommends two-phase serologic testing due to false-positives, using two screening and one confirmatory test.19
As with SARS, there are no guidelines to direct MERS management. Early supportive therapy is recommended, which includes supplemental oxygen therapy and/or mechanical ventilation depending on respiratory status, conservative fluids (if no evidence of shock), and management of co-morbidities.20
The role of antivirals to treat MERS or SARS is not definitive due to high mortality and morbidity rates; however, antivirals may be considered in addition to supportive care as soon as MERS is diagnosed in severe cases. 21 Antiviral therapies have shown efficacy in laboratory studies, but not in clinical trials.21 A retrospective cohort study in patients with severe MERS-CoV infection showed that combination therapy with ribavirin and interferon-alpha-2a was associated with significantly improved survival at 14 days (typical therapy duration) compared with supportive care alone, but lack additional clinical data due to the high mortality rate.20,22 The dose for ribavirin should be clinically adjusted according to the patient’s renal function and tolerability to its side effects (cytopenia and hemolytic anemia).21 Glucocorticoids, while shown to be beneficial in COVID-19 infection, were not found to reduce mortality in MERS and were associated with delays in viral clearance.23 Convalescent plasma studies are limited due to the low numbers of MERS-CoV survivors, but could be administered within 2 weeks of infection onset in patients with severe MERS that are refractory to antivirals.21 Other agents studied, but not recommended for MERS treatment, include polyclonal anti-MERS-CoV human antibodies, nucleoside viral RNA polymerase inhibitors (e.g. remdesivir), and peptide inhibitors (e.g. HR2P-M2).20 Like SARS and COVID-19, there is currently no FDA approved vaccine, but clinical trials are ongoing.24
The first known cases of COVID-19 were reported in Wuhan, China in late 2019 and rapidly spread across the world infecting millions. COVID-19 was declared an international public health concern on January 30th, 2020, and a pandemic on March 11th, 2020, and continues to affect almost every country worldwide.3,26-29 As of the writing of this paper (October 31st, 2020), there have been over 45 million reported cases globally and over 1.1 million deaths.27 On average, patients exhibit symptoms 5 days following infection, but symptoms may emerge up to 14 days after exposure.30 Patients >50 years have the highest rate of hospitalization.31 Furthermore, chronic kidney disease, obesity, heart failure, coronary artery disease, smoking, sickle cell disease, immunocompromising conditions, cardiomyopathy, type II diabetes mellitus, and cancer are established risk factors for severe COVID-19.32,33 SARS-CoV-2 has the highest rate of transmission compared to SARS-CoV and MERS-CoV.3,34
Common initial signs and symptoms of COVID-19 include cough, headache, fatigue, fever of >38oC, and diarrhea, like that of MERS and SARS.3 And, like MERS and SARS, it is thought that the symptoms vary at onset, with many COVID-19 patients presenting with mild symptoms, with severe cases following a progressive course.3,35 Severe or critical cases may present with hypoxia, shock, respiratory failure, and/or multi-organ dysfunction and failure. Furthermore, patients may be asymptomatic or pre-symptomatic, but may present with chest abnormalities upon imaging.35
Oral or nasopharyngeal swabs, sputum, and fluid from bronchoalveolar lavage are examined for presence of SARS-CoV-2 molecular PCR. Multiplex assays (RT-PCR tests) are available to detect both influenza and COVID-19.36,37 Sensitivity of SARS-CoV-2 PCR testing ranges from 57.9% to 94.6%.38-43 With such a wide range, depending on the test, there may be a chance of false negative results with lower sensitivity testes.38-43 The range could be due to different manufacturers, integrity of samples, rate of false negatives, etc. Serologic tests have also been developed for COVID-19 to detect prior exposure to SARS-CoV-2.44,45 Sensitivity for these tests have ranged from 66.0% to 97.8%.46 In people who have been infected 1 to 3 weeks previously, the serology test has a specificity of greater than 99% and a sensitivity of 96%.47 Antibodies are able to be detected approximately 1 to 3 weeks following onset of symptoms, but it is unknown for how long can antibodies to SARS-COV-2 may persist.48
Treatment guidelines for COVID-19 management are updated and published by the Infectious Diseases Society of America (IDSA) and the National Institutes of Health (NIH) as new data are made available. Currently, there is one FDA-approved drug for COVID-19 treatment: remdesivir, an antiviral nucleotide analog.49 Remdesivir is indicated for the treatment of COVID-19 in hospitalized adult and pediatric (>12 years and >40 kg) patients.50 From the multinational Adaptive COVID-19 Treatment Trial (ACTT-1), remdesivir reduced recovery time (10 vs. 15 days, 95% CI 13 to 18) and decreased mortality rates (11.4% vs. 15.2% on day 29, HR, 0.73; 95% CI, 0.52-1.03) compared to placebo.51 Based on available data, glucocorticoids, like dexamethasone 6 mg by mouth daily for up to 10 days, and/or remdesivir 200 mg intravenous (IV) on day one, then 100 mg IV once a day for 4 days are recommended for severe cases of COVID-19 (SpO2 < 94% on room air or requiring oxygen).52,53
The guidelines strongly recommend against initiation of hydroxychloroquine (HCQ) and/or azithromycin (AZI) in hospitalized COVID-19 patients, as HCQ was not associated with lower mortality rates, and the combination of HCQ and AZI was associated with increased mortality.52-54 There are agents still under investigation and are recommended for use only in the setting of a clinical trial, including lopinavir/ritonavir, famotidine, interleukin (IL)-6 inhibitors, IL-7 therapy, mesenchymal stem cells, convalescent plasma, etc. 52,53,55-57 Furthermore, many agents, i.e., convalescent plasma, remdesivir, etc., were initially approved for emergency use authorization to administer in COVID-19 patients; remdesivir has now received full FDA approval.58
Vaccines are also currently in development by several companies in the US. As of October 2020, none have been approved by the FDA, but initial reports are promising.59 They are being developed in record time with 11 already in Phase 3 clinical studies and 6 for limited or early use at the time of this writing (October 31st, 2020).60
MERS and SARS are examples of past deadly coronaviruses in the 21st century that became global threats. Since early 2020, the COVID-19 pandemic has spread worldwide. In response, many have looked back to previous, similar pandemics of viral diseases. Experience with past SARS and MERS outbreaks have changed the way we combat viral outbreaks today. COVID-19 treatment and vaccine discovery and development are advancing in record time, with emergency use authorization (EUA) agents being approved and remdesivir being the first FDA approved COVID-19 treatment.49,58-60 However, there is still much unknown about the current pandemic. We hope that by analyzing the previous clinical and epidemiological features of past-related viruses and applying them to current and future research, we will develop better insight into understanding and fighting COVID-19.
By: Jesse Smith, PharmD Candidate 2021, St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy in St. Louis
Mentor: Bryan Lizza, PharmD, MS, BCCCP, Barnes-Jewish Hospital – St. Louis
In the United States, more than 2.8 million antibiotic-resistant infections occur annually, leading to more than 35,000 deaths.1 Despite recent initiatives in infection prevention and antibiotic conservation, multi-drug resistant organisms (MDROs) continue to be a global health crisis as mortality and morbidity from MDROs continue to rise.2 As a result of this need for new antibiotic therapy, advancements in antimicrobial development have led to several recently approved antibiotics. Pharmacists will play a vital role in ensuring appropriate use of these new novel agents as well as understanding their mechanisms of action and their important clinical features. The purpose of this article is to describe new antibiotics with activity towards MDROs and summarize important studies that led to their FDA approval.
(Click on tables below to view full size image.)
The randomized double-blind phase 3 study Lefamulin Evaluation Against Pneumonia (LEAP 1) trial evaluated lefamulin’s ability to treat community-acquired bacterial pneumonia (CABP). The study compared the use of lefamulin at a dose of 150 mg intravenously every 12 hours to moxifloxacin at a dose of 400 mg intravenously every 24 hours for five to seven days. After taking six doses of intravenous therapy, patients in both groups could then be converted to oral formulations of their respective medication if improvement criteria were met. In addition, if methicillin-resistant Staphylococcus aureus (MRSA) was suspected, blinded linezolid was added to moxifloxacin and a placebo was added to lefamulin and the duration of treatment was extended to ten days. The study’s primary endpoint was early clinical response (ECR) 96 ± 24 hours after the first dose of the study drug defined as improvement in ≥2 CABP signs/symptoms, had no worsening in any CABP sign/symptom, and had not received a concomitant, nonstudy antibiotic for CABP. Lefamulin was shown to be non-inferior to moxifloxacin for ECR at a rate of 87.3% for lefamulin and 90.2% for moxifloxacin in treating CABP in the intention-to-treat analysis (95% confidence interval (CI), -8.5 to 2.8). In the subsequent double-blind, double-dummy, parallel-group randomized LEAP 2 clinical trial, oral lefamulin at a duration of five days compared to moxifloxacin at a duration of seven days was evaluated in treating CABP. The study found that ECR at 96 hours ± 24 hours after the first dose of study drug was 90.8% in the lefamulin group and 90.8% in the moxifloxacin group, meeting the noninferiority margin of 10%. Like LEAP 1, LEAP 2 demonstrated lefamulin to be non-inferior to moxifloxacin in treating CABP and both agents were deemed safe and generally well tolerated.
One of the major phase 3 trials that led to delafloxacin’s FDA approval was A Phase 3 Study to Compare Delafloxacin With Moxifloxacin for the Treatment of Adults With Community-Acquired Bacterial Pneumonia (DEFINE-CABP). This randomized, double-blind, comparator-controlled, multicenter, global study compared delafloxacin 300 mg intravenously, with an option to switch to 450 mg orally every 12 hours, to moxifloxacin at 400 mg intravenously daily, with an option to switch to 400 mg orally daily, in patients with CABP. The study’s primary end point was ECR, defined as improvement at 96 ±24 hours after the first dose of study drug. The study found that patients receiving delafloxacin demonstrated an ECR rate of 88.9% compared with 89% in the moxifloxacin group (95% CI, -4.4% to 4.1%). Overall, the authors concluded that delafloxacin was a viable and well tolerated treatment option as monotherapy for CABP in adults where broad spectrum coverage, including MRSA, is indicated.
The efficacy of cefiderocol was evaluated in the Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. The study compared cefiderocol 2 g over 1 hour intravenously every 8 hours or imipenem-cilastin 1 g/1g intravenously every 8 hours for 7-14 days in patients with complicated urinary tract infection, with or without pyelonephritis, or those with acute uncomplicated pyelonephritis. The primary efficacy endpoint for the study was the composite outcome of clinical response defined as the resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms and microbiological response defined as he bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less. The study showed that 73% of patients in the cefiderocol group versus 55% of patients in the imipenem-cilastin group achieved the primary efficacy (95% CI 8.23-28.92; p=0.0004). Thus, cefiderocol was deemed to be non-inferior to imipenem-cilastin in the treatment of complicated urinary tract infections.
The Future of Antibiotics
Although a steady number of novel antibiotics have received FDA approval over the past few years, providers continue to question if new medication approvals can keep up with evolving bacterial resistance. The World Health Organization (WHO) reports that as of September 1, 2019, there are 50 antibiotics and combinations (with a new therapeutic entity), and 10 biologicals in the clinical pipeline (Phase 1– 3) of which 32 target the WHO priority pathogens.2 A large barrier moving forward is whether pharmaceutical companies will allocate the necessary resources to develop new antibiotics as private investment funding continues to decrease.2 Regardless of the pace at which antibiotic therapy evolves, pharmacists will continue to play a key role in ensuring safe and effective use moving forward.
By: Rexhian Brisku, PharmD Candidate 2021, St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy in St. Louis; Elizabeth Neuner, PharmD, BCPS, BCIDP, Barnes-Jewish Hospital – St. Louis
In 2014, the Centers for Disease Control and Prevention (CDC) released the Core Elements of Hospital Antimicrobial Stewardship Programs (Core Elements) to provide guidance and structure for antimicrobial stewardship programs (ASPs). Regulatory bodies including Centers for Medicare and Medicaid Services and The Joint Commission have since incorporated the Core Elements into accreditation standards. Despite advancements in stewardship, antibiotic resistance is still increasing and remains a public health hazard. The updated 2019 Antibiotic Resistance Threats Report by the CDC estimates 2.8 million cases of resistant infections lead to 35,000 deaths each year.2
The CDC recently updated the original Core Elements to continue optimizing hospital ASPs. The new document provides more granularity and specificity related to ASP activities and identifies priority interventions based on new literature and learned experiences over the past six years. This newsletter provides a summary of the updated 2019 CDC ASP Core Elements.1
1. Hospital Leadership Commitment: The first Core Element discusses the critical role of hospital leadership support for implementing a successful ASP. Priority examples include providing the ASP with time, resources and routine communication with executive leadership. Literature is emerging with recommendations for minimal ASP fulltime equivalent (FTE)-to-bed staffing ratios. A 2018 cross-sectional survey of 208 hospitals examined the relationship between ASP staffing levels and ASP effectiveness which they defined as a positive survey response to at least one of the following: established cost saving, decreased antibiotic utilization and decreased multi-drug resistance rates of organisms within the last four years.3 Every 0.5 increase in combined physician and pharmacist FTE availability predicted a 1.48-fold increase in ASP effectiveness (95% confidence interval, 1.06-2.07).3
2. Accountability: This Core Element emphasizes the need for a designated leader responsible for management and outcomes and highlights the effectiveness of a co-leadership model between pharmacists and physicians. The 2019 National Healthcare Safety Network (NHSN) Hospital Survey report of all U.S hospitals with stewardship programs, 59% utilize the co-leadership model.1
3. Pharmacy Experience: The previous “Drug Experience” Core Element is now referred to as “Pharmacy Experience” to highlight the importance of pharmacy engagement for the success of a stewardship program.1 A 2016 commentary on behalf of the Society of Infectious Diseases Pharmacists (SIDP) and the American Society of Health-System Pharmacists (ASHP) emphasizes the role of pharmacists, especially those trained in infectious diseases or antimicrobial stewardship, as essential.4
4. Action: This section was expanded to include evidence-based recommendations of effective ASP actions. The priority actions are prospective audit and feedback (PAF review of antibiotic therapy by an expert in antibiotic use), preauthorization (PA approval required prior to use of certain antibiotics) and facility-specific treatment guidelines.1 Several recent studies provide rationale for prioritizing PAF and PA by demonstrating the effectiveness in reducing overall antimicrobial use and improving appropriateness. A 2017 quasi-experimental, crossover trial comparing PAF and PA concluded that the incorporation of PAF had a more profound effect on reducing antimicrobial days of therapy.5 However, guideline adherence was found to be higher on day one in the PA group. The CDC considers both actions “foundational” for ASPs as they are complementary; PA optimizes initial empiric therapy and PAF reassesses continued therapy.1 Facility specific treatment guidelines can augment the effectiveness of both PAF and PA through optimizing antibiotic selection and therapy duration. ASPs should focus on the most common infections (e.g. lower respiratory tract, urinary tract, skin and soft tissue, etc.) and consider other infection-based interventions for sepsis, S. aureus and C. difficile infections.1
The usefulness of antibiotic timeouts, designated reassessment of antibiotic therapy by providers, is reframed as a supplemental strategy.1 Limited data suggests timeouts may improve appropriateness, but not reduce overall antimicrobial use. Therefore, this strategy should not replace PAF.6
Other supplemental actions organized around different ASP key stakeholders (pharmacy, microbiology and nursing) may help improve antibiotic prescribing, duration and safety. Pharmacy focused interventions include requiring indications, IV to PO switches, dose optimizations, alerts for duplicate therapy or drug interactions, and automatic stop orders. Microbiology-based interventions involve selective and cascading susceptibility reporting and “nudge” based interpretive comments.7 ASP actions for nursing discuss optimizing culture acquisition.
5. Tracking: The CDC recommends that ASPs track a variety of different measures to identify intervention opportunities and assess the impact of their efforts. It is highly recommended to submit antimicrobial use data to the NHSN Antimicrobial Use module to allow benchmarking with the use of the standardized antimicrobial administration ratio.8 Tracking of both outcomes (including C. difficile infections, resistance and financial impact) and process metrics is also recommended. Priority process measures include intervention types and acceptance rates, ensuring PA does not delay therapy and adherence to institution specific treatment guidelines.
6. Reporting: The CDC continues to recommend ASPs report antimicrobial use and resistance to hospital staff and leaders on a regular basis. Provider-level feedback is an effective outpatient ASP strategy; however, limited data exists for hospital ASPs given the complexity of inpatient prescribing.
7. Education: Antimicrobial stewardship education is important for many disciplines including prescribers, nurses and pharmacists. A variety of ways to provide education exist including a case-based approach through PAF or PA. For pharmacists specifically, SIDP, ASHP and CDC developed a campaign on the 5 Ways Hospital Pharmacists Can Be Antibiotic Aware. Hospital pharmacists should (1) verify penicillin allergies, (2) avoid duplicative anaerobic coverage, (3) reassess antibiotic therapy, (4) avoid treatment of asymptomatic bacteriuria and (5) use the shortest effective duration possible. Additional campaign material can be found at www.sidp.org/AMRchallenge.
In conclusion, as antimicrobial resistance continues to evolve, so too must antimicrobial stewardship practices. Hospital ASPs should work to incorporate the updated Core Elements to combat current and developing antibiotic resistance threats.
By: Gadison Quick, PharmD; PGY1 Pharmacy Resident
Mentor: Kerry Yamada, PharmD, BCPS; PGY-1 Pharmacy Residency Coordinator, Truman Medical Center – Kansas City, Mo
Program Number: 2020-11-01
Approval Dates: December 1, 2020 to May 1, 2021
Approved Contact Hours: 1 hour
TAKE CE QUIZ
Electrolyte disorders like hyponatremia or hypernatremia are not diseases, but rather a pathophysiologic process indicating a disturbance in water homeostasis.1 Sodium is abundantly used throughout every major body system to maintain homeostasis. One of sodium’s many vital roles is to help maintain normal fluid volumes throughout various intracellular and extracellular compartments.2 Sodium and blood osmolarity are highly dependent upon each other, hence the phrase “where goes water, goes salt”. Physiologically, we see if the serum sodium concentrations (SNa) are elevated (>145mEq/L), fluid will move into plasma to dilute the high sodium concentration. Likewise, if SNa is low (<135mEq/L) fluid will move out of the plasma to concentrate and correct the sodium concentration. Understanding the pathophysiology related to changes in sodium concentrations, as well as serum osmolarity (SOsm) will help identify the underlying causes of sodium disorders and allow for a proper treatment course in clinical practice. This review will not be highlighting gaps in therapy, or new treatments, but rather review the complexity of sodium disorders in practice. It is necessary to periodically review the foundations of physiology to appreciate treating the patient rather than the number.
Symptomatic vs Asymptomatic Hyponatremia
Hyponatremia defined as a SNa <135mEq/L is a common electrolyte disorder that possess a therapeutic challenge when treating in clinical practice. Hyponatremia can be categorized based on sodium concentration, timing of onset, presence of symptoms, serum osmolarity, and fluid status. The vast categorization of hyponatremia can easily confuse practitioners and make identifying and treating the underlying cause difficult. Currently there are two sets of guidelines developed discussing the management of hyponatremia. One by professional organizations within the United States (“American guideline”) and one from within Europe (“European guideline”).3
Recognizing symptomatic hyponatremia is vital for patient outcomes, as severe symptomatic hyponatremia is life threatening and requires emergent intervention. Key symptoms to monitor for when assessing symptomatic hyponatremia can be divided into either moderately severe or severe symptoms. Moderately severe symptoms include nausea, vomiting, altered mental status, and headache. Severe symptoms can include cardiac arrest, deep somnolence, seizures, or coma. Both the European and American guidelines recommend aggressive therapy with infusion of hypertonic saline in the presence of symptoms. However, dosing differs between guidelines. The American guidelines recommend a 10 minute infusion of 100ml of 3% saline repeated 3 times as needed versus the European guideline recommendations of 2 150ml boluses of 3% saline each over 20 minutes. Although both guidelines recommend a rapid, intermittent treatment using hypertonic saline, there is also literature to support an alternative dosing strategy with a slow continuous infusion of hypertonic saline to minimize the risk of overcorrection. The SALSA trial is one trial currently being conducted comparing rapid intermittent infusion of hypertonic saline versus slow continuous infusion of hypertonic saline. Additionally, Garrahy et al5 compared rapid, intermittent infusion vs slow, continuous infusion of hypertonic saline in symptomatic hyponatremia patients with syndrome of inappropriate antidiuretic hormone (SIADH). This study concluded intermittent bolus dosing of hypertonic saline resolved serum sodium levels quicker, and had a positive effect on patient’s Glasgow-Coma Scale (GCS) score. Additionally, this study did not have any cases of osmotic demyelination syndrome (ODS) in either group, therefore this study reinforces guideline recommendations to use rapid, intermittent doses of hypertonic saline in symptomatic hyponatremic cases.
Asymptomatic hyponatremia is much more common in practice, but requires careful evaluation in order to identify the underlying cause. A stepwise approach is key when determining the correct underlying factor. The first step in this stepwise approach is to determine if your patient is truly hyponatremic without other confounding factors like hyperglycemia. Second, check the serum osmolarity. Various institutions may have different absolute cutoffs for osmolarity, but a standard serum osmolarity (SOsm) ranges from 275-290mOsm/kg. Identifying the serum osmolarity will help you determine whether this is a hypotonic, isotonic, or hypertonic disorder. Third, evaluate the fluid status. Does your patient have signs of dehydration or excess fluid? For example, signs of dehydration or low fluid volume can include hypotension, tachycardia, polydipsia, weight loss, dry mucous membranes, sunken eyes, decreased skin turgor, and increased capillary refill time. On the other hand, signs of excessive fluid status can included hypertension, shortness of breath, weight gain, peripheral edema, ascites, and a positive jugular venous distension (JVD). Lastly, ordering a urinalysis to assess urine sodium and urine osmolarity will allow you to assess for salt wasting syndromes, or dilution of sodium.
Approaching hyponatremia in a stepwise process can help the practitioner approach each case in a more simplified manner. The next step to treating hyponatremia is to recognize the various categories, that being hypotonic hyponatremia, isotonic hyponatremia, and finally hypertonic hyponatremia. The latter two are less complex, and easier to recognize; therefore will be discussed first before moving onto hypotonic hyponatremia. First, isotonic hyponatremia, also known as “pseudo-hyponatremia” is classified as a falsely low SNa. The falsely low SNa is due to excess substances in the plasma. These excessive substances can include triglycerides, cholesterol, and plasma protein. Mathematical equations can be utilized to predict the true SNa but the treatment of this process is to treat the underlying cause.
Plasma triglycerides (g/L)x 0.002=mEq/L decrease in Na
Plasma Protein- 8(g/L)x 0.025=mEq/L decrease in Na
Second is hypertonic hyponatremia. The etiology of hypertonic hyponatremia is similar to isotonic hyponatremia in that SNa is falsely low due to an excess of serum substances, specifically in this case glucose. Hypertonic hyponatremia is commonly seen in hyperglycemic states like diabetic ketoacidosis (DKA) or hyperosmotic hyperglycemic state (HHS). Similar to isotonic hyponatremia, there is a mathematical equation used to predict the true SNa, as well as the treatment goal to treat the underlying cause.
Corrected Sodium=measured sodium+1.6 ((serum glucose-100))/100
Moving onto the third and last, but easily the most complex hyponatremic disorder is hypotonic hyponatremia. This category of hyponatremia can be more complex because this disorder is further categorized based on patient fluid status. Because of the vast sub-categorization within this disorder, it is worth mentioning again the importance to use the previously mentioned stepwise approach to identify the underlying disorder. First using the stepwise approach, hypotonic hypovolemic hyponatremia, can be identified by recognizing SNa <135mEq/L, SOsm <275mOsm/kg, and finally incorporating patient specific symptoms of dehydration. The next step is to identify urine sodium (UrNa) and urine osmolarity (UrOsm). Measurement of UrNa and UrOsm can help distinguish between disorders like SIADH and hypervolemic hyponatremia.6 Increased concentrations of UrNa and UrOsm in this case can be due from renal losses of sodium, including an excess of diuresis, or a deficiency in aldosterone. Diuretics work by blocking the reabsorption of electrolytes, and subsequently water, and therefore in states where diuretics are used in excess, a higher ratio of sodium, and other electrolytes can be found in the urine. Secondly, aldosterone is an endogenous mineralocorticoid secreted by the adrenal glands, and regulated by the renin-angiotensin-aldosterone system. Aldosterone is secreted in response to low systemic blood pressure, or increased serum potassium. It works by regulating the nephrons to retain a higher amount of sodium and water, while also secreting more potassium into the filtrate to increase blood pressure and decrease potassium. In states with a deficiency of aldosterone, the nephron fails to retain sodium and a higher concentration of sodium is eliminated in the urine. On the other hand, if the urine study shows a diluted sodium and osmolarity, the loss of sodium is from a non-renal source, whether that be gastrointestinal in the form of emesis or diarrhea, blood loss or skin loss, in the form of burns, open wounds, or excessive diaphoresis. Regardless of the source of non-renal loss, treating the underlying cause will correct the low SNa.
Taking the same stepwise approach to hypotonic euvolemic hyponatremia, objectively will show a low SNa <135mEq/L, low SOsm <275mOsm/kg, but with an absence of patient symptoms for both dehydration, and edema. Examining the urine study, a diluted urine osmolarity can be due from beer potomania, or psychogenic polydipsia. Beer potomania is a unique syndrome of hyponatremia,7 as alcohol, in this case, beer combined with a poor diet causes a dilution hyponatremia. Remembering water reabsorption in the nephrons of the kidney is dependent on the reabsorption of solutes and electrolytes, if a patient were to have poor intake of solutes and electrolytes, the kidney would not be able to reabsorb water in normal homeostasis, leading to more free water in the urine, and thus a diluted UrOsm. Secondly, in psychogenic polydipsia (PPD), there is a disruption in the thirst control mechanism related to the endocrine system. Although PPD is most commonly seen in chronic schizophrenia, other mental illnesses including psychotic depression and bipolar disorder can portray polydipsia behavior.8 The pathogenesis of the polydipsia may be related to a hypersensitivity to vasopressin, an increase in dopamine activity, or a defect in osmoregulation.8 The mainstay of treatment for PPD is fluid restriction, as excessive fluid intake can lead to life-threatening water intoxication, manifesting as symptomatic hyponatremia. On the other hand, when examining the urine study, and UrOsm is concentrated, the underlying disorder can include hypothyroidism, glucocorticoid deficiency, or most commonly SIADH. Hypothyroidism is a common disease affecting millions of Americans, and countless others across the globe every year. Patients with moderate to severe hypothyroidism and mainly patients with myxedema may exhibit reduced sodium levels.10 The main mechanism related to hypothyroidism-associated hyponatremia is due to a decreased capacity of free water excretion secondary to elevated antidiuretic hormone (ADH) levels. The hypothyroidism-induced decrease in cardiac output (CO) stimulates carotid baroreceptors to release more ADH to retain fluid, and increase CO. This overtime causes a buildup of ADH, and subsequently a dilution of SNa. Next, relating hyponatremia to glucocorticoid deficiency, the mechanism of hyponatremia seen in glucocorticoid deficiency is similar to what was previously discussed with hypothyroidism-induced hyponatremia. A lack in the principle glucocorticoid cortisol may cause a reduction in systemic blood pressure and CO, stimulating a release of ADH. However, a second mechanism may be related to glucocorticoid deficiency-induced hyponatremia in that cortisol deficiency results in increased hypothalamic secretion of corticotropin releasing hormone (CRH), an ADH secretagogue.10 Lastly, and most commonly observed in practice in euvolemic hyponatremia is SIADH, which is a condition defined by the unsuppressed release of ADH. ADH is a hormone that stimulates water reabsorption in the kidney, primarily through stimulating the insertion of aquaporins to help the nephron reabsorb more water. When left unsuppressed, copious amounts of water gets reabsorbed back into the serum, causing SNa to be diluted. SIADH is most commonly treated non-pharmacologically through fluid restricting, however pharmacologic options are available including loop diuretics, vasopressin receptor antagonists (aka “vaptans”), and demeclocycline. Conivaptan (Vaprisol®) and tolvaptan (Samsca®) are examples of vaptans. Conivaptan is only available IV, while tolvaptan is available PO. These medications should be used cautiously as they can unpredictably change SNa and in some instances overcorrect. Secondly, these medications are hepatotoxic, and should be avoided in hepatic dysfunction. Demeclocycline (Declomycin®) is a tetracycline antibiotic that blocks ADH. It is only orally available, has a long onset of action, and is not recommended in patents with renal or hepatic dysfunction. One last point is as pharmacists, it is important to monitor for medication-induced disorders. Although there is a plethora of medications that have been linked to SIADH, the five most common drug classes related to medication-induced SIADH include antidepressants, anticonvulsants, antipsychotics, cytotoxic agents, and pain medications, and more specifically selective serotonin reuptake inhibitors (SSRIs), and carbamazepine are among the most common agents.
Lastly, in hypotonic, hypervolemic hyponatremia, patient’s objectively will have a SNa <135mEq/L, SOsm <275mOsm/kg, but ultimately are fluid overloaded. Signs and symptoms of fluid overload have been previously mentioned in the content and should be applied here. This category of hyponatremia may be the most straightforward as it can be theorized the excessive fluid dilutes sodium, causing SNa to drop below normal limits. Disease states that can cause a buildup of fluid in this scenario can include liver cirrhosis, heart failure, and kidney failure. Treating the underlying disease state, in combination with fluid diuresis can help raise the SNa back within to normal limits.
As previously discussed, some hyponatremic disorders are treated with fluids, while others are treated with fluid restriction. When the underlying condition warrants the need for fluids. It is imperative to know how much sodium the body is deficient in, and how much fluid is theoretically necessary to correct the problem. There is a mathematical equation that can be used to figure out the total body deficit of sodium. Once calculating the total body deficit of sodium, a practitioner can translate that amount to a volume of fluid needed to correct the electrolyte imbalance.
Total Body Na Deficit (mEq)=(desired Na-serum Na) x TBW
TBW=weight (kg) x correction factor
Each liter of crystalloid fluid contains a different amount of sodium. As previously mentioned, once the total body sodium deficit is calculated, one can theoretically predict how much volume of fluid is needed to correct the electrolyte.
Although less commonly seen in clinical practice, hypernatremia on the other hand can also present in practice. It is seen as the opposite of hyponatremia by having an excess of solute, and a deficit of water. Hypernatremia can be categorized by volume status just like hyponatremia. The same causes of hypovolemic hyponatremia can further progress and lead to hypovolemic hypernatremia. As a reminder, these causes can include emesis, diarrhea, skin loss through open wounds, or burns, as well as excessive diaphoresis. Other causes that have not been previously mentioned include water loss from hyperventilation, and nasogastric sanctioning. In euvolemic hypernatremia, a condition known as diabetes insipidus can cause a lack of ADH, leading to excessive water wasting in the urine and a more concentrated serum. Diabetes insipidus (DI) is commonly known to be the exact opposite to SIADH and can be divided into either central DI or nephrogenic DI. In central DI, there is a disruption in normal ADH production, storage, and release. On the other hand, in nephrogenic DI, the aquaporins responsible for water reabsorption are not able to insert themselves into the nephron, failing to reabsorb water. Lastly, hypervolemic hypernatremia is usually the result of a large amount of fluid, overcorrecting hyponatremia with hypertonic saline, sodium bicarbonate, or even hormonally via Cushing syndrome, or primary hyperaldosteronism. Cushing syndrome is an excess of glucocorticoids, which can impair the hypothalamic-pituitary axis (HPA) and cause a lack of osmoregulation through ADH. The mechanism of aldosterone has been previously discussed, but reiterating it to hypervolemic hypernatremia, an excess of aldosterone causes sodium and water reabsorption, leading to increase volume, and increase SNa. Regardless of volume status as it relates to hypernatremia, it is always key to calculate the water deficit to correct the problem.
Water deficit (liters)=TBW x [((serum Na)/140)-1]
Using the mathematical equation provided above will help practitioners know how much fluid to theoretically give to allow the SNa to retreat to within normal limits. However, it is vital to closely monitor as in clinical practice, this water deficit calculation can often over-predict, putting patients at risk for rapid changes in SNa. When replacing the deficit, replace half of the deficit over the first 24 hours, and the remaining over the next 24-72 hours, always keeping into account never to decrease SNa >10-12mEq/L per 24 hours.
Rate of Correction
The rate of correcting SNa should be closely monitored, as the consequences of a rapid increase in SNa can lead to osmotic demyelination syndrome, while a rapid decrease in SNa can lead to cerebral edema. Regardless, both are deadly and difficult to reverse once a patient begins to exhibit symptoms. Both the European and American guidelines agree the correction of SNa should not exceed 10mEq per 24 hours. Additionally the American guidelines elaborate on this recommendation, and further recommend an even more conservative approach of 8mEq/24 hours correction in patients at high risk for ODS. Patients who are at high risk for ODS include hyperkalemia, alcoholism, liver disease, and malnutrition.4 The more conservative approach in these patients come from case reports of post-therapeutic neurologic complications after correction with once thought to be safe conservative therapy.
In summary, sodium is one of the most abundant solutes disturbed throughout the body and human cells rely on osmoregulation to maintain homeostasis. When there is a breakdown in this osmoregulation, an uneven distribution of solute and water causes a shift in normal cell physiology, which can manifest into life-threatening complications. Early recognition of symptomatic hyponatremia is vital to provide positive patient outcomes. As noted, sodium imbalances can be vastly sub-categorized based on the underlying cause and can easily confuse practitioners. Therefore by taking a stepwise approach when investigating the objective data available can help the provider identify the most pertinent underlying cause of the electrolyte imbalance. Practitioners can then easily calculate a theoretical amount of either solute or fluid needed to correct the imbalance. Remembering to correct the imbalance slowly over hours to days will help ensure life-threatening complications of overcorrection are avoided.
By: Jennifer Tran, PharmD; PGY1 Pharmacy Resident
Mentor: Lisa Sterling, PharmD, BCPS, BCGP; Residency Program Director/Clinical Pharmacy Specialist, Mercy Hospital – Springfield, MO
Program Number: 2020-11-03
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Psychiatric disorders affect 450 million people across the world.1 According to the World Health Organization (WHO), one in four people will have one or more mental disorders in their lifetime.1 Listed in Table 1 are common risk factors for psychiatric disorders:
Medications used to treat a variety of major psychiatric disorders include antipsychotics, antidepressants, mood stabilizers, and anti-anxiety, however the efficacy of these medications varies and many of them have significant adverse effects. Treatment failure and adverse effects along with significant adherence issues lead to many patients with psychiatric disorders needing adjunctive or alternative therapy. As a result, several nontraditional medications have been investigated in psychiatric disorders with sufficient data for some of these medications to be included in clinical guidelines. This article will discuss medications that have been investigated in the treatment of major depressive disorder, anxiety disorders, schizophrenia, and bipolar disorder.
Patients with major depressive disorder feel persistently depressed or lose interest in activities. Despite the numerous antidepressant medications, remission in depression is difficult to achieve. Failure to respond to antidepressants leads to the diagnosis of treatment resistant depression and may result in treatment with alternative medications. In the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trials, researchers evaluated the effectiveness of antidepressants in clinical practice. The first study found that only 25-33% of patients achieved remission in the first 14 weeks of therapy.2 The number of patients who fail to achieve remission continues to decrease after consecutive trials of antidepressants in later stages.3 The STAR*D trial shows that patients who progressed through the treatment algorithm were at high risk for relapse during the follow-up phase.3 These trials show how difficult depression may be to treat due to lack of efficacy.
Generalized anxiety disorder is characterized by excessive, uncontrollable, or irrational worry about events or activities. Medications used for depression have also demonstrated efficacy in anxiety and are used as first line agents in anxiety, as serotonin regulates both fear and worry in the amygdala.4 Anxiety can be difficult to treat. In a systematic review, remission of anxiety symptoms varied between antidepressants with fluoxetine having the highest remission rate (60.6%) and escitalopram having the second highest remission rate (26.7%). 5
In schizophrenia, patients are not in touch with reality due to psychotic symptoms such as hallucinations or delusions. This occurs due to increased levels of dopamine in the brain. First line treatment for schizophrenia is antipsychotics. However, these medications have been shown to have high discontinuation rates and adherence is difficult to achieve. In the landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trials, more than 60% of patients discontinued their antipsychotic medication due to lack of efficacy, intolerance, patient’s decision, or other reasons.6 In a systematic review, clinicians estimated that approximately 40% of schizophrenia patients were nonadherent to their medications. Factors that may be associated with nonadherence include poor insight, negative attitudes towards medications, or inadequate discharge planning.7
In bipolar disorder, patients experience extreme mood shifts that can lead to manic symptoms including delusions of grandiosity, extremely easy distractibility, and flight of ideas. Bipolar disorder tends to have a higher risk of relapse in comparison to other psychiatric disorders.8 Nonadherence may be attributed to bipolar patients’ risk of relapse. In this patient population, nonadherence rates are approximately 50%.8 Factors that may influence nonadherence include negative attitudes towards medication, severity of illness, complexity of medication regimen, and side effects.8 Antipsychotics and mood stabilizers are two medication classes used to treat bipolar disorder. Mood stabilizers are used to prevent and treat mania. The purpose of this class is to stabilize a patient’s emotions from intense mood shifts.4
Anticonvulsants affect four main molecules which may have a role in treating bipolar disorder: GABA, excitatory amino acids like glutamate, dopamine, and serotonin.10 Anticonvulsant medications used to treat bipolar disorder represent some of the first alternative agents used in psychiatric disorders. Specifically, anticonvulsants that have shown a high level of efficacy in stabilizing mood in bipolar disorder include carbamazepine, lamotrigine, and divalproex sodium.4 Carbamazepine and valproate were the first anticonvulsant agents to be studied in treating the manic phase of bipolar disorder. This led to the investigation of other anticonvulsant agents in treating bipolar disorder. Not all anticonvulsants have been found to be efficacious, as each anticonvulsant has a different mechanism of action.
Valproic acid’s mechanism of action in bipolar disorder may be due to its diminished flow of sodium through voltage-sensitive sodium channels. The result of less sodium release leads to diminished release of glutamate. Another possible theory could be due to valproate increasing the release of GABA. Carbamazepine acts differently compared to valproic acid, as it works by binding to the alpha subunit of voltage-sensitive sodium channels. This leads to enhancing the inhibitory effects of GABA.4 Another anticonvulsant used in bipolar disorder is lamotrigine, which is specifically indicated for bipolar depression. Lamotrigine, like carbamazepine, blocks the alpha subunit of voltage-sensitive sodium channels. However, the mechanism of action in treating bipolar depression with lamotrigine may be due to its ability to reduce the release of glutamate. Lamotrigine has not been found as effective in treatment of mania as carbamazepine.4
Other anticonvulsants have been investigated in psychiatric disease states. Pregabalin and gabapentin have demonstrated no significant efficacy as a mood stabilizer4 but may have a role in anxiety. The mechanism of action in bipolar disorder of both gabapentin and pregabalin are thought to be due to binding selectively to voltage-sensitive calcium channels, which inhibits the release of excitatory neurotransmitters.4 Pregabalin is a GABA analog and recommended as first-line treatment in Canadian guidelines for social anxiety disorder and generalized anxiety disorder.11 Pregabalin was found to be superior to placebo in two randomized control trials, but the response rate was low at 30-43% compared to 20-22% for placebo.11 The anxiety effects of pregabalin relieved symptoms quickly. Pregabalin is a schedule V medication and should be used with caution in patients with a history of substance use disorder. Gabapentin has been shown to relieve symptoms of social phobia or social anxiety disorder. In a double-blind, placebo-controlled trial, 69 patients were randomized to receive either gabapentin flexibly dosed 900-3600mg/day in three divided doses or placebo for 14 weeks. A significant reduction of symptoms and a higher response rate was shown in the group that received gabapentin (32%) compared to those who received placebo (14%).12 Side effects were more frequently with gabapentin including dizziness and dry mouth. The response rate to gabapentin is low but provides a treatment option for those who are unable to tolerate a SSRI or at risk of dependence with benzodiazepines.
Ketamine has demonstrated anti-depressive effects, which are thought to result from glutaminergic N-methyl-D-aspartate (NMDA) receptor antagonism. In a systematic review of parallel-group or cross-over randomized controlled trials that compared single-dose intravenous ketamine to placebo in patients with unipolar or bipolar depression. The primary outcome was symptoms change measured by Hamilton Depression Rating Scale (HAM-D) or Montgomery-Asberg Depression Rating Scale (MADRS). The review found that ketamine was statistically significant in reducing depression in comparison to placebo at 40 minutes of infusion (p<0.001) and lasting until days 5-8.13 The systematic review showed that ketamine has an ultra-rapid effect on improving depressive symptoms. In a single-site, active placebo control, randomized, double-blind crossover study, forty-one patients suffering from treatment-resistant depression with single infusions of ketamine or midazolam. After patients relapsed with depressive symptoms, they received 6 open-label ketamine infusions three times a week for 2 weeks. Ketamine infusion was found to significantly reduce depressive symptoms with 59% of patients meeting response criteria (>50% decrease MADRS score 24 hours post infusion). This study showed how ketamine infusion can quickly reduce depressive symptoms, as well as maintain cumulative and sustained antidepressant effects with repeated infusions.14 Although the trial showed fast improvement in depressive symptoms there is a possibility of the placebo effect, which is high during the first couple of weeks of treatment. Long-term studies are needed to determine if ketamine infusion should be used as a treatment option. The efficacy of ketamine has led to the development of esketamine (Spravato®) specially for the treatment of major depressive disorder.
Dextromethorphan has been investigated as a treatment for depression and, like ketamine, is a NMDA receptor antagonist. Dextromethorphan also has an effect on serotonin and norepinephrine. Recently, the results of the GEMINI study were released in a press release. This was a Phase III randomized, double-blind, placebo-controlled, multi-center trial completed in the United States. The study randomized 327 patients with moderate to severe major depressive disorder to receive either dextromethorphan/bupropion modulated delivery tablet or placebo once daily for the first 3 days and twice daily thereafter for a total of 6 weeks. The active drug combination was found to be statistically significant in reducing the MADRS score compared to placebo (16.6 vs 11.9, respectively).15 In a phase IIA, open-label clinical trial, the efficacy and tolerability of the combination of dextromethorphan 45 mg and quinidine 10 mg twice daily over a 10-week period in 20 patients with treatment resistant depression was investigated. The researchers found that the treatment group statistically significantly reduced the MADRS score by -13 (p<0.001). Although the results show promise in reducing depression, tolerability may be an issue as 30% of patients discontinued treatment. The treatment was discontinued primarily due to tolerability. 16
Two anti-hypertensive agents’ prazosin and propranolol are frequently used to treat symptoms of psychiatric disorders. Prazosin is used to treat post-traumatic stress disorder (PTSD) induced nightmares. The mechanism of action is due to its alpha-1 adrenergic antagonism that reduces adrenergic response in the central nervous system. Thus, relieving symptoms of PTSD due to overstimulation of adrenergic activity.17 The use of this medication is controversial due to its place in the Veterans Affairs and Department of Defense (VA/DOD) guidelines, which do not include recommendations for or against the use of prazosin in PTSD associated nightmares.18 Smaller trials had shown promising results in reducing nightmares in PTSD patients. A larger, VA multi-site trial with 304 subjects found that prazosin failed to separate from placebo in treatment of global symptoms of PTSD and nightmares. The Prazosin and Combat Trauma PTSD trial (PACT) was a 26-week, multicenter, double-blind, randomized, controlled trial. Investigators found that there was no significant difference between the prazosin and placebo groups in the PTSD scale, sleep quality index, and global impression of change score. 19 In conclusion, they found that prazosin did not reduce symptoms of distressing dreams or improve sleep quality. Although there is conflicting evidence for the use of prazosin PTSD, pharmacists may continue to see it used.
Propranolol is a highly lipophilic beta receptor blocker, a property allowing it to cross into the blood brain barrier. Propranolol is used to treat the physical symptoms of performance anxiety including tremor, tachycardia, and sweating. The medication is dosed initially at 10mg/day as needed to a target of 10-40mg/day.17 Propranolol only reduces the physical symptoms of performance-anxiety but does not treat the underlying anxiety.
Anti-inflammatory and Salicylic Acid Agents
Inflammation has been shown to play a major role in depression, schizophrenia, and bipolar disorders. This is thought to be due to dysregulation of immune response leading to abnormal pro- and anti-inflammatory cytokine findings in patients.20 In depression, the theory of increased inflammation and an altered immune response has led to the investigation of non-steroidal anti-inflammatory agents (NSAIDs) as possible treatment options. Along with inflammation having a role in depression, specifically COX-2 inhibitors have been shown to have direct effects on the serotonergic system by increasing serotonin levels in rats.21 Celecoxib, a selective COX-2 inhibitor, was used to augment the SSRI sertraline over 8 weeks of therapy in female patients experiencing a first episode of major depression. Patients were randomized to receive either sertraline (up to 100mg/day) plus celecoxib 200mg/day or sertraline plus placebo. Both groups showed improvement with the celecoxib group having a greater decrease in HAM-D.21 During week 4, the difference in the change in the HAM-D score was statistically significant and in favor of the treatment group (-13.7 in the treatment group vs -8.8 in placebo, p=0.021). However, the investigators did not provide p values for week 8. Another double-blind, randomized controlled trial with similar findings looked at another selective serotonin reuptake inhibitor (SSRI), fluoxetine 20-40mg/day. Celecoxib was dosed higher in this trial at 400mg/day. Both groups showed a decrease of the HAM-D score, but the celecoxib group showed greater improvement in symptoms (p=0.04).22,23
Aspirin has been studied in the treatment of depression. In a randomized clinical trial, 100 patients with major depressive disorder were assigned to either aspirin plus sertraline (treatment group) or placebo plus sertraline for 8 weeks. Mean Beck Depression Inventory (BDI) scores for depression severity were statistically significantly lower in the aspirin treated group (p=0.001). Both groups were similar in terms of side effect profile with more than half of the aspirin group (64%) not experiencing side effects at all.24 Key points to consider with this trial is that depression in the placebo group was more severe in comparison to the treatment group, which could have influenced results.
Pramipexole is a dopamine agonist at the D2 and D3 receptors and used in the treatment of Parkinson’s disease and restless leg syndrome. It has been demonstrated efficacy as a treatment option in treatment-resistant depression and bipolar depression I. One of the most common symptoms with depression is anhedonia or loss of interest in activities. Anhedonia has been associated with decreased levels of dopamine.25 In 60 patients with treatment-resistant major depressive episode, flexibly dosed pramipexole was added to standard antidepressant treatment in an 8-week, randomized, double-blind, placebo-controlled trial. The standard antidepressant therapy included both SSRI’s and serotonin-norepinephrine reuptake inhibitor (SNRI). The mean dose of pramipexole as augmentation was 1.35 mg/day. The primary outcome was change in MADRS score. Mixed-effects linear regression model was used to determine the change in MADRS. The results found a statistically significant time effect favoring pramipexole (p=0.038). However, response (p=0.27) and remission (p=0.61) comparing pramipexole to placebo was not statistically significant.26
Estrogen and Progesterone Agents
The onset of schizophrenia for women commonly occurs five years later in comparison to men which have an earlier onset at usually in their 20’s. Women with schizophrenia are more vulnerable or at risk for relapse during the postpartum period after pregnancy or during menopause when estrogen levels are down.27 In a dose-finding, double-blind, placebo-controlled study, adjunctive transdermal estradiol 100 mcg compared to placebo was investigated in 102 female child-bearing schizophrenia patients for 28 days. The results showed the addition of estradiol significantly reduced positive and general symptoms on the psychopathological symptom ratings (PANSS subscale scores) compared to women who received antipsychotic medication alone (p<0.05). 27 This trial included primarily a younger subset of patients who may be in the early phases of the disease.
Estrogen has been investigated in the management of depression. Depression risk increases in women who are perimenopausal. One trial examined the efficacy of transdermal estradiol plus intermittent micronized progesterone in preventing depressive symptom onset among euthymic perimenopausal and early postmenopausal women. Patients (n=172) were randomized to receive transdermal estradiol 100 mcg plus progesterone 200 mg/day for 12 days or placebo plus progesterone every 3 months for 12 months. The study found that patients in the treatment group (17.3%) were less likely to score a 16 on the Center for Epidemiological Studies – Depression Scale (CES-D) in comparison to placebo (32.3%) which would indicate a diagnosis of depression (p=0.03).28 This was one of the first studies to look at long-term effects of prophylactic mood benefits of transdermal estrogen and progesterone alone in women during menopause transition and early postmenopausal period.
Other agents used in psychiatric disorders that are mechanistically involved with estrogen are raloxifene and tamoxifen. Both are selective estrogen receptor modulators (SERM) that are used to treat hormone-sensitive breast cancer. Recently, they have been studied as a potential treatment option for schizophrenia and bipolar disorder. There have been some studies that show estrogen’s potential in a protective role in the pathophysiology of schizophrenia due to lowering psychotic and negative symptoms in pre-menopausal women.27,28 A systematic review of nine randomized controlled trials of raloxifene versus placebo for the treatment of schizophrenia in 561 patients showed improvement in total symptom severity (p=0.009), and a reduction in positive (p=0.02) and negative symptoms (p=0.02). Dosing ranged from 60 to 120 mg per day.29
Tamoxifen’s efficacy in bipolar disorder is thought to result from inhibition of protein kinase C (PKC). Studies suggest that excessive PKC activation leads to disruption of the prefrontal cortex in regulating thinking and behavior. A systematic review of five randomized, placebo-controlled trials evaluated tamoxifen as monotherapy or as augmentation therapy with lithium or valproate in the treatment of acute mania in bipolar patients. The results found that tamoxifen had improved mania scale score compared to placebo.30 Although, these results are promising it does not provide information of the effect of tamoxifen with other agents such as antipsychotics.
Dysfunction of the hypothalamic-pituitary-adrenal axis (HPA) is thought to affect psychiatric disorders such as depression and anxiety due to its release of cortisol. In the STAR*D trials, one of the studies compared the effectiveness of lithium to triiodothyronine (T3) augmentation in patients with major depressive disorder. Patients were augmented with T3 up to 50 mcg/day for up to 14 weeks. Remission rates were greater in the T3 group compared to the lithium group (24.7% vs 15.9%, p=0.4258). The difference between groups was not statistically significant.31 As a result, T3 augmentation is recommended by the American Psychiatric Association (APA) in the 2010 Major Depressive Disorder treatment guidelines.
The CANMAT/IBSD guidelines recommend levothyroxine as a third-line option for treatment of acute bipolar I depression.32 In a 6-week, double-blind, randomized, placebo-controlled trial of supratherapeutic levothyroxine (300 mcg/day) dose as augmentation in 62 patients the mean decrease of HAM-D score was greater in the levothyroxine group compared to the placebo group (-5.1 vs -7.8; p=0.198).33 However, the study failed to show statistical significance between the two groups. The trial used the maximum dosing of levothyroxine, which can cause symptoms of hyperthyroidism including nervousness, hair loss, tachycardia, tremors, and fatigue.
(Click Tables below to view full-size images.)
Future Treatments in Psychiatric Disorders and Conclusion
With the limitations of therapies available to treat psychiatric disorders, clinicians are finding value in other medications that may not typically be used in psychiatric disorders. There is an abundance of data to support possible use of some of these agents, but further studies with larger sample sizes are needed for many of the medications. The efficacy of these alternative therapies has given new insight into the pathophysiology of psychiatric disorders through their mechanisms of actions. This has created the opportunity for new therapies to be developed such as esketamine. In addition, clinicians may have available medications to treat psychiatric disorders not previously treatable as our understanding of these conditions expands
The use of non-psychiatric medications in psychiatric disorders provides us a greater understanding about the pathophysiology as well as another option in treating disease states. Overall, many of the trials had small sample sizes and were used primarily as adjunctive therapy. Before considering these treatment options, ensure that patients have adequate trials of psychiatric medications.
By Nathan Hanson, PharmD, MS, BCPS; Healthtrust Supply Chain
As we push for provider status and other new possibilities, let’s focus on actually doing the things that we are already allowed to do!
It is good that we are not satisfied with the status quo because that fuels us to continue to create new possibilities. It reminds us that our patients need the services that we can provide, so we need to keep pushing for the ability to provide them. However, as we knock on the doors of new possibilities we may be missing out on the possibilities already available to us!
Thinking Inside the Box
While we need to keep thinking outside the box, let’s put some creativity into making our current box work as well as it can. In other words, let’s make the best of the current circumstances. We in pharmacy often let the perfect become the enemy of the good. If we will instead push into some of these innovative practices that are currently options for us, we may find that it helps us make more rapid progress in the future. You will have real life examples of patients you have helped to strengthen your business case. You will have specific barriers you have encountered that we can advocate to eliminate. You will have built the infrastructure and expertise to capitalize on new opportunities as they are developed.
Interested? Here are 4 ideas of areas to explore with your team and your leaders.
Yes, it is complicated. No, the payment structure does not provide your organization with easy money. But we really can serve our physicians and nurses on our teams by providing our medication expertise to patients who need the access. If you get something going you will be able to find that there really are some opportunities for reimbursement. You can start building your team, building relationships, and making a difference in patients’ lives.
The information is changing by the day, but a couple things are clear: A lot of patients will need to be vaccinated, and pharmacy can help. Did you know that pharmacists, interns, and technicians are authorized to administer the vaccine? Tune in to webinars, get trained, and talk with your team about how you can support the testing and vaccination efforts.
Reducing Waste and Patient Costs
Fixing the problems with waste disposal and the cost of healthcare is far above our pay grades. However, did you know that if a patient is on an inhaler or other multiuse item in your hospital, it is legal for you to send it home with them at discharge? An authorized practitioner must order it, and written instructions for use must be sent with the patient at the time of discharge. This is a great way to reduce your waste and helping a patient at the same time.
How do you utilize your staff to perform basic quality assurance activities in the pharmacy? Ask yourself, “Does this job actually require a pharmacist? Could a technician check this process?” Of course there must be a strong process in place, and of course the pharmacist and the managers must verify that everything is being done safely. But too often we limit our technicians just because that’s the way it’s always been done. Check out the Tech Check Tech best practices document on the MSHP website for information about this program.
Not Easy – But a Great Start
Brainstorm about these areas with your team. Do you have questions? Never hesitate to reach out to us for clarification. We may not know the answer, but we can point you in the right direction. If we creatively tackle current problems and current opportunities, we will be ready to take on more responsibility and more opportunities in the future. To paraphrase, we need to be faithful with what we have if we want to be entrusted with more. Start looking in to these opportunities to see what you can accomplish in your world, today.
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Advocacy 101 Webinar:
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By: Zachary Moszczenski, PharmD; PGY1 Pharmacy Resident (2019-2020)
Mentor: Jackie A. Harris, PharmD, BCPS, Christian Hospital – St. Louis, MO
The use of anti-psychotics to treat delirium has been a controversial topic in recent years, owing to the short supply of high-quality trials and a shift in guideline recommendations. However, the debate started earlier in the beginning of the millennium when we began to ask ourselves: does what we’ve simply been doing for years actually work?
Anti-psychotics certainly made logical sense, as the symptoms of delirium largely mimic psychoses and other symptoms associated with cognitive disorders such as schizophrenia, and non-controlled studies along with expert opinion supported their use. We certainly wanted and felt the obligation to do something about delirium, as it not only can cause significant distress to the patient, family, and caregivers but also is associated with detrimental outcomes, as we’ll discuss. The difference/problem of anti-psychotic use for delirium is that it’s the result of a non-cognitive cause, whether it be a disease state, medication(s), severity of illness, and other factors. Additionally, the course and resolution of the delirium is heavily related to the presence or resolution/absence of the causative factor. Delirium can also be quite subjective in its presentation and assessment (it’s not as easy to assess as blood pressure!).
Since there were not any trials that directly compared anti-psychotics to placebo, the above-mentioned question was starting to and continues to be asked: is treating these patients with anti-psychotics actually doing anything? We’ll address that question in this review of the literature, while also giving an overview of delirium.
What is Delirium?
Before we dive into the available data, it’s important to understand exactly what delirium is and how it can present differently. According to the DSM-V, delirium is a state of attentional, cognitive, and emotional disturbances with or without psychomotor hyper and/or hypo activity.1 It occurs outside of a coma/significantly reduced state of arousal, which may seem like common sense, but it is an important distinction. Disturbances cannot be evident if a patient is too sedated or comatose to show hardly any function at all. This becomes relevant if we overly sedate a patient. They’re technically no longer showing signs of delirium, but we now have another problem on our hands and most likely just not able to tell if we’ve gotten rid of the delirium. The delirious state also differs from baseline mentation/behavior, develops over hours/days, fluctuates throughout the day, and as mentioned above, is not due to another cognitive disorder. There also has to be at least some evidence of another offending medical state or substance, which is essentially never an issue with our critically-ill ICU patients. A higher severity of illness is strongly related to the incidence of delirium, but the copious amount of delirium-inducing agents (opioids, benzodiazepines, steroids, etc.) that these patients commonly receive likely play a larger role.2,3 Simply laying in a bed in the same room for days to weeks at a time certainly doesn’t help either (which is something society as a whole started to understand while on quarantine during the COVID-19 epidemic).
It is also important to distinguish the different types of delirium, as we’ll see, which are described in Table 1.
The hyperactive subtype is easier to identify, though when we screen correctly, it’s easy to see how hypoactive could be more commonly diagnosed.2 SSD is not quite considered clinical delirium and is often not distinguished in comparative trials, though it has been linked with undesirable outcomes in the literature.4
The Problem with Delirium
Depending on the estimate, which is related to how well and often an institution screens for delirium, the prevalence in the ICU can range from 16% to 80% of patients.2 The older and sicker the patient, the higher the risk of delirium, which also tends to exhibit within 48 hours of ICU admission.5 Delirium is also touted to cost the US healthcare system up to an estimated $16 billion annually,2 largely due to the complications associated with delirium listed in Table 2.
Due to these significant complications, it is important to appropriately screen for and diagnose delirium. There are currently two bedside scales recommended by the 2018 Society of Critical Care Medicine (SCCM) Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) guidelines for diagnosing delirium.3 The first and most commonly used scale in the US is the Confusion Assessment Method for the ICU, or the CAM-ICU (Table 3).
This is cousin to the Intensive Care Delirium Screening Checklist, or ICDSC, which is relatively more popular in Canada and other countries. The presence of 4 or more of the symptoms listed in Table 4 will get you a positive diagnosis of delirium.7
Note the differences. The CAM-ICU is potentially more convenient, while the ICDSC is perhaps more useful in distinguishing between hyperactive and hypoactive delirium on its own. Both scales rely on the Richmond Agitation and Sedation Scale (RASS) to measure level of consciousness, ranging from -5 (unresponsive) to +4 (combative). The RASS can be combined with the CAM-ICU to differentiate hyper and hypoactive delirium. It is important to note that both only screen for the presence of delirium, as a higher score does not indicate severity or worse prognosis. Once again, both are recommended for use, with neither one preferred over the other.3
First, we start with our non-pharm methods for managing delirium, which have shown the most positive data and are subsequently the only interventions recommended for the treatment of delirium by the PADIS guidelines.3 These methods are also recommended for the prevention of delirium, though the focus of this review is on treatment only. “ABCDE” is the acronym describing the non-pharm bundle of strategies used in the guidelines, and the components are listed in Table 5. There are various methods used to meet this bundle of interventions, such as sedation vacations, proper sleep hygiene, cognitive stimulation, music, using hearing aids and glasses, etc., but the goal is to address all of them if possible.3
Aside from anti-psychotics, many other agents and classes of agents have been trialed for the treatment of delirium, such as statins, acetylcholinesterase-inhibitors, and ketamine due to their mechanisms of action and theorized pathophysiology of delirium, but none have had great success or are recommended.3 The possible exception is dexmedetomidine, which can be useful for delirium when trying to wean sedation, and it actually is recommended by the PADIS guidelines specifically for agitation preventing extubation (not for routine/general use for delirium).3 The focus then shifts back to anti-psychotics where the main controversy lies, as no agent is FDA-approved for the treatment of delirium. As stated earlier, this controversy was ramped-up by a change in the SCCM guidelines in 2018 not recommending their routine use, which is summarized in Figure 1.
There is an important caveat that is often overlooked, as the 2018 edition also states that “patients who experience significant distress secondary to symptoms of a delirium such as anxiety, fearfulness, hallucinations, or delusions, or who are agitated and may be physically harmful to themselves or others, may benefit from a short-term course of haloperidol or an atypical anti-psychotic”.3 That description paints a picture of hyperactive delirium, and so that is why it is important to distinguish the subtype when determining whether or not a patient would potentially benefit from therapy.
The reasoning behind the recommendation in Figure 1 is that the lack of proven benefit is out-weighed by the potential risk of harm/side effects. So then, the first question is one of efficacy, which can only properly be answered by looking at the available randomized controlled trials (not trials of other anti-psychotics vs. haloperidol). The PADIS guidelines cite four such trials behind their reasoning, and so we’ll combine those (with the one exception of a trial comparing olanzapine to haloperidol from 2004)9 with other available controlled trials to evaluate the efficacy of anti-psychotics for the treatment of delirium.
Randomized Controlled Trials for Anti-Psychotics
The first controlled trial was in 2010, and it is known as the MIND-ICU study.10 It was primarily designed to test the feasibility of a placebo-controlled trial answering this question, which in fairness, is not so easy given the population, setting, ethical considerations, and the subjective nature of delirium. It also set out to see if anti-psychotics, haloperidol or ziprasidone, had a positive effect on days alive without delirium or coma in mechanically ventilated surgical and medical ICU patients. Patients received either haloperidol 5 mg (n=35), ziprasidone 40 mg (n=30), or placebo (n=36) every 6 hours for up to 14 days. Patients were also allowed as needed haloperidol based on provider discretion. No significant differences were found across the above primary outcome (p=0.66) or secondary outcomes, including mortality, ventilator-free days, length of stay, and others. Thus, this is chalked-up as a study against anti-psychotic use, though the trial had notable limitations, with one being an issue of power/actual sample size. Less than half of the patients had an actual diagnosis of delirium based on the CAM-ICU (delirium diagnosis was not required for inclusion). Non-pharm strategies discussed above were not documented as well.
The next trial is also from 2010 and evaluated quetiapine for the treatment of delirium in the ICU.11 The primary outcome was time to first resolution of delirium, and secondary outcomes included time spent in delirium along with the secondary outcomes listed above for the MIND-ICU trial that are common in all of the trials mentioned here. Patients received quetiapine (n=18) 50 mg every 12 hours, titrated to a max of 200 mg per dose per provider discretion, or placebo (n=18) for a max of 10 days. Patients were also allowed to receive open-label as needed anti-psychotics (an order for as needed haloperidol was an inclusion criterion). The treatment group did exhibit a significantly shorter time to resolution compared to placebo (1 vs. 4.5 days, p=0.001) and patients spent less total and percentage of time spent in delirium (36 vs 120 hrs, p=0.006; 53% vs. 69%, p=0.02). This, as we’ll see, is a rare positive result, though the use of as needed haloperidol, the same lack of documentation of non-pharm strategies, and the very small sample size limit the conclusions we could draw about quetiapine.
The HOPE-ICU trial in 2013 was the next hopeful study to try its luck at this question.12 It’s objective was to see if haloperidol had an effect on delirium and coma-free days alive in the first 14 days of ICU admission. Patients were included if they were mechanically ventilated within the first 72 hours, but as with the MIND-ICU trial, baseline diagnosis of delirium was not required. Thus, this borders on evaluating prevention rather than treatment, but it is one of the studies cited by the PADIS guidelines against treatment. Our purely treatment population is likely somewhere within the total study population as well. Patients received IV haloperidol (n=71) 2.5 mg or placebo (n=70) every 8 hours for a max of 14 days, with doses being decreased (but not increased) per provider discretion. Once again, open-label haloperidol was allowed. There was not a significant difference in the primary outcome (p=0.53), though fewer patients in the haloperidol group exhibited agitation (13% vs. 18%, p=0.0075). Also, more patients in the placebo group received open-label haloperidol (8 vs. 18, 95% CI: 0.20-0.94). This was another strike against anti-psychotics with a larger sample size relative to its predecessors, though it was not without its limitations including the afore-mentioned question of prevention vs. treatment, the potential under-dosing of haloperidol, and the common limitations of the previous trials.
Flowing further through time brings us a study in 2015 by Michaud et al. looking at quetiapine again and its effect on the duration of hypoactive delirium in ICU patients.13 This is the one study included that was retrospective; patients were matched with a historical control. Hypoactive delirium was defined as a positive CAM-ICU and a RASS score of 0 to-3. 52 patients that received quetiapine during their ICU stay were matched with 61 patients without any pharmacologic treatment for delirium. The dosing regimen was not provided. The mean duration of delirium was found to be significantly shorter in the quetiapine group (1.5 vs. 2.0 days, p=0.04). Additionally, in the treatment group, if quetiapine was administered within 24 hours of delirium diagnosis, patients spent less time in delirium (1 vs. 3.5 days, p<0.001) and exhibited less time to extubation (1.5 vs. 5 days, p=0.003). This is a potential positive finding for the real population in question (hypoactive), and patients were excluded if they received any other pharmacologic treatment for delirium (no as needed haloperidol). However, the retrospective nature, small-sample size, and lack of a dosing protocol make this more hypothesis generating rather than definitive evidence for the efficacy of quetiapine.
The last and most recent randomized trial is the MIND-USA trial from 2018.14 This highly anticipated study was published after the 2018 update to the PADIS guidelines, and so we can use it to supplement their recommendations. Similar to the MIND-ICU study, it also evaluated the effect of haloperidol and ziprasidone on delirium and coma-free days alive. Patients received either IV haloperidol 2.5 mg (n=192), IV ziprasidone 5 mg (n=190), or placebo (n=184) every 12 hours for a max of 14 days. Doses were titrated per provider discretion up to 20 mg daily for haloperidol and 40 mg daily for ziprasidone, while patients greater than 70 years old received half of the initial and max dose. In keeping with the other trials for haloperidol, no significant differences were seen for any of the primary (p=0.26) or secondary outcomes. Regarding study design, this likely the strongest trial available, due to its larger sample size, standardization and documentation of ABCDE non-pharm interventions, and more practical dose titration strategies. It is not without limitations, though. Open-label as needed anti-psychotics were also allowed, and if you’re scratching your head at IV ziprasidone, you’re not alone (approved for PO and IM use). The investigators needed IND approval from the FDA for this route of administration, and the determination that IV Ziprasidone is half as potent as IV haloperidol is certainly debatable.
A table summarizing the findings of the above trials is located in the Appendix for your reference. Based on these results, coupled with the guideline recommendations, it would appear quality evidence is lacking that supports the use of anti-psychotics. Regarding haloperidol, this notion is further supported by a meta-analysis in 2019 which showed no benefit for any our adverse clinical outcomes.15 Use of quetiapine remains quite popular due to the 2013 PADIS guideline recommendation for atypicals based on the above positive data for quetiapine. Any time spent in delirium can be more than a hindrance to all involved, and so the possibility of reducing delirium even by just half a day can be attractive. Its use for delirium refractory to non-pharm interventions may be reasonable based on the above studies, especially if dosed at night time if the patient is having sleep/wake cycle disturbances, though the available evidence just isn’t quite strong enough to fully recommend the routine use of quetiapine.
The Problem with Anti-Psychotics
We’ve answered (or at least addressed) the question of efficacy, and so the question of safety or potential harm remains. Anti-psychotics are by no means benign, and some common adverse effects are listed in Table 6. This list is by no means exhaustive, and some agents are associated with greater frequencies or cause more serious adverse effects than others.
Some of these effects are more associated with long-term use, and so we typically wouldn’t be concerned with short-term treatment for delirium. However, one institution estimated that nearly half of their anti-psychotic naïve ICU patients received anti-psychotics, and 24% of them were prescribed at discharge.17 These results are similar in other studies,18 and while inappropriate continuation can and should be addressed by more systematic interventions, long-term effects could still be considered when initiating therapy.
QTc prolongation can happen in the short-term and is a common concern, especially in our critically-ill cardiac patients. What’s interesting is that in all of the trials discussed above, no differences in QTc prolongation, or any adverse effects for that matter, were seen compared to placebo. A retrospective chart review in 2018 replicated these results with quetiapine, showing a mean baseline increase of just 2 msec in patients that received quetiapine for delirium.19 So, while it is certainly possible, QTc prolongation may not be as much of a concern as previously thought, especially for quetiapine. However, another previously non-associated adverse event may exist for quetiapine use in ICU patients. Recently, the concern for pulmonary complications has arisen for short-term use, with one retrospective review showing an increase in these complications for critically injured trauma patients that received quetiapine for delirium, which included respiratory failure and aspiration, bacterial and ventilator-associated pneumonia.20
Conclusions and Future Directions
The incidence of delirium in critically-ill patients is associated with significant morbidity and mortality. What is not always focused-on is the serious short and long-term psychological toll this disease state can have on patients, families, and caregivers, and so we should and have taken measures to combat this issue. Patients in the ICU should be routinely screened using guideline-recommended tools, especially if they are at higher risk, such as the elderly, more severely-ill, and patients receiving medications associated with the induction of delirium.3 We can use proven and recommended non-pharm interventions (the ABCDE bundle) to prevent and treat delirium, though when this fails, we often turn to anti-psychotics to mitigate the above complications. However, as we’ve seen, there is an absence of quality data supporting the efficacy of anti-psychotics for delirium, while the actual risks of short-term use are not as evident as once thought and are still under debate.
There may still be hope for the future, though. Haloperidol has failed to show any benefit, but does that mean all anti-psychotics won’t? Unlike other classes of medications, these agents can vary widely in their receptor profiles in affinity and activity, and so the failure of one does not necessarily rule-out the efficacy of another. Two controlled trials discussed above have shown a potential benefit with quetiapine, and while the results may not be strong enough to recommend the routine use of quetiapine, they are certainly promising. As it so happens, a clinical trial, aptly named the HALOQUET trial, evaluating quetiapine or haloperidol against placebo is ongoing in Canada (NCT01811459, ClinicalTrials.gov), and so this study and further research can help us better evaluate this agent. Other agents could potentially be evaluated as well. For example, cariprazine is a newer anti-psychotic that has shown benefit for the treatment of negative symptoms of schizophrenia (cognition, disorganized thoughts, blunted affect, etc.), which largely mimic symptoms of hypoactive delirium.21 While investigation of this agent for delirium is currently unlikely due to cariprazine still being brand name (VraylarÒ) and therefore expensive, it’s possible this and similar agents could be evaluated or developed in the future. Once again, the main issue is the lack of large controlled trials, and so further quality research will be the only remedy to the practitioner’s own delirium regarding this debate.
By: Brooke Jacobson and Kyle Roof, PharmD Candidates 2021; UMKC School of Pharmacy
Mentor: Ekeni Livingston, PharmD, BCPPS; Children’s Mercy Kansas City
Managing patients in the pediatric intensive care unit (PICU) has evolved immensely over the years. While striving to successfully treat the patient’s underlying conditions, providers have often encountered consequences from their own interventions. The goals of caring for critically ill patients not only entails preventing mortality but also avoiding complications associated with prolonged stays in the PICU.1 Delirium is a common consequence addressed in the adult intensive care unit (ICU) population. Conversely, delirium in the pediatric population is often not addressed and rarely studied. The Diagnostic and Statistical Manual of Mental Disorders: Fifth Edition (DSM-5) characterizes delirium as an acute onset of fluctuating disturbances of consciousness, attention, cognition, and perception.2 According to multiple studies, delirium is associated with higher rates of increased hospital length of stay, long-term cognitive impairment, increased time on mechanical ventilation and mortality.1,3
Multiple proposed mechanisms exist to explain the manifestation of delirium in critically ill patients. The first mechanism is the predisposition of patient-related factors (e.g. age, genetics, underlying diseases) and the second is precipitating factors.1 Some examples of precipitating factors can include medications, metabolic dysfunction, progression of disease, and the stressful environment that is associated with a PICU stay.4 Prolonged use of sedatives and analgesics are often the predominant medications that contribute to delirium in the PICU. There are a few processes thought to contribute to delirium in the pediatric population.
The first process proposes an alteration in the blood-brain barrier’s (BBB) permeability secondary to a high prevalence of systemic inflammation.1,4 This leads to an increased production of cytokines and the transport of cytokines across the BBB resulting in ischemia and the destruction of neurons.1,4 The second hypothesis suggests an alteration of neurotransmitter regulation. Decreased levels of acetylcholine and increased levels of dopamine are likely the main contribution to delirium, however, the dysregulation of norepinephrine, serotonin, melatonin, gamma amino-butyric acid (GABA), histamine, and glutamate are also thought to play a role in the process.1,4 The last proposed hypothesis suggests a production of reactive oxygen species as a result of hypoxia and increased cerebral metabolism.1,4 Multiple studies have demonstrated that hypoxia in the intraoperative setting is associated with a reduction in cognitive function.1 The above proposed hypotheses give insight as to how delirium manifests in the pediatric population and can help determine possible treatment options.
Presentation and Screening
There are three main subtypes used to classify delirium in the PICU based on the patient’s presenting behaviors.5 Patients can be classified as hypoactive, hyperactive, or mixed-type delirium depending on the presence or absence of dopamine.5 Hypoactive delirium, the most common form, results from a significant deficiency of dopamine and is demonstrated in patients through a depressed level of consciousness and withdrawal from their environment.5 Unfortunately, hypoactive delirium rarely raises concern within the medical team and patients are often incorrectly categorized as non-delirious. Hyperactive delirium results from an excess of dopamine and triggers agitation, restlessness, emotional instability, and psychosis.5 Mixed-type delirium consists of the fluctuation between hypoactive and hyperactive states.5
Several tools have been created to assess delirium in PICU patients. One of the earlier tools created was the Pediatric Confusion Assessment Method for the Intensive Care Unit (pCAM-ICU). This tool assesses the clinical features of altered mental status, inattention, altered level of consciousness, and disorganized thinking.6 There are multiple limitations associated with the pCAM-ICU including but not limited to: requirement of patient cooperation, extensive nurse training, limitations in patients with developmental delay, and restricted use to children greater than 5-years-old.7 Another tool designed for the assessment of pediatric delirium is the Pediatric Anesthesia Emergence Delirium (PAED) screen.7 This screening tool only detects the hyperactive subtype of delirium which entails obvious limitations. Lastly, the Cornell Assessment of Pediatric Delirium (CAPD) screening tool is an adaptation of PAED. CAPD is a more ideal screening tool due to its additional components that allow detection of all three subtypes of delirium.6,7 Table 1 demonstrates the CAPD screening tool. Elements 7 and 8 allow the detection of both hypoactive and mixed-type delirium. Using this tool, a collective score of 9 or above indicates detection of delirium. Table 2 is included below to characterize the normal behavior of a developing child in the PICU environment.7
Risk factors for developing pediatric delirium include younger age, male gender, preexisting cognitive impairment, development delay, previous delirium, positive family history of delirium, and preexisting emotional and behavioral problems.4 While these factors are not adjustable, there are other non-pharmacological interventions that can help prevent and treat pediatric delirium. Environmental factors such as physical restraints, high noise levels, poor lighting, frequent staff changes, and disease entities may exacerbate delirium and are often associated with high mortality risk.4 Environmental interventions may be sufficient to manage pediatric delirium without the use of medications. These strategies include repeated reorientation by family or familiar nurse, calendars and clocks, pictures of family, familiar toys from home, maintaining bright light during the day and dimming light at night, keeping a regular routine, and minimizing noise levels.4 These strategies help decrease confusion and fear and ultimately decrease the risk and prevalence of delirium.
Delirium is most often related to the use of pain and sedation medications. This can include benzodiazepines, opioids, propofol, barbiturates, and ketamine.6 Utilization of these medications is often necessary as they are crucial for the comfort and care of the patient. However, reducing the dose of these medications whenever possible and using pain and sedation scoring tools [e.g. Faces, Legs, Activity, Cry and Consolidation (FLACC) tool and Richmond Agitation Sedation Scale (RASS)] to obtain an appropriate pain and sedation level is imperative.7 Daily sedation interruption or a “sedation holiday,” is an important element of PICU management. These interruptions not only reduce opioid and sedative exposure, but also orients the patient to time and place which can reduce delirium and delirium-associated complications.
The disruption of the sleep-wake cycle and alterations of sleep stages are prevalent in delirium.6 Benzodiazepines affect both the slow-wave and non-REM sleep.6 This might explain the mechanism by which this drug class causes delirium. Although an effective sedative class, multiple studies render benzodiazepines a high-risk medication for delirium and should carry limited use in critically ill patients and avoided in patients experiencing delirium. Because the circadian rhythm appears to be disrupted with high sedation and in the presence of delirium,4 this introduces a theory that melatonin may be reduced in critically ill patients.6 Kain et al,8 a randomized placebo-controlled double-blind trial, is a small study (n=140) that compared midazolam with melatonin for pre-operative anxiety (primary outcome), compliance with induction, emergence behavior, and parental anxiety (secondary outcomes). The study compared melatonin 0.05 mg/kg, 0.2 mg/kg, 0.4 mg/kg (max 20mg), and midazolam 0.5 mg/kg. Although midazolam demonstrated greater reduction in preoperative anxiety (p < 0.001), patients who received melatonin at higher doses demonstrated less emergence delirium than those who received midazolam (p < 0.05). It should be noted that this study only assessed short-term use of melatonin for emergence delirium. However, there might be a role for melatonin in the prevention of delirium in the PICU, but further studies are needed to make this claim.
The alpha-2 adrenergic agonists, dexmedetomidine and clonidine, are useful anxiolytic and sedative agents utilized in the pediatric population.6 These agents carry minimal risk for respiratory depression and have a decreased amnestic effects reducing the risk for delirium.6 Although dexmedetomidine is the only agent of the two that are approved for pediatric sedation, they are both widely used.6 Dexmedetomidine decreases the need for benzodiazepines, blunts the sympathetic stress response and catecholamine release, and may reduce the need for other sedatives.4 However, prolonged use of these agents can cause significant hemodynamic instability. Dexmedetomidine can be transitioned to clonidine for a continued, long-term alpha-2 agonist effect.4
Important aspects for the management of delirium are identifying the underlying cause and treating patients early. Delirium is typically multifactorial, and it is important to resolve the underlying cause while also avoiding agents that may worsen delirium. Most often, delirium will improve with management of the underlying illness, minimizing triggers, and optimizing the patient’s environment.1 However, if delirium persists, pharmacologic therapies should be used. As previously mentioned, one hypothesized delirium mechanism suggests that excessive dopamine and deficiency of acetylcholine contributes to delirium.9 As a result, antipsychotics, specifically atypical antipsychotics, are most often used for treatment. They relieve agitation, perceptual disturbance, sleep-wake cycle abnormalities, and behavioral abnormalities. In comparison with the earlier generations of antipsychotics, atypical antipsychotics have less extrapyramidal side effects and drug interactions.9 Antipsychotic therapy is used off-label as they are not approved by the Food and Drug Administration for treatment of delirium in adults or children.9
In a recent retrospective matched cohort study, the University of Maryland Children’s Hospital compared the use of antipsychotics versus no pharmacological interventions for the treatment of delirium in critically ill children.9 The most common antipsychotic drugs that were used were haloperidol, risperidone, and quetiapine. This study demonstrated that patients treated with antipsychotics had more delirium days (6 vs. 3, p=0.022), longer mechanical ventilation days (14 vs. 7, p=0.017), and longer PICU stay (34 vs. 16 days, p=0.029). However, although no significant differences were found, more patients requiring pharmacological treatment for delirium had previously been medicated with benzodiazepines (2 vs. 12), opioids (3 vs. 13), and dexmedetomidine (2 vs. 13) than with the untreated group.9 It is also important to note that the sample size for the study was 15 patients, and only 8 of 15 patients were treated on day 2 of diagnosed delirium.
Haloperidol, although a first generation antipsychotic, is frequently used in the adult population to treat hyperactive delirium in the ICU.5 Haloperidol is a dopamine antagonist that exerts its action in the brain to reduce hallucinations, anxiety, sedation, and restore attention.5 It has few anticholinergic and hypotensive side effects and is less sedating than other agents. However, due to its significant extrapyramidal and cardiac adverse effects it has been generally replaced by atypical antipsychotics with similar efficacy.6 Haloperidol is an option for patients with hyperactive delirium and/or requiring intravenous (IV) medication administration.9
Atypical antipsychotics such as risperidone, olanzapine, ziprasidone, and quetiapine are the most commonly used atypical antipsychotics in critically ill patients with delirium.5 This class of medication not only blocks dopamine, but also significantly blocks serotonin, norepinephrine, and acetylcholine.5 Due to the activity on additional receptors, they are generally more sedating and may cause tachycardia, hypotension, lower seizure threshold, and weight gain. Tukel SB, et al,10 compared the effectiveness and safety of olanzapine, risperidone, and quetiapine in pediatric patients with delirium. This was a retrospective descriptive study of 110 patients that concluded the following: the final Delirium Rating Scale-Revised-98 scores in pharmacologically treated patients were significantly lower than the original scores at diagnosis (p<0.001).10 The authors concluded that higher doses were needed when delirium was drug-induced. No significant adverse effects occurred.10 Although this study had many limitations, it is important to note that there were no differences between the effectiveness of antipsychotics, and no significant side effects were discovered in the study. Because side effects are still a concern, it is suggested to use antipsychotics for the shortest duration and smallest dose necessary in order to avoid unwanted side effects.10 Information about each medication is indicated in Table 3.
Delirium can cause severe and irreversible cognitive impairments if not appropriately addressed and managed. Although there is limited literature available, it is a rising area of concern due to its increasing incidence and poor outcomes. The morbidity of delirium may manifest as post-traumatic stress, depression, anxiety, and permanent changes in cognitive function.6 Despite high prevalence rates and concern for delirium, hesitation remains to embrace pharmacological therapy due to uncertainty of clinical diagnosis and lack of clear treatment options within available literature. This provides a clear need for additional studies for the treatment of delirium in critically ill pediatric patients.
By: Kathryn Renken, PharmD Candidate 2021 and Morgan Luttschwager Rose, PharmD Candidate 2022; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis
Mentor: Amanda Grapperhaus, PharmD, BCPS; SSM Health DePaul Hospital
According to the Centers for Disease Control and Prevention, of children age 3 to 17 years old in the United States, 7.1% have diagnosed anxiety and 3.2% have diagnosed depression. Following diagnosis, 78.1% of the children with depression and 59.3% of the children with anxiety received treatment.1 In adults, first-line treatment for both anxiety and depression is antidepressant medication from the drug class of selective serotonin reuptake inhibitors (SSRIs).2 In children, these drugs are often less helpful. When used in pediatric patients, antidepressants can cause a state of hyperarousal known as activation, which can cause an increase in activity, impulsivity, disinhibition, restlessness and insomnia.3 These symptoms typically occur following antidepressant initiation or dose changes, and they can be harmful. In a placebo-controlled study of fluoxetine, an SSRI, five out of seven pediatric patients experiencing these symptoms discontinued their medication as a direct result of these symptoms.4
The pathophysiology of antidepressant-induced activation is not fully understood, but there are many hypotheses that predict its pathway. Some predict that it is a variant of the manic phase of bipolar disorder, which is supported by the fact that patients with a family history of bipolar disorder are often more susceptible to experiencing activation. Others believe that some individuals are inherently more sensitive to the increased serotonergic tone in areas of the brain that regulate arousal that follows SSRI use, which can manifest itself as the classic symptoms of activation.3 No matter the source, pediatric antidepressant-induced activation is a serious problem in treatment of children with depression and anxiety.
Prevention of Activation
Some patients have a higher risk of antidepressant-induced activation based on factors including age, cytochrome P450 (CYP) polymorphism, and primary disorders, which cannot be changed. In addition, an individual's drug metabolism can lead to changes in bioavailability, drug concentration, and cumulative drug exposure, which also influences activation. There is an increased risk of activation in patients with the poor metabolizer polymorphism of CYP2D6 when CYP2D6 metabolizes the drug as it can cause a higher serum concentration of the drug. Increased activation with SSRIs can also occur when there are changes in serotonin transporter expression. For management of activation, use low doses of SSRIs with slow, planned titration to reduce the likelihood of the high rates of serum SSRI concentrations.5 Correct pediatric dosing and titrations can be accessed through the Clinical Practice Guidelines (e.g.: Guidelines for Adolescent Depression in Primary Care). Another way to reduce high serum concentration of SSRIs is to switch from immediate release to extended release, which will allow the drug to be released over a period of time. This will reduce the maximum drug concentration in the blood, reducing the risk of activation. Even with these strategies, activation may occur when increasing patient doses. Research has found that discontinuation of the medication and reinitiating at a lower dose can resolve the adverse effects.6
Currently, two SSRIs and one serotonin-norepinephrine reuptake inhibitor are FDA-approved for the treatment of major depressive disorder and generalized anxiety disorder in children, respectively. Escitalopram is approved for children ages twelve years old and older, while fluoxetine is approved for use in children ages eight years old and older. Duloxetine is approved for children ages seven years old and older. In addition, clomipramine, fluoxetine, fluvoxamine, and sertraline hold FDA indications for obsessive compulsive disorder in children, and an olanzapine with fluoxetine combination drug has an FDA indication for bipolar depression in children.7 These medications are less likely than other antidepressants to cause activation in children, which leads to their official labelled indication for use in children.
Management of Activation
When initiating a child on any antidepressant, it is important to closely monitor for symptoms of activation and to understand what to do if activation occurs. The guidelines recommend either face-to-face or telehealth appointments between the patient and prescriber regularly during initiation and dose changes to ensure that the patient is not getting clinically worse or experiencing adverse effects of the prescribed medication.8 Between appointments, parents should watch for symptoms of activation or suicidality. Researchers at the University of Florida have developed a screening tool for parents, called the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP), to use to monitor their children after starting antidepressant medication. This tool assesses activation across five different areas of symptoms, allowing parents to easily see if their child is displaying these symptoms and if this should be a cause for concern. The TEASAP has been shown to have internal consistency reliability, test-retest stability, concurrent validity, and predictive validity, even when conducted by parents.9
If a child taking antidepressants shows symptoms of activation, it is important to contact the prescriber to let them know about it. After that, there are a few different options for management. One of the most likely proposed causes of activation is a high blood concentration of the drug, so either decreasing the dose or changing to an extended-release rather than immediate-release formulation can help to relieve symptoms. Otherwise, discontinuing the drug and prescribing a new one at a low dose is appropriate; however, if a child shows activation symptoms with one antidepressant, then they are likely to experience these symptoms with other antidepressants.3,10 It is also important to assess medication adherence in children showing activation. Oftentimes, the symptoms of antidepressant withdrawal are similar to the symptoms of activation. Lastly, individual symptoms can be treated with other medications, such as treating insomnia with melatonin.