TY - JOUR
AU - Thomas, Michael, C
AB - Abstract Purpose To summarize recently published research reports and practice guidelines on emergency medicine (EM)–related pharmacotherapy. Summary Our author group was composed of 14 EM pharmacists, who used a systematic process to determine main sections and topics for the update as well as pertinent literature for inclusion. Main sections and topics were determined using a modified Delphi method, author and peer reviewer groups were formed, and articles were selected based on a comprehensive literature review and several criteria for each author-reviewer pair. These criteria included the document “Oxford Centre for Evidence-based Medicine – Levels of Evidence (March 2009)” but also clinical implications, interest to reader, and belief that a publication was a “key article” for the practicing EM pharmacist. A total of 105 articles published from January 2011 through July 2018 were objectively selected for inclusion in this review. This was not intended as a complete representation of all available pertinent literature. The reviewed publications address the management of a wide variety of disease states and topic areas that are commonly found in the emergency department: analgesia and sedation, anticoagulation, cardiovascular emergencies, emergency preparedness, endocrine emergencies, infectious diseases, neurology, pharmacy services and patient safety, respiratory care, shock, substance abuse, toxicology, and trauma. Conclusion There are many important recent additions to the EM-related pharmacotherapy literature. As is evident with the surge of new studies, guidelines, and reviews in recent years, it is vital for the EM pharmacist to continue to stay current with advancing practice changes. drug therapy, emergency medicine, key articles, pharmacist, review KEY POINTS This article provides a concise summary of relevant literature and guidelines organized by thematic clinical areas of importance for emergency medicine clinical pharmacy practice. This review includes 105 studies or practice guidelines chosen based on applicability to emergency medicine clinical pharmacy practice. This is a pharmacotherapy review of key articles and guidelines selected in a systematic way but does not include all pertinent literature from 2011 through July 2018. It is increasingly important for emergency medicine (EM) clinical pharmacists to stay current in medication therapies relevant to the EM population. This is especially difficult in a specialty like EM pharmacy as it encompasses many clinical practice areas. The goal of this publication is to provide a resource and summary of relevant primary literature and guidelines since the publication of a similar review of EM pharmacy key articles and guidelines in 2011.1 An author group of 14 EM pharmacists was convened to develop the following update. A list of major and minor topic areas was developed by the 2 lead authors, and the entire author group submitted suggestions. The author group used a modified Delphi method to determine the final major and minor topic areas. Twelve of the authors were available for voting and were asked to vote on each major and minor topic as “absolutely include” or “absolutely exclude.” Prior to voting it was determined that a score of 67% would determine inclusion and exclusion; this percentage was chosen as it represented 9 of 12 voting members. Those topics that did not receive a consensus through voting were then reconciled over a conference call with the author team. Following final selection of major and minor topics, each manuscript section was assigned an author and reviewer (both from the author team) to conduct a literature search and complete the summary. The author team developed methodology for literature selection; articles were selected based on the online “Oxford Centre for Evidence-based Medicine – Levels of Evidence (March 2009)” but also clinical implications, interest to the reader, and belief that this is a “key article” for the practicing EM pharmacist.2 Articles before 2011 were not considered, and preference was given to articles published in the last 5 years. Each author team was instructed to search for articles separately (search strategy determined by individual teams) and come to consensus on 2 key articles for each subsection. Additional articles could be considered by research leadership’s discretion. Following article review by the lead authors to ensure manuscript consistency, sections were developed and peer reviewed by the assigned authors following the group-determined author’s instructions. All literature and guideline selection, as well as development of each authored section, was performed with the input of multiple authors to minimize bias. ANALGESIA AND SEDATION Postintubation analgosedation Stephens et al. Analgosedation practices and the impact of sedation depth on clinical outcomes among patients requiring mechanical ventilation in the ED: a cohort study.3 In mechanically ventilated patients, deep sedation (ie, a Richmond Agitation and Sedation Scale [RASS] score of –3 to –5, with the latter indicating maximum sedation) during the first 48 hours of an intensive care unit (ICU) stay, has been associated with increased duration of mechanical ventilation and mortality. However, it was unclear if these data could be extrapolated to the ED setting. This was a secondary analysis of prospectively collected registry data that included 414 patients who required mechanical ventilation in the ED. The authors evaluated the association of deep sedation in the ED with hospital mortality. In multivariable logistic regression analysis, a higher vs a lower RASS score in the ED (ie, a median [range] score of –3 [–4 to –2] vs –4 [–4 to –3]) was associated with decreased mortality (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.63–0.94). In other words, deeper sedation was associated with increased mortality. Patients who were more deeply sedated also had fewer ventilator-, ICU-, and hospital-free days. The results suggest that lighter sedation may be preferred (even in the immediate postintubation phase) while patients remain in the ED. Given that this was a secondary analysis, RASS data were not consistently recorded, and the first ICU RASS score was used as a surrogate measure in some cases (it is unclear from the report how many cases). Since this study had an observational design, there was the possibility of unmeasured confounders. Patients with a lower RASS score in the ED may have had a higher propensity for death unrelated to medications administered or depth of sedation. This study is hypothesis generating but highlights the potential for harm with deep sedation even in the ED setting. EM pharmacist takeaway Deep levels of sedation in the ED are associated with increased mortality. Postintubation sedatives should be dose-titrated to achieve a lighter level of sedation in the ED. Devlin et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.4 These practice guidelines were developed with a focus on ICU patients. However, given that the early phase of critical care begins in the ED, the recommendations in these guidelines are important for EM clinicians. While a full summary of the guidelines cannot be covered here, there are a few key concepts that are worth mentioning. First, pain should be assessed routinely using a validated scale such as the Critical Care Pain Observation Tool or Behavioral Pain Scale. Analgosedation- or analgesia-first or -based sedation and multimodal analgesia (eg, acetaminophen, low-dose ketamine, neuropathic pain medications) should be maximized before a sedative agent is used. Intravenous (i.v.) opioids remain the mainstay of therapy. Sedation agents may predispose patients to increased mortality and, when used, should be routinely assessed using a scale such as the RASS or Sedation-Agitation Scale (SAS), which are considered to be most the valid and reliable. This is especially true in the ED setting, where formal pain and sedation assessment may be missed due to competing priorities during the initial phase of resuscitation and critical care. Light sedation with nonbenzodiazepines (eg, propofol, dexmedetomidine) may be preferred to benzodiazepine sedatives due to better outcomes. Compared with benzodiazepines, propofol and dexmedetomidine are both associated with reduced time to light sedation, reduced mechanical ventilation time, and decreased ICU length of stay (LOS). Among these agents, dexmedetomidine is associated with a lower prevalence of delirium. EM pharmacist takeaway Early ICU care commonly begins in the ED. Analgosedation is the preferred strategy and should be guided by validated assessment scales. These practice guidelines are particularly helpful to the EM pharmacist in advising on analgesia and sedation management in critical care. Opioid prescribing Barnett et al. Opioid prescribing by emergency physicians and risk of long-term use.5 It has been suggested that physician opioid prescribing behavior has contributed to the opioid epidemic in the United States. Emergency physicians are commonly at the front lines in terms of this patient-clinician interface. The authors evaluated a 20% random sample of Medicare beneficiaries with an index ED visit during a 3-year period (n = 377,629). All patients were opioid naive (ie, they had not used opioids in the previous 6 months) at the time of the ED visit. Physicians at each involved ED site were categorized into quartiles based on individual prescribing rates within the hospital. Physicians were labeled as “high-intensity” if they were in the top quartile or “low-intensity” if they were in the bottom quartile of prescribers at their institution. The primary outcome was long-term opioid use by patients, defined as 180 or more days of opioid use in the next 12 months. The multivariable analysis showed that long-term opioid use was significantly associated with high-intensity prescribers (OR, 1.3; 95% CI, 1.23–1.37; P < 0.001). Also, opioid prescribing was approximately 3 times more common for high-intensity vs low-intensity prescribers (24.1% vs 7.3%; P < 0.001). This was an observational study; thus, causality cannot be established. However, the 3-fold variation in prescribing patterns suggests that opioid overprescribing may be occurring, assuming that all physicians saw a similar case-mix of patients. This information, in conjunction with Centers for Disease Control and Prevention (CDC) data showing that approximately 16% of patients receiving more than a 1-week supply of opioids and 6% receiving a 1-day supply report continued use after 1 year, highlight an opportunity for EM pharmacists to help refine the opioid prescribing process at ED discharge.6 EM pharmacist takeaway Unnecessary opioid prescribing may occur for patients discharged from the ED, which may contribute to chronic opioid use. High-intensity prescribers contribute to this phenomenon. Jeffery et al. Opioid prescribing for opioid-naive patients in emergency departments and other settings: characteristics of prescriptions and association with long-term use.7 Pain is a common complaint of patients presenting to the ED, and it is anticipated that opioid prescribing will occur during the care of some of these patients. It is also known that short-term opioid use can contribute to long-term dependence.7 The ED may be a driver of such long-term dependency, especially if opioid prescribing is inappropriate. The authors used an administrative database (5.2 million opioid prescriptions) to compare opioid prescribing in the ED vs non-ED (eg, inpatient, outpatient, ambulatory surgery, dental) settings. Opioid-naive patients were included in the study cohort at the time of the index visit and were stratified into 3 groups by type of insurance and other characteristics: (1) commercially insured, (2) disabled with Medicare, and (3) aged with Medicare. Concordance of prescribing patterns with CDC guidelines was determined for ED and non-ED settings. The authors found that ED opioid prescribing was more likely to be adherent to the CDC guidelines with regard to prescribing for the shortest duration of therapy (ie, less than 3 days or less than 7 days), initiating therapy at the lowest possible dose (ie, less than 50 or 90 morphine milligram equivalents), and avoidance of long-acting opioids. Given the volume of data reported in the study, we do not report values here for each criterion and stratum. Notably, 40% of prescriptions for disabled Medicare beneficiaries in non-ED settings exceeded the 7-day limit, whereas less than 5% of ED prescriptions exceeded this same limit. Opioid prescriptions from the ED were half as likely to lead to long-term use as those originating from other settings. EM pharmacist takeaway While opioid prescribing practices can continue to be optimized in the ED setting, a comprehensive approach targeting all settings is important. Nonopioid analgesics Oliveira et al. Safety and efficacy of intravenous lidocaine for pain management in the emergency department: a systematic review.8 Lidocaine is commonly used as a local or topical anesthetic agent. It can also be given i.v. for pain control, which has been investigated in operating room settings for perioperative pain. This has led to interest in the use of lidocaine in the ED. This systematic review aimed to investigate literature pertaining to ED use of i.v. lidocaine for pain. The authors identified 6 randomized controlled trials (RCTs) and 2 case series that met their inclusion criteria. A meta-analysis was not conducted because of clinical heterogeneity. The studies had relatively small sample sizes (n = 13 to 120 in the intervention arms), and varying doses (eg, 1–2 mg/kg) were used for different indications (eg, migraine, renal colic, back pain, limb ischemia). The authors concluded that lidocaine may improve pain for renal colic and critical limb ischemia, but it may not be effective for migraine. Six of the studies reported on adverse effects, which included 19 nonserious adverse events (nausea, vomiting, dizziness, and lightheadedness) and 1 serious adverse event (seizure followed by bradycardia and cardiac arrest). The rate of any adverse event was 8.9% (95% CI, 5.5%-13.4%). Overall, these data were limited and 4 of 6 RCTs had unclear or high risk of bias. Most outcomes were focused on change in pain score (measured using a visual analog scale) and short-term efficacy (30–60 minutes [120 minutes in one study]). This systematic review provides a valuable summary of the state of the evidence for i.v. lidocaine for pain in the ED setting. One study published following this review investigated the need for opioid rescue following lidocaine i.v. for renal colic in the ED.9 Although there was no comparator group, 43% of patients (n = 86) received opioid rescue, but 17% returned to the ED within 7 days for a similar chief complaint. Adverse effects in this report and the systematic review should be noted. EM pharmacist takeaway Evidence for the use of lidocaine for pain in the ED setting is limited. Lidocaine may have some benefits in controlling pain related to renal colic or limb ischemia. Pathan et al. Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial.10 A recent Cochrane review evaluated nonsteroidal anti-inflammatory drugs (NSAIDs) and other nonopioids with regard to analgesia for renal colic and found NSAIDs to be an effective treatment but did not evaluate opioids. Another Cochrane review was inconclusive regarding the superiority of NSAIDS vs opioids for renal colic.11,12 The lack of conclusive results was related to deficiencies and variability in the studies. Pathan et al conducted the largest trial to date comparing analgesic options for the management of renal colic in the ED. The study was conducted in Qatar, where patients (n = 1,644) were randomly assigned 1:1:1 to receive intramuscular (i.m.) diclofenac 75 mg/3mL, morphine 0.1 mg/kg i.v., or paracetamol 1 g/100 mL i.v. The primary outcome was a 50% reduction in pain, as measured on a standard 0 to 10 numerical pain rating scale (NRS), at 30 minutes. This outcome was achieved in 68% of patients with diclofenac, in 61% of patients with morphine, and in 66% of patients with paracetamol, showing an advantage of diclofenac over morphine (OR, 1.35; 95% CI, 1.05–1.73; P = 0.0187). There were also lower numbers of adverse effects with diclofenac and paracetamol compared to morphine. It is unclear if these results can be extrapolated to ketorolac, which is more commonly used in the United States, but the study shows the potential benefit of NSAIDS compared to opioids for this indication. EM pharmacist takeaway NSAIDS may be used as an alternative to opioids for renal colic in the ED. Motov et al. Comparison of intravenous ketorolac at three single-dose regimens for treating acute pain in the emergency department: a randomized controlled trial.13 Ketorolac is a commonly used pain medication in the ED setting, but the optimal dose is unclear. In this study, patients with renal colic (n = 240) were randomly assigned 1:1:1 to 3 different doses of i.v. ketorolac (10 mg, 15 mg, and 30 mg). The primary outcome was pain reduction at 30 minutes, as measured using an NRS. The mean NRS scores improved by 2.5, 2.4, and 3.0 points in the 3 groups, respectively, none of which improvements were statistically different. The rates of use of rescue analgesia and of adverse events were similar between groups. The follow-up duration was insufficient to identify occurrence of drug-induced renal impairment or gastrointestinal (GI) bleeding. The results suggest that lower doses of ketorolac can be used, especially for at-risk patients (eg, the elderly or those with preexisting renal impairment), without loss of analgesic effect. The findings challenge the current paradigm regarding the need for a standard 30-mg i.v. dose for adults. EM pharmacist takeaway Ketorolac i.v. may have a ceiling dose of 10 mg when used for renal colic in the ED. Pain in pediatrics Le May et al. Oral analgesics utilization for children with musculoskeletal injury (OUCH Trial): an RCT. 14 Children commonly present to the ED with musculoskeletal injuries, and there is a lack of evidence regarding the optimal approach to pain management in these patients. The authors hypothesized that the combination of morphine and ibuprofen would be more effective than either drug alone. Children 6 to 17 years of age (n = 501) with musculoskeletal injuries involving an upper or lower limb were randomly assigned 2:2:1 to receive oral morphine (0.2 mg/kg) in combination with oral ibuprofen (10 mg/kg), oral morphine (0.2 mg/kg) alone, or ibuprofen (10 mg/kg) alone. The primary outcome was a pain score of less than 30 mm on a visual analog scale 60 minutes after drug administration. Approximately one-third of patients in each group achieved this primary outcome, suggesting that all regimens were inadequate. There were no significant differences between groups in terms of efficacy. However, patients who received morphine with or without ibuprofen were more likely to have adverse effects such as nausea, abdominal pain, and drowsiness (2%-6% of patients). No serious adverse effects were reported. The results bring to light that optimal pain management in this patient population is challenging. Future studies are needed to determine drug therapy combinations that may be more effective. The authors describe the potential for using intranasal fentanyl (to achieve a more rapid effect) combined with an NSAID or opioid for sustained analgesia. However, this requires investigation. EM pharmacist takeaway The combination of oral ibuprofen and oral morphine was not superior to either agent alone for acute pain in children with musculoskeletal injuries. Ibuprofen without morphine appears to have the least adverse effects. Sin et al. The use of intranasal analgesia for acute pain control in the emergency department: a literature review.15 The intranasal route provides a painless route of drug administration, with relatively rapid onset of effect, especially for lipophilic analgesics. This is advantageous when i.v. access is not available. Although this article is not specific to pediatric patients, it has great implications for analgesia in the pediatric patient population, in which i.v. access is often undesirable. The literature review identified 11 RCTs involving intranasal analgesia in the ED as the primary analgesic. Of these RCTs, 6 involved pediatric patients. The review included studies comparing intranasal fentanyl (1.4 µg/kg) vs i.v. morphine (0.1 mg/kg), intranasal fentanyl (1 µg/kg) vs i.m. morphine (0.2 mg/kg), and intranasal fentanyl (2 µg/kg) vs intranasal normal saline in combination with either i.v. morphine (0.1 mg/kg) alone or i.v. hydromorphone (0.015 mg/kg) with i.v. ketorolac (0.5 mg/kg). This article also included a study of intranasal ketamine (1 mg/kg) vs i.v. morphine (0.1 mg/kg). The trials were heterogeneous in terms of patient population, indication, agent used, and dose. Sample sizes ranged from 29 to 404 patients. In 4 trials, greater reductions in pain scores with use of intranasal analgesia were reported, but these reductions were transient and other trials showed either no difference or superiority with a comparator route. EM pharmacist takeaway There is conflicting evidence with regard to the effectiveness of intranasal analgesia use in the ED. However, this may be an option when a rapid analgesic effect is needed and i.v. access cannot be obtained. ANTICOAGULATION Bleeding and reversal Tomaselli et al. 2017 ACC Expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.16 This guideline, formatted as a concise decision pathway, provides updated recommendations in the management of patients with bleeding due to oral anticoagulants, including direct-acting oral anticoagulants (DOACs) and vitamin K antagonists (VKAs). A practical approach to every stage of patient care with oral anticoagulant–related bleeding, including bleeding classification, laboratory assessment, reversal strategies, and considerations for restarting anticoagulation therapy, is presented. Reversal agents discussed in the context of VKA therapy include fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), and vitamin K. A proposed treatment algorithm for VKA-associated bleeding recommends 4-factor PCC (4F-PCC) as a first-line reversal agent. Several dosing schemes for PCC exist; however, this guideline recommends the US Food and Drug Administration (FDA) dosing strategy requiring patient weight and pretreatment determination of International Normalized Ratio (INR). The efficacy of this dosing strategy was verified in a study that demonstrated similar or improved outcomes with 4F-PCC compared to FFP in patients with major bleeding while receiving VKA therapy.17 Alternatively, this guideline also suggests low fixed doses of 4F-PCC (1,000 units for major bleeding or 1,500 units for intracranial hemorrhage [ICH]) in lieu of the FDA-approved dosing scheme. Idarucizumab is recommended for dabigatran-associated coagulopathy. The RE-VERSE AD trial recruited patients receiving dabigatran who had uncontrolled bleeding (group A) or required emergent invasive procedures (group B).18 In group A, bleeding cessation was achieved in a median of 2.5 hours. Normal periprocedural hemostasis was seen in 93.4% of patients in group B. Rates of thrombotic events in both groups were low (6.3% and 7.4%, respectively), with 90-day mortality rates of 18.8% and 18.9%, respectively. For cases of acute bleeding, this guideline also suggests additional consideration of hemodialysis in patients with impaired renal function. Activated charcoal may be used if dabigatran was ingested within the previous 2 to 4 hours. Prior to FDA approval of andexanet alfa in May 2018, there were no specific reversal agents for factor Xa inhibitors. To treat factor Xa inhibitor–related bleeding, PCC was suggested; activated PCC (eg, FEIBA) may also be considered. Unfortunately, supporting data for PCC for this indication is limited to preclinical data, observational case series, and case reports. Ciraparantag (PER977), a small water-soluble molecule capable of binding factor Xa and thrombin inhibitors through noncovalent bonding, is currently undergoing trials in healthy volunteers. The decision of whether to restart anticoagulation requires caution in determining risk and benefit. Subsequently, the optimal time to restart anticoagulation varies according to bleed location and clinician discretion. EM pharmacist takeaway 4F-PCC is recommended as first-line therapy for VKA-associated bleeding, although the optimal dose is not clear. Idarucizumab is recommended for dabigatran reversal and PCC for factor Xa inhibitor reversal; however, these recommendations were made prior to andexanet alfa availability. Connolly et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors (ANNEXA-4).19 Until recently, a specific reversal agent for factor Xa inhibitors did not exist. Trials in healthy, older volunteers using the recombinant human factor Xa decoy andexanet alfa have demonstrated near-complete reversal of anti-Xa activity and restoration of endogenous thrombin potential.20 This was a prospective, multicenter, open-label, single-group study evaluating andexanet alfa in patients with acute major bleeding (interim report published in 2016). Two hundred fifty-four patients who received a dose of apixaban, rivaroxaban, edoxaban, or enoxaparin (1 mg/kg/d) within the previous 18 hours and presented with acute major bleeding were evaluated in the efficacy analysis, which had 2 coprimary endpoints: percent change in anti–factor Xa activity and rate of excellent or good hemostasis at 12 hours. Andexanet alfa was administered as a bolus over 15 to 30 minutes, followed by a 2-hour infusion. Patients who took a DOAC more than 7 hours prior received a 400-mg bolus followed by a 480-mg infusion, and those who took a DOAC within 7 hours (or at an unknown time of ingestion) or enoxaparin received an 800-mg bolus and a 960-mg infusion. Anti–factor Xa activity decreased 92% after andexanet alfa administration for apixaban or rivaroxaban reversal. In 16 patients who had major bleeding due to enoxaparin use, anti–factor Xa activity decreased 75% following andexanet alfa administration. Similar to reported experience in healthy volunteers,20 anti–factor Xa activity began to increase upon completion of the infusion dose, raising questions of rebound/redistribution phenomenon. At 4, 8, and 12 hours after infusion, median anti–factor Xa activity in patients taking apixaban and those taking rivaroxaban was reduced from baseline by 32% and 42%, 34% and 48%, and 38% and 62%, respectively. Hemostatic efficacy was achieved in 249 patients (82% of evaluated cases). At 30 days thrombotic events had occurred in 10% of patients (18% of those included in the interim report). The authors concluded that andexanet alfa rapidly reverses anti–factor Xa activity and was not associated with serious adverse effects. There are many questions regarding the optimal indications, dosing scheme, and administration strategies, as well as efficacy, safety, and cost. Patients undergoing emergent procedures requiring anticoagulation reversal were not included, nor were patients who had edoxaban-related bleeding, and it is unknown what dose may be appropriate for these indications. Additionally, patients presenting more than 18 hours since their last DOAC dose were not included; however, DOAC activity persists beyond this time frame, especially in elderly patients and those with renal insufficiency, and may require reversal. Currently, the efficacy, safety, and optimal dose of andexanet alfa in this population are unknown. The absence of a control group prevented evaluation of the rebound/redistribution phenomenon of unbound anti–factor Xa inhibitor or understanding if previous guideline recommendations of PCC use (at approximately one-tenth of the cost of andexanet alfa) are noninferior. There is no mention of what occurred in patients with refractory bleeding, and it is unknown if repeat doses or lengthening the infusion may be necessary or the impact this may have on an already high thromboembolic event rate. Lastly, there are logistical issues regarding the timely preparation of the bolus and infusion (eg, several vials are required for preparation, bolus and infusion can be administered from either 1 or 2 infusion bags) and overall administration that need to be addressed before use at individual institutions. EM pharmacist takeaway: Andexanet alfa quickly reduces anti–factor Xa activity in patients taking rivaroxaban, apixaban, or enoxaparin. Despite an early rebound effect in terms of anti–factor Xa concentrations, hemostatic efficacy at 12 hours was good or excellent in 82% of patients. Currently, the efficacy of andexanet alfa and the appropriate dosing strategy for patients who require DOAC reversal for an emergent procedure, have edoxaban-related bleeding, or received the last DOAC dose more than 18 hours ago are unknown. It is also unclear if a reversal strategy with andexanet alfa is superior to a supportive strategy using PCC for factor Xa inhibitor–associated bleeding. CARDIOVASCULAR EMERGENCIES Acute coronary syndrome O’Gara et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction (STEMI): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.21 Amsterdam et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes (NSTEMI): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.22 These guidelines were developed in collaboration with the American College of Emergency Physicians (ACEP) as updates or full revisions to previous 2009 STEMI and 2007 unstable angina/NSTEMI versions. A large emphasis is placed on reperfusion therapy, time-to-treatment goals, and evidence-based antithrombotic therapies for the management of STEMI. Primary percutaneous coronary intervention (PCI), with a “door-to-balloon” goal of 90 minutes or less, remains the recommended method of reperfusion. Aspirin 162 to 325 mg and a loading dose of a P2Y12 inhibitor (eg, clopidogrel 600 mg, ticagrelor 180 mg, or prasugrel 60 mg [harm associated with use in patients with history of prior stroke/transient ischemic attack]) is recommended prior to primary PCI. Although i.v. glycoprotein IIb/IIIa receptor antagonists (eg, abciximab, eptifibatide) and anticoagulation with unfractionated heparin (UFH) or bivalirudin (fondaparinux is not recommended due to a risk of catheter thrombosis) are often initiated in the cardiac catheterization laboratory, these recommendations are discussed and EM pharmacists should be familiar with the indications and dose. Fibrinolytic therapy should be administered to patients with STEMI and ischemic symptoms within 12 hours of onset at non–PCI-capable centers when no contraindications exist and time to PCI will exceed 120 minutes (this is classified as a strong recommendation based on high-quality evidence). Fibrin-specific agents like tenecteplase and alteplase are recommended, but ease of preparation and administration should be considered with agent selection as the “door-to-needle” time goal is 30 minutes or less. Aspirin 162 to 325 mg, clopridogrel (300 mg for patients 75 years of age or younger or 75 mg for those over age 75), and anticoagulation (with UFH, low-molecular-weight heparain [LMWH], or fonaparinux) should be administered with fibrinolytic therapy. For patients presenting with NSTEMI, the guideline discusses the place in therapy of medications foundational to the baseline knowledge of an EM pharmacist, including nitrates (sublingual or i.v.); analgesics (i.v. morphine), including contraindications to NSAIDs [except aspirin]); and antiplatelet (aspirin plus clopidogrel or ticagrelor) and anticoagulant (LMWH [level A evidence], bivalirudin, fondaparinux, or UFH [all level B evidence]) therapies. Of further importance, EM pharmacists should be aware of 2 treatment pathways for NSTEMI—ischemia-guided and early invasive strategies (ie, coronary angiography)—and understand how medication recommendations differ for each pathway. EM pharmacist takeaway In patients with STEMI, the door-to-balloon goal is 90 minutes or less for primary PCI; when fibrinolytic therapy is used as the primary reperfusion strategy, the door-to-needle time goal is 30 minutes. Aspirin, antiplatelet, and anticoagulation therapies are recommended for patients with STEMI undergoing primary PCI or fibrinolytic reperfusion and in the management of patients with NSTEMI. Pu et al. Efficacy and safety of a pharmaco-invasive strategy with half-dose alteplase vs primary angioplasty in ST-segment-elevation myocardial infarction: EARLY-MYO Trial (Early routine catheterization after alteplase fibrinolysis vs primary PCI in acute ST-segment-elevation myocardial infarction).23 This prospective, multicenter, randomized, parallel-group, open-label noninferiority trial compared a pharmaco-invasive strategy vs routine primary PCI in patients with STEMI presenting no more than 6 hours after symptom onset and with an expected PCI-related delay of ≥60 minutes. The pharmaco-invasive strategy consisted of half-dose alteplase (an 8-mg bolus followed by 42 mg over 90 minutes) and UFH (60 units/kg followed by 12 units/kg/h) with routine PCI to be performed 3 to 24 hours after alteplase administration. The primary outcome was complete epicardial and myocardial reperfusion after PCI. Key safety outcomes were the incidence of major bleeding and the incidence of ICH. Across 7 Chinese centers, 171 patients were treated via the pharmaco-invasive strategy and 173 patients underwent primary PCI. The pharmaco-invasive strategy resulted in a higher rate of complete reperfusion than the PCI strategy (34.2% vs 22.8%), a difference that was significant for both noninferiority and superiority. At 30 days, there was no significant between-group difference in rates of major bleeding events (0.6% vs 0%) or ICH (0% in both), but minor bleeding was more frequent in the pharmaco-invasive group (26.9% vs 11.0%). Limitations of this trial included low external validity related to the study population, the fibrinolytic agent used, and the very specific inclusion criteria (ie, short time to STEMI presentation and age of ≤75 years). It is important to note that the methodology of this study was consistent with 2013 ACCF/AHA guidelines on the management of STEMI in cases involving an expected PCI-related delay of ≥60 minutes; that the novel strategy of half-dose alteplase therapy, when compared with primary PCI, was similarly effective; and that the pharmaco-invasive strategy resulted in lower rates of major bleeding and ICH than full-dose tenecteplase therapy for STEMI.24 EM pharmacist takeaway: A pharmaco-invasive strategy of half-dose alteplase therapy followed by PCI within 3 to 24 hours was found to have efficacy similar to that of PCI, with low rates of major bleeding and ICH. This may be a promising reperfusion strategy, as bleeding rates were less than those reported with use of full-dose tenecteplase for STEMI. Venous thromboembolism Kearon et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.25 This guideline provides an update of 2012 recommendations on the management of venous thromboembolism (VTE). While many recommendations remain unchanged, such as those regarding the duration of anticoagulation therapy for provoked and unprovoked deep vein thrombosis (DVT) of the leg or pulmonary embolism (PE), several new recommendations were generated. The most notable changes involve increased utilization of DOACs. Dabigatran, rivaroxaban, apixaban, and edoxaban are now considered first-line therapies for use in preference to warfarin or VKAs and LMWH in noncancer patients with VTE (a grade 2B recommendation). For low-risk patients with PE, initiation of treatment at home is now recommended (a grade 2B recommendation); the previous guideline suggested treatment initiation during an inpatient hospital stay, with early discharge. Aspirin is now suggested to prevent recurrent VTE when anticoagulation is being discontinued for treatment of unprovoked VTE (a grade 2B recommendation). In cases of recurrent VTE in compliant patients receiving VKA or DOAC therapy, it is suggested that therapy be switched to LMWH temporarily. Patients with recurrent VTE receiving LMWH may be considered for a dose increase of one-quarter to one-half of their current dosage. Both of these recommendations are hindered by poor supporting evidence (ie, they are grade 2C recommendations). While data quality has improved overall since the last guideline update, the guideline authors note that none of their 54 recommendations were based upon high-quality evidence. The current recommendations highlight the increasing use of DOACs to treat VTE in cases in which VKA therapy was previously recommended. EM pharmacist takeaway VTE management continues to evolve, with an increased role for DOACs now recommended. DVT and low-risk PE can be managed in the outpatient setting without the need for a short term admission for anticoagulation initiation. Hao et al. Thrombolytic therapy for pulmonary embolism.26 There is continued controversy surrounding use of thrombolytic therapy routinely for submassive or intermediate-risk PE due to mixed reports regarding outcomes (short- and long-term) and associations with an increased risk of bleeding. This systematic review and meta-analysis (an update of a review published in 2009) included 17 RCTs (11 focused on submassive PE, 1 focused on massive PE, and 5 focused on PE of unknown severity; n = 2,167 patients in total) comparing thrombolytic therapy plus heparin use vs control treatments (heparin alone, heparin plus a placebo, or surgical intervention) in patients with acute PE. Relative to control treatments, thrombolytic therapy plus heparin use reduced the odds of death (OR, 0.57; 95% CI, 0.37–0.87) and recurrence of PE (OR, 0.51; 95% CI, 0.29–0.89); however, these differences were not statistically significant after sensitivity analysis excluding 4 studies deemed to involve a high risk of bias (OR for death, 0.66; 95% CI, 0.42–1.06). As expected, the incidences of major and minor hemorrhagic events were higher in the thrombolytic therapy groups (pooled ORs, 2.90 [95% CI, 1.95–4.31] and 3.09 [95% CI, 1.58–6.06], respectively). The authors concluded that compared with heparin alone, thrombolytics reduce death following acute PE, but they acknowledged that their conclusion was based on low-quality evidence because of several important design limitations, the possible influence of pharmaceutical companies, and small sample sizes in the included RCTs. Furthermore, thrombolytic therapy approaches evaluated in this review were heterogeneous (eg, different thrombolytic drugs and dosing strategies were used). Overall, there is consensus that patients with massive PE should receive thrombolytics, but the severity of submassive PE varies widely, and specific patient characteristics and presentation need to be evaluated by the interdisciplinary clinical team to determine the appropriateness of thrombolytic use. EM pharmacist takeaway Based on low-quality evidence, it appears that thrombolytic therapy vs heparin alone for treatment of acute PE may reduce the likelihood of death and recurrent PE but with a greater risk of hemorrhagic events. Patient-specific characteristics and evaluation of risks and benefits should be considered in determining appropriateness of thrombolytic therapy in the context of PE. Meyer et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism.27 Konstantinides et al. Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism.28 Pulmonary embolism treatment is an approved indication for alteplase only, but alteplase administration is complicated by admixing, continuous-infusion administration over several hours, and different dose strategies (bolus with continuous infusion, continuous infusion alone, and half-dose therapy). Tenecteplase is desirable since it can be administered as a single weight-based bolus over 5 seconds. The publication by Meyer et al27 reports results from the Pulmonary Embolism Thrombolysis (PEITHO) trial, a multicenter, double-blind, placebo-controlled randomized trial of normotensive adult patients with acute PE, right ventricular (RV) dysfunction confirmed by computed tomography or echocardiography, and a positive cardiac troponin result. Patients at 76 study sites were randomly assigned to receive tenecteplase (n = 506) or a placebo (n = 499). All patients received heparin following tenecteplase or placebo administration. Although there was an improvement in the composite outcome of death or hemodynamic compensation at 7 days with tenecteplase vs placebo use (odds of outcome event, 2.6% vs 5.6%; OR, 0.44; 95% CI, 0.23–0.87; P = 0.02), there was no significant between-group difference in terms of the death rate at 30 days and a significant increase in the rate of major bleeding within 7 days with tenecteplase use (11.5% vs 2.4%, P <0.001). Overall this study showed improvement in short-term outcomes with tenecteplase use, but those benefits came with an increased risk of bleeding events. The publication by Konstantinides et al28 reported results of a long-term follow-up evaluation of PEITHO trial participants across 28 of the 76 study sites: 353 patients in the tenecteplase group and 343 patients in the placebo group (median follow-up, 37.8 months). At long-term follow-up, there were no significant between-group differences in mortality rates (20.3% and 18.0%), rates of persistent dyspnea or functional limitation (36.0% and 30.1%), and rates of residual pulmonary hypertension or RV dysfunction (44.1% and 36.6%). Overall, thrombolytic therapy did not affect long-term mortality rates, and approximately 33% of patients reported some degree of persistent functional limitation after intermediate-risk PE. The study conclusions are limited with respect to rates of pulmonary hypertension or RV dysfunction because only 290 of 696 patients completed follow-up echocardiography examinations. These findings provide the highest-quality data available to assess long-term outcomes in patients treated with thrombolytics for intermediate-risk PE. EM pharmacist takeaway Thrombolytic therapy with tenecteplase for intermediate-risk PE resulted in improvement of short-term outcomes but higher rates of major bleeding at 7 days. Long-term mortality did not differ with thrombolytic vs placebo use, and about a third of patients had persistent functional limitations. Sharifi et al. Pulseless electrical activity in pulmonary embolism treated with thrombolysis (from the “PEAPETT” study).29 There have been many retrospective and prospective reports of alteplase and tenecteplase use during cardiac arrest for presumed myocardial infarction (MI) or PE, with researchers reporting mixed outcomes related to return of spontaneous circulation (ROSC), survival to hospital admission and discharge, and favorable neurologic outcomes. The largest prospective, multicenter, randomized trial evaluating tenecteplase vs placebo use in out-of-hospital cardiac arrest (OHCA) found no difference in favorable outcomes but was limited, like most previous relevant studies, in that patients included had undifferentiated cardiac arrest and there were long intervals from collapse to thrombolytic administration.30 This report describes 23 patients with pulseless electrical activity (PEA) and confirmed PE (reduced right and left ventricular ratios and pulmonary artery systolic pressures) who received alteplase 50 mg by i.v. push over 1 minute (mean [SD] time to administration, 6.5 [2.1] minutes) and had ROSC.29 Two patients died in the hospital, and 87% were alive at a mean 22-month follow-up. No patients had bleeding complications despite chest compressions. Although this study was limited by its retrospective design, small size, and lack of formal assessment of quality of life or neurologic outcomes, it is hypothesis generating (ie, there may be a subset of patients with confirmed PE for whom quick administration of thrombolytics may be beneficial). EM pharmacist takeaway Based on very limited evidence, it might be that patients with cardiac arrest and confirmed PE and subsequent PEA could benefit from early administration of thrombolytics (ie, administration within minutes from loss of pulses). Arrhythmias Al-Khatib et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary.31 This guideline, an update of a 2006 guideline, provides recommendations for the management of adults who have ventricular arrhythmia or are at risk for sudden cardiac death and includes diseases and syndromes associated with this occurrence. Three sections of particular importance to EM pharmacists are those pertaining to medication therapy, acute management of specific ventricular arrhythmias, and medication-induced arrhythmias. There is no evidence from RCTs to demonstrate that any antiarrhythmic medications given for ventricular arrhythmia, with the exception of β-adrenergic blockers, improve survival when used for primary or secondary sudden cardiac death prevention. However, sodium channel blockers, amiodarone, sotalol, calcium channel blockers (CCBs), and electrolytes may improve symptoms and control arrhythmias, but individual medication risks should be assessed (risks are described in the guideline). The guideline recommends that amiodarone be administered for unstable ventricular arrhythmia refractory to shock and procainamide therapy (this recommendation is based on higher-level evidence); amiodarone or sotalol can be administered for stable ventricular tachycardia (VT). In patients with polymorphic VT due to MI or with recent MI and VT/VF (ventricular fibrillation) storm (ie, recurrent VT/VF despite cardioversion and antiarrhythmic medications), i.v. β-blockers are recommended. Interventions providing no benefit include high-dose epinephrine (i.v. boluses of >1 mg) in cardiac arrest and i.v. magnesium in refractory VF not related to torsades de pointes. It should be noted that prophylactic use of lidocaine or high-dose amiodarone for prevention of VT in suspected MI, as well as use of CCB for wide-QRS-complex tachycardia of unknown origin, is potentially harmful. Lastly, there is high-quality evidence to support use of digoxin antibodies in sustained ventricular arrhythmia due to digoxin toxicity; i.v. magnesium in patients with medication-induced QT prolongation, hypokalemia, hypomagnesemia, or torsades de pointes; and i.v. isoproterenol to increase the heart rate (HR) in recurrent torsades de pointes with QT prolongation and bradycardia that cannot be suppressed with i.v. magnesium. EM pharmacist takeaway Beta-blockers are efficacious and safe for treating ventricular arrhythmias and reducing the risk of sudden cardiac death. Amiodarone is recommended for unstable ventricular arrhythmias, whereas stronger evidence supports use of procainamide in patients with stable wide-complex tachycardias. Magnesium should be used for torsades de pointes or QT prolongation resulting from electrolyte abnormalities or medication use, but there is no evidence for its use in refractory VF unrelated to torsades de pointes. Page et al. 2015 ACC/AHA/HRS guidelines for the management of adult patients with supraventricular tachycardia: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.32 These guidelines were developed through collaboration by the American College of Cardiology (ACC), American Heart Association (AHA), and the Heart Rhythm Society (HRS) and update guidelines published in 2003. Supraventricular tachycardia (SVT) is an umbrella term defined by the guidelines as any atrial and/or ventricular tachycardia greater than 100 beats per minute at rest and involving tissue from the His bundle or above. However, in this guideline SVT does not include atrial fibrillation (AF), which is addressed in the 2014 AHA/ACC/HRS guideline on AF management (summarized below).33 Main updates include clear treatment algorithms for each type of SVT (for both acute and chronic management), recommendations on managing Wolff-Parkinson-White syndrome, and considerably more detail on pharmacologic treatment options for each type of SVT. Acute management of regular SVT of unknown mechanism continues to consist of vagal maneuvers and/or adenosine first, followed by i.v. β-blockers, diltiazem, or verapamil (if the patient is hemodynamically stable) and then synchronized cardioversion if those agents are ineffective or the patient is hemodynamically unstable. Dose, frequency, adverse effects and other considerations in use of these agents as well as digoxin, amiodarone, and ibutilide for ongoing management are detailed. Notably, classifications of recommendations and level of evidence for medication use in the management of each type of SVT are often not high, and the evidence cited is often extrapolated from AF outcomes data or data regarding specific disease states such as heart failure. EM pharmacist takeaway Vagal maneuvers and/or use of adenosine followed by use of i.v. β-blockers or diltiazem are recommended for patients with hemodynamically stable regular SVT. Synchronized cardioversion should be used if a patient is hemodynamically unstable or if SVT is refractory to other interventions. January et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.33 This update of a 2011 guideline focuses on the management of AF, specifically rate and rhythm control recommendations. Use of β-blockers or an i.v. nondihydropyridine CCB is recommended (a strong recommendation based on moderate-quality evidence) to slow ventricular HR in hemodynamically stable rapid AF (neither medication class is favored over the other). Hemodynamically unstable patients should undergo electrical cardioversion. Patients with decompensated heart failure should not receive a nondihydropyridine CCB whose use can lead to further hemodynamic compromise; in those with pre-excitation and AF, digoxin, nondihydropyridine CCBs, and amiodarone can increase ventricular response and result in VF and therefore should not be used. If electrical cardioversion is necessary, anticoagulation should be administered even if the patient has a low thromboembolic risk. If AF has been present for less than 48 hours, administration of UFH, LMWH, or a DOAC is recommended immediately before and after cardioversion. If AF has been present for 48 hours or more, longer periods of anticoagulation before and after cardioversion would be ideal but are not possible if immediate cardioversion is necessary; in this case, anticoagulation should be administered as soon as possible before cardioversion. In the absence of medication-related contraindications, flecainide, dofetilide, propafenone, and i.v. ibutilide are given the highest recommendation for pharmacological cardioversion. EM pharmacists should be aware that the guideline contains further recommendations for assessment of thromboembolic risk and treatment both acutely and after ED discharge. EM pharmacist takeaway Hemodynamically stable patients with rapid AF should be managed with β-blocker and CCB therapy. Electrical cardioversion, with anticoagulation started as soon as possible beforehand, is recommended in hemodynamically unstable patients with AF. Fromm et al. Diltiazem vs. metoprolol in the management of atrial fibrillation or flutter with rapid ventricular rate in the emergency department.34 This prospective, randomized, double-blind study compared the effectiveness of i.v. metoprolol (n = 28) vs i.v. diltiazem (n = 24) for rate control in adult patients with rapid AF or atrial flutter. After randomization, patients received metoprolol 0.15 mg/kg (maximum dose, 10 mg) or diltiazem 0.25 mg/kg (maximum dose, 30 mg). If the goal HR of <100 beats per minute was not achieved after 15 minutes, repeat doses of metoprolol or diltiazem (0.25 mg/kg and 0.35 mg/kg, respectively, with the maximum dose limits as those listed above) were administered. The primary outcome was achievement of the goal HR of <100 beats/minute within 30 minutes of drug administration and was achieved in 46.4% of metoprolol patients and 95.8% of diltiazem patients (P < 0.0001). Moreover, this outcome occurred within the first 5 minutes in 50% of patients in the diltiazem group and 10.7% of those in the metoprolol group (P < 0.005). Six patients (5 who received metoprolol and 1 who received diltiazem) experienced hypotension (systolic blood pressure [SBP] of <90 mm Hg) and 1 diltiazem patient experienced bradycardia (HR of <60 beats/minute). The authors concluded that diltiazem was more effective than metoprolol, with no significant between-group differences in adverse events. The study included a convenience sample of patients from a single center, did not meet the researchers’ sample size goal, and excluded patients who received prehospital treatment with diltiazem or another atrioventricular nodal blocking agent further limiting sample size. Although diltiazem was found to be more efficacious, it was suggested that metoprolol dosing may have contributed to that finding. Metoprolol 5 mg i.v., the standard dose used in MI, is also commonly used in AF as there are no specific dosing recommendations for rapid AF. In other studies metoprolol doses of 10 mg have been used for rapid AF, and it is possible that higher doses are needed to show a treatment effect similar to that of diltiazem. EM pharmacist takeaway Diltiazem may be more effective than metoprolol for early HR control in patients presenting to the ED with rapid AF or atrial flutter, but optimal dosing of metoprolol in this setting has not been established. Ortiz et al. Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study.35 This was a randomized, open-label study comparing i.v. procainamide (10 mg/kg infused over 20 minutes) vs i.v. amiodarone (5 mg/kg over 20 minutes) in patients with well-tolerated, regular wide QRS complex tachycardia (heart rate of ≥120 beats/minute, QRS duration of ≥120 milliseconds, SBP of ≥90 mm Hg, no dyspnea at rest, no signs of hypoperfusion, and no severe angina symptoms). The study period was 40 minutes (20 minutes for drug administration and 20 minutes after), and the observation period extended for 24 hours after the end of the study period. The primary outcome was the incidence of major cardiac adverse events (clinical signs of peripheral hypoperfusion, heart failure, SBP of ≤70 mm Hg if pretreatment SBP was no more than 100 mm Hg or ≤80 mm Hg if pretreatment SBP was greater than 100 mm Hg, HR increase of >20 beats/minute, or fast polymorphic VT), and secondary outcomes included tachycardia termination and rate of adverse events. After nearly 6 years of study recruitment for the a priori sample size of 302 patients, the investigators closed the study secondary to declining enrollment. Sixteen of 29 participating hospitals enrolled a total of 74 patients; however, only 62 patients (33 who received procainamide and 29 who received amiodarone) were included in the final analysis. Major cardiac adverse events occurred less frequently in patients treated with procainamide vs amiodarone (9% vs 41%; OR, 0.1; 95% CI, 0.03–0.6). The most common major cardiac adverse event was severe hypotension requiring immediate direct current cardioversion, which occurred in 2 procainamide- and 6 amiodarone-treated patients. Sensitivity analyses by age, sex, history of structural heart disease, and previous treatment with oral amiodarone resulted in similar findings. The incidence of tachycardia termination was higher with procainamide use than with amiodarone use (67% vs. 38%; OR, 3.3; 95% CI, 1.2–9.3), and the incidence of all adverse events in total was lower with procainamide use during both the study period (24% vs 48%; OR, 0.3; 95% CI, 0.1–1.0) and observation period (18% vs. 31%; OR, 0.5; 95% CI, 0.2–1.6), although those differences were not statistically significant. The authors concluded that procainamide was associated with less major cardiac adverse events and a higher incidence of tachycardia termination than amiodarone, but they acknowledged that the study was significantly underpowered. Also, the design was unblinded, which may have led to bias in reporting adverse events, and the dosing protocols differed from those routinely used in the United States. Major cardiac adverse events occurred at higher rates with amiodarone use. Procainamide may be an option in this specific population. EM pharmacist takeaway Compared to amiodarone (5 mg/kg over 20 minutes), procainamide (10 mg/kg over 20 minutes) was associated with less major cardiac events, less overall adverse effects, and higher rates of tachycardia termination for treatment of regular wide QRS complex tachycardia. EMERGENCY PREPAREDNESS Alkhalili et al. Defining roles for pharmacy personnel in disaster response and emergency preparedness.36 EM pharmacists are in a position to be leaders in emergency response and preparedness and facilitate collaboration between the prehospital setting, the ED, and pharmacy; develop unique roles and responsibilities for pharmacists; and lead or participate in disaster drills and other emergency preparedness activities. This article describes the results of a 3-phase, focused literature review designed to report roles and key activities for pharmacy staff members in preparation and response to both manmade and natural disaster scenarios. Phase 1 involved a literature search assessing the actions of pharmacy personnel before, during, and after acute response to declared emergencies, phase 2 involved development of a classification scheme for pharmacy personnel, and in phase 3 role mapping was performed to define pharmacy personnel roles and responsibilities during disaster response. A total of 505 pharmacy personnel work activities were derived from 26 publications, of which 41% of personnel functions were related to medication supply and the remainder classified as professional practice (leadership and consultation), population health planning (planning and protocol development), direct patient care (related to dispensing and execution of patient care plans), legislation (related to application of regulations during a crisis event), or communications (record keeping and interdisciplinary communications) activities. Eleven articles were used to categorize pharmacy personnel based on 5 characteristics: education level, experience and training, skill sets, tasks completed, and level of independence. Final personnel categories included 2 levels of pharmacist personnel and 2 levels of nonpharmacist support personnel. Through role mapping the researchers evaluated personnel activities across 3 time periods (before, during, and after emergency response), and assigned responsibilities across the 4 identified categories of pharmacy personnel. Nonpharmacist staff, including pharmacy technicians, completed fewer activities as the emergency response progressed, while general clinical pharmacist staff performed more activities as the response progressed. Specialist clinical pharmacists and administrators executed a focused role during active response to the emergency in their area of expertise. Although the study had a number of limitations, such as a lack of result validation and uncertainty as to whether the framework developed can be applied to international pharmacy practice, this publication is the first to create a general framework for pharmacy activities in emergency management and disaster response and to provide a foundation for planning and role delineation during various time phases of emergency response. EM pharmacist takeaway This publication proposes a framework for key pharmacy personnel activities to consider before, during, and after emergency management and disaster response events. Awad et al. Assessment of hospital pharmacy preparedness for mass casualty events.37 Hospital pharmacy preparedness to provide pharmaceutical services during mass casualty scenarios was assessed through a cross-sectional electronic survey completed by 18 of 60 New Jersey hospitals invited to participate (a 30% response rate). Hospital pharmacy directors (or representatives) answered 12 questions on a 5-point Likert scale and 12 multiple-choice questions. The majority of participating hospitals were community hospitals (66.6%) and/or did not identify as designated trauma centers (72%). All hospitals reported an institutional disaster preparedness protocol, which is consistent with expected institutional compliance to regulatory standards for emergency management, but only 10 hospitals (56%) reported a pharmacy department–specific disaster protocol. The majority of respondents (56%) indicated that they were unsure about the adequacy of their institutional supply of emergency medications. Lastly, only 44% reported information on institutional disaster drills; 4 reported that drills were conducted twice yearly, 3 reported annual drills, and 1 hospital reported no disaster drills. This article provides insight into general pharmacy department preparedness for response to disaster scenarios and demonstrates variability across institutions in the level of pharmacy-specific preparedness plans and training plans. Although the results represent a specific geographic location and the survey response rate was low, the study highlights a potential gap in pharmacy department activities and an opportunity for EM pharmacists to investigate and develop institution-specific guidelines to improve hospital pharmacy department preparedness. EM pharmacist takeaway This survey demonstrates variability in reported hospital pharmacy preparedness for mass casualty scenarios, highlighting an opportunity for the development of standardized guidelines in this area. Narayanan et al. Disaster preparedness: biological threats and treatment options.38 This article provides a pharmacist-focused therapeutics review of the background and clinical presentation of biologic threats, preventative methods, treatment strategies, medication availability and procurement procedures, vaccination, and emerging research on biologic disease threats significant for high-risk to public health and national security, such as anthrax, botulism, plague, tularemia, smallpox, and emerging natural infections like those caused by Ebola and Zika viruses. Recent reports and considerations of atypical cutaneous anthrax affecting i.v. drug users at risk for exposure to contaminated heroin, optimized dosing strategies for anthrax treatment in the pediatric population, recent FDA approval of 3 antibody-based antitoxin therapies (anthrax immune globulin i.v., raxibacumab, and obiltoxaximab) available for inhalational anthrax, and a 4-item diagnostic screening tool that predicts the likelihood of meningitis in patients treated for systemic anthrax are detailed in this article. The role of the EM pharmacist in the management of biologic threats is well described in this review, with emphasis on the importance of pharmacist expertise in preparedness, planning, and response. EM pharmacist takeaway This pharmacist-focused review article summarizes prevention and treatment strategies for biologic threats, including anthrax, botulism, plague, tularemia, smallpox, and emerging viral infections. ENDOCRINE EMERGENCIES Diabetic ketoacidosis Doshi et al. Prospective randomized trial of insulin glargine in acute management of diabetic ketoacidosis in the emergency department: a pilot study.39 Patients with diabetic ketoacidosis (DKA) may be hospitalized for several days in the ICU, contributing to rising healthcare costs. Management of DKA has traditionally centered on the use of i.v. insulin and protocol-driven care (initiation of insulin at 0.1 units/kg/h and dose titration to maintain a suitable decline in serum glucose), followed by initiation of subcutaneous insulin with closure of the elevated anion gap. In this small study (n = 40) the effect of concurrent administration of insulin glargine 0.3 units/kg administered within 2 hours of DKA diagnosis and i.v. insulin for the treatment of DKA was compared to a control treatment (i.v. insulin, with use of long-acting subcutaneous insulin after anion gap closure) in hemodynamically stable patients with a blood glucose concentration of >200 mg/dL, pH of <7.3, a bicarbonate concentration of <18 mg/dL, ketonemia and/or ketonuria, and an anion gap of >16. Results yielded similarities between both the experimental and control groups in mean time to anion gap closure, incidence of hypoglycemic events, rate of ICU admission, and ICU and hospital LOS. Although this was a small single-center study, the findings indicate that DKA treatment may be optimized in the ED through use of an alternative technique of insulin administration to improve disposition and resource utilization. EM pharmacist takeaway Administration of insulin glargine within 2 hours of DKA diagnosis along with i.v. insulin may be considered in the ED as a treatment alternative to usual management with i.v. insulin and transitioning to subcutaneous insulin following anion gap closure. Andrade-Castellanos et al. Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis.40 A number of studies have proposed the use of subcutaneous rapid-acting insulin analogs in the treatment of mild to moderate DKA as an alternative to i.v. regular insulin, which in some EDs and institutions requires a higher level of care. Due to these agents’ more rapid onset of action, it has been recommended to initiate treatment at a dose of 0.2–0.3 units per kg (ideal body weight) followed by doses of 0.1–0.2 units/kg every 1–2 hours, with dose adjustment based on glucose changes. In this systematic review, 5 clinical trials (n = 201 in total; n = 110 for subcutaneous rapid-acting insulin and n = 91 for i.v. regular insulin) were evaluated to determine effects of subcutaneous insulin lispro/insulin aspart compared to i.v. regular insulin on clinical outcomes such as time to DKA resolution, hypoglycemic events, and hospital LOS. Overall the study yielded low-quality evidence, but no significant between-group differences were observed in time to DKA resolution, hypoglycemic events, or LOS. No advantages of either treatment modality were described, but these data show that subcutaneous insulin is a reasonable option for mild to moderate DKA and should be considered in the ED or in off-site or stand-alone EDs as an alternative to bedside insulin infusion admixing if 24/7 pharmacy services are unavailable. EM pharmacist takeaway Rapid-acting subcutaneous insulin analogues may be considered in mild or moderate DKA management as an alternative to i.v. insulin administration. Two-bag intravenous system for DKA Veverka et al. A pediatric diabetic ketoacidosis management protocol incorporating a two-bag intravenous fluid system decreases the duration of intravenous insulin therapy.41 Optimal fluid resuscitation in the setting of DKA remains a challenge in resolution of fluid and electrolyte abnormalities and correction of anion gap metabolic acidosis. In a pediatric, single-center, retrospective study, a 2-bag i.v. fluid system containing 0.45% sodium chloride, potassium acetate, and potassium phosphate (bag 1) and 10% dextrose with 0.45% sodium chloride, potassium acetate, and potassium phosphate (bag 2) concomitantly administered via Y site was implemented in 46 patients, and treatment outcomes were compared with outcomes in 73 patients not treated using the two-bag protocol; both groups received i.v. insulin by continuous infusion. Mean times to DKA resolution did not differ (9 hours in both groups, P = 0.14), but the durations of i.v. insulin therapy differed in protocol and nonprotocol patients (16.9 and 21 hours, respectively; P = 0.03). There were no significant differences in the incidence of hypokalemia, hypoglycemia, or cerebral edema. Use of the 2-bag i.v. system minimized the need for adjustments of the insulin infusion rate and the number of wasted bags of i.v. fluids compared to use of the nonprotocol system. One study of adult patients with DKA managed in the ED evaluated use of a 2-bag system (n = 68): 0.45% sodium chloride and potassium chloride (bag 1) and dextrose 10% with 0.45% sodium chloride and potassium chloride (bag 2) compared to the traditional 1-bag method (n = 107); both were administered with a concomitant i.v. insulin infusion.42 Resolution of acidosis occurred more quickly with use of the two-bag system than with traditional treatment (mean time to resolution, 13.4 hours vs 20 hours; P < 0.05); therefore, the mean duration of i.v. insulin infusion was less (14.1 hours vs 21.8 hours, P < 0.05). There were no statistical differences in the incidence of hypoglycemia or hyperkalemia, although both were reduced with use of the 2-bag system. Also, there was no significant between-group difference in hospital LOS, but ICU admissions were fewer among patients receiving the 2-bag system, and a higher percentage of those patients were discharged directly from the ED. The 2-bag i.v. fluid system for DKA is becoming more common in pediatric EDs to limit continuous i.v. insulin dose titration, overall waste, and for ease of transition to the ICU, and it is important for EM pharmacists to understand the rational for use and overall protocol and patient management. This form of treatment may be feasible in adult patients, although patients with severe DKA were likely underrepresented in this study. EM pharmacist takeaway The 2-bag method of i.v. fluid delivery in patients with DKA may ease titration of i.v. insulin therapy and minimize waste in pediatric patients with DKA. INFECTIOUS DISEASES National guideline updates McDonald et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).43 There are several major updates from the previous 2010 version that are important for the EM pharmacist. Specifically, for an initial episode of nonsevere or severe Clostridium difficile (now called Clostridioides difficile) infection (CDI) in adult patients, oral vancomycin (125 mg 4 times daily) or oral fidaxomicin (200 mg twice daily for 10 days) are recommended as first-line agents over metronidazole (a strong recommendation based on high-quality evidence). For initial episodes of nonsevere CDI in geographic areas where these medications are unavailable, oral metronidazole (500 mg 3 times daily for 10 days) can be considered. For fulminant CDI (cases involving shock, ileus, or megacolon), higher doses of either oral or rectal vancomycin (500 mg 4 times daily) in combination with metronidazole (500 mg i.v. every 8 hours) are required. Metronidazole is no longer recommended for treatment of recurrent CDIs. Recurrent CDIs should be managed with either fidaxomicin, a vancomycin taper and pulsed regimen, or fecal microbiota transplantation (in cases involving multiple CDI recurrences). Unlike the 2010 guidelines, this update also provides information about managing the pediatric population. Based on weak, low-quality evidence, vancomycin or metronidazole is recommended for an initial episode of non-severe CDI. EM pharmacist takeaway Vancomycin or fidaxomicin are the preferred first-line agents for the management of mild or moderate CDIs in adults. The use of metronidazole in managing CDIs is limited to use in combination with vancomycin for the treatment of severe or fulminant disease or for initial episodes of nonsevere infection when vancomycin or fidaxomicin are not available. Kalil et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.44 It is important for EM pharmacists to know the most up-to-date classifications of common disease states seen in the ED. One major change in this updated guideline (previous version published in 2005) is the removal of the healthcare-associated pneumonia (HCAP) classification. Previously, patients meeting criteria for HCAP were thought to be at a greater risk for infection by multidrug-resistant (MDR) pathogens given their contact with the healthcare system; however, newer evidence does not support this. For patients presenting from the community, it is now recommended to assess risk of infection by MDR pathogens based on patient-specific factors such as receipt of i.v. antibiotics within the previous 90 days. For patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP), antibiotics with activity against Staphylococcus aureus and Pseudomonas aeruginosa are still recommended, but specific antibiotic treatment should be determined by local antibiotic resistance data. These data should also be used to decrease unnecessary double coverage of gram-negative bacteria and determine when empiric treatment for methicillin-resistant S. aureus (MRSA) infection is necessary. There is a new recommendation that 7 days of antibiotic therapy is sufficient for HAP or VAP treatment, which is based on data demonstrating no significant differences in rates of mortality, clinical cure, or recurrent pneumonia with 7 days vs 8 to 15 days of antibiotic therapy. The guidelines also suggest using measured procalcitonin levels in conjunction with clinical criteria to help guide antimicrobial discontinuation. Updates to the Infectious Diseases Society of America’s 2007 guidelines on treatment of community-acquired pneumonia were slated to be published fall 2019. EM pharmacist takeaway The classification of HCAP has been removed, as there is insufficient evidence to support increased risk of infection by resistant organisms in this patient population. Community patients should be assessed for MDR pathogens on an individual basis to guide treatment. Antibiotic selection should be directed by local antibiotic resistance data. The recommended treatment duration for HAP and VAP is now 7 days. Skin and soft tissue infections Wang et al. Antibiotics for uncomplicated skin abscesses: systematic review and network meta-analysis.45 This systematic review and network meta-analysis of 14 RCTs (n = 3,541 adult and pediatric patients) compared the impact of antibiotics plus incision and drainage (I&D) to I&D alone in the management of uncomplicated skin abscesses (any body location). The majority of trials occurred in the ED setting, and the most common pathogen isolated was MRSA (44%-88%) and methicillin-sensitive S. aureus (MSSA) (8%-18%). Antibiotic use was shown to be associated with lower risk of treatment failure at 1 month (OR, 0.58; 95% CI, 0.37–0.90), recurrence or new lesion at 1 month (OR, 0.48; 95% CI, 0.30–0.77), and recurrence or new lesion at extended follow-up (>1 month) (OR, 0.64; 95% CI, 0.48–0.85). Hospitalization was also less common in patients receiving antibiotics (OR, 0.55; 95% CI, 0.32–0.94); however, there was no difference in risk of invasive infection at 7–14 days based on one study that reported this outcome (OR 1.02, 95% CI 0.14–7.24). Treatment failure was lower when antibiotics with MRSA activity (trimethoprim/sulfamethoxazole [TMP/SMX] and clindamycin) were used compared to antibiotics without MRSA activity, like first-generation cephalosporins (ORs, 0.45 [95% CI, 0.33–0.62] for antibiotics with MRSA activity and 1.82 [95% CI, 0.68–4.85] for antibiotics without MRSA activity). Predictably, compared to no antibiotic therapy, use of TMP/SMX and use of clindamycin were more likely to cause GI adverse effects (ORs, 1.28 [95% CI, 1.04–1.58] for clindamycin and 2.29 [95% CI, 1.35–3.88] for TMP/SMX), particularly diarrhea for clindamycin and nausea for TMP/SMX. The authors of this systematic review concluded that TMP/SMX and clindamycin appear to offer a modest benefit in those with uncomplicated skin abscesses but at the expense of antibiotic-related adverse effects. This publication prompted new clinical practice guidelines from the BMJ Rapid Recommendation group re-emphasizing these findings.46 However, these recommendations conflict with current recommendations from the IDSA practice guidelines for diagnosis and management of skin and soft-tissue infections, which recommend I&D alone as the primary treatment for uncomplicated abscesses.47 Another systematic review and meta-analysis of 12 studies (including 5 RCTs) involving a total of 1,969 patients found no evidence to support routine use of antibiotics with I&D for uncomplicated abscesses.48 Given that the benefit of antibiotic therapy was only modest in the study conducted by Wang et al, the decision to initiate antibiotics should be made on an individual patient basis and weighed against the risk of adverse drug events, recurrence, and resistance patterns. Future studies assessing specific patient factors associated with lower rates of treatment failure (ie, size of abscess, local resistance patterns, comorbidities) would be helpful to guide clinicians. EM pharmacist takeaway There continues to be conflicting evidence regarding the use of antibiotics in combination with I&D vs I&D alone for patients with uncomplicated abscesses. Some literature suggests that use of antibiotics (particularly those that cover MRSA) has been associated with decreases in treatment failures, reoccurrence or development of new lesions, and hospitalizations. However, antibiotics have not been shown to decrease the risk of invasive infections and their benefits may be offset by a higher rate of adverse drug events. Cadena et al. Dose of trimethoprim-sulfamethoxazole to treat skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus.49 The IDSA practice guidelines for diagnosis and management of skin and soft-tissue infections (SSTI) recommend TMP/SMX for the treatment of MRSA SSTIs (a level A-II recommendation).47 However, the optimal dose of TMP/SMX for this indication is unclear. This study was a prospective, observation cohort with nested case control study designed to evaluate the efficacy of TMP/SMX for treatment of MRSA SSTIs using 2 dosing regimens: standard-dose TMP/SMX (160 mg/800 mg [1 double-strength tablet]) twice daily and high-dose TMP/SMX (320 mg/1,600 mg [2 double-strength tablets]) twice daily. Adult patients with signs and/or symptoms of SSTIs such as tenderness, erythema, and purulent secretions were included. Those with recurrent MRSA SSTIs, folliculitis, and deep tissue, bone, or tendon infections were excluded. Clinical resolution of infection was identified through medical records or telephone interaction, and treatment failure was defined as documented worsening infection beyond 2 days of initial therapy plus one of the following: additional surgical drainage, hospital admission, occurrence of new MRSA SSTI infection at a different body site during antibiotic therapy, and persistent infection. Over a 5-month period, rates of clinical resolution were similar in the 2 groups: 75% in the standard-dose group (n = 170) vs 73% in the high-dose group (n = 121) (P = 0.79). Patients in the high-dose group were more likely to have I&D performed; however, this did not affect clinical resolution trends. Although there were no differences in clinical resolution by study definition, a higher percentage of patients in the standard-dose group required a change in antimicrobial agents due to lack of response (44% vs 24%, P = 0.06) and/or hospital admission at 48 hours (16% vs 3%, P = 0.1). The authors concluded that rates of SSTI clinical resolution were similar with use of the standard- and high-dose TMP/SMX regimens. A potential study limitation was the lack of a subgroup analysis assessing the impact of higher TMP/SMX doses on clinical outcomes in obese patients (>100 kg) given that the median patient weights were 77 kg (range, 44.5–156 kg) and 86 kg (range, 42–141 kg) in the standard- and high-dose groups, respectively. A small retrospective cohort study (n = 106) found that obese patients who received standard TMP-SMX doses (160 mg/800 mg) had a significantly higher rate of treatment failures compared to those who received higher TMP/SMX doses (320 mg/1,600 mg) (P = 0.002).50 Current practice is often to prescribe higher-dose regimens for patients weighing more than 100 kg; however, more literature is needed to determine if this impacts patient clinical outcomes. EM pharmacist takeaway There appears to be no difference in clinical resolution amongst patients who received standard dose regimens of TMP/SMX (160 mg/800 mg) compared to high-dose regimens (320 mg/1,600 mg) for treatment of MRSA SSTI. Although not a statistically significant, more patients required a change in antibiotic therapy, as well as hospitalization, in the standard-dose arm. Furthermore, there is some evidence to support higher dosing in obese patients (>100 kg), which was not investigated in this study. Vancomycin loading doses Reardon et al. Vancomycin loading doses: a systematic review.51 This systematic review assessed the impact of vancomycin loading doses (LDs) on pharmacokinetics, pharmacodynamics, and clinical efficacy and safety in adult and pediatric patients. Five published studies (2 RCTs and 3 observational studies) and 3 abstracts of unpublished trials were included in this systematic review. Studies were included if a vancomycin LD was used to obtain target trough concentrations of 15 to 20 mg/L (in 1 pediatric study, the target concentration was 10 to 20 mg/L). Loading doses varied between studies in regards to a weight-based approach (22.5 to 30 mg/kg) vs fixed dose regimens (2 g), and one-time doses vs divided LD regimens (ie, 15 mg/kg for 2 doses, for a total of 30 mg/kg). Timing of vancomycin concentrations also varied between studies and were separated into 2 categories for the pharmacokinetic assessment: (1) initial vancomycin concentration obtained after the LD but before the first vancomycin maintenance dose and (2) initial vancomycin concentration in patients who received a LD followed by multiple maintenance doses. Overall findings were conflicting. While some studies demonstrated a benefit in achieving goal concentrations when using a LD, these studies all varied in dosing (both LDs and maintenance doses), making them too heterogeneous and difficult to compare and assess. Although the ideal vancomycin pharmacodynamic parameter is a ratio of area under the curve (AUC) to minimum inhibitory concentration (MIC) of ≥400, this is not routinely measured in clinical practice and was not measured in any of the included studies. Based on AUC/MIC ratios calculated using a hypothetical MIC of 1 mg/L in one pediatric study, the authors concluded that doses of 60 mg/kg/d might be a better marker of efficacy than LD to achieve a specific concentration rapidly in the pediatric population. This interpretation is limited to a single MIC value and may not be reflective of vancomycin efficacy in cases involving higher MICs. The impact of vancomycin LD on clinical efficacy could not be determined, as all studies were underpowered to detect differences in patient outcomes. Also, the relationship between LD and nephrotoxicity was underpowered and could not be evaluated. The authors concluded that vancomycin LDs are inconsistent in rapidly achieving goal concentrations of 15 to 20 mg/L in adults and that available literature does not support the use of LD in pediatric patients. Overall, variations in dosing and trough procurement in each of the studies, as well as the small sample sizes, made it challenging to evaluate. At this point, it can still be argued that LD may be beneficial in critically ill patients given the slower kill time observed with vancomycin therapy. EM pharmacist takeaway Literature supporting the use of vancomycin LD to achieve faster goal trough concentrations is conflicting. For adult patients, it appears reasonable to administer a LD in critically ill patients, whereas LDs are not recommended in the pediatric population. This study was underpowered and not able to determine whether a LD impacts patient outcomes and incidence of nephrotoxicity. Vancomycin and beta-lactam association with nephrotoxicity Hammond et al. Systematic review and meta-analysis of acute kidney injury associated with concomitant vancomycin and piperacillin/tazobactam.52 Vancomycin-induced nephrotoxicity is well known; however, recent literature suggests that there may be increased risk of acute kidney injury (AKI) with the commonly used antipseudomonal β-lactam piperacillin/tazobactam. This systematic review and meta-analysis of 14 observational studies (n = 3549) evaluated the incidence of AKI in patients receiving vancomycin and piperacillin/tazobactam (VPT) compared to those receiving vancomycin without piperacillin/tazobactam (either vancomycin alone or with another β-lactam antibiotic). The definition of AKI in the individual studies, usually the definition specified in the RIFLE (risk, injury, failure, loss, and end-stage renal disease) criteria, was retained for the pooled primary analysis. Use of the VPT combination was associated with an overall higher incidence of AKI compared to vancomycin without piperacillin/tazobactam (OR, 3.12; 95% CI, 2.04–4.78; adjusted OR, 3.11; 95% CI, 1.77–5.47). These findings were consistent across unadjusted and adjusted (when feasible) subgroup analyses accounting for age (≥18 years vs <18 years), additional antimicrobials used (other β-lactams, cefepime, and cefepime or meropenem), and study quality (good vs fair/poor). This effect was seen in critically ill patients in the unadjusted analysis only (OR, 3.83; 95% CI, 1.67–8.78; adjusted OR, 2.83; 95% CI, 0.74–10.85) and in both analyses for non–critically ill patients (OR, 2.44; 95% CI, 1.40–4.27; adjusted OR, 3.04; 95% CI, 1.49–6.22) when separated by acuity. When vancomycin was used as monotherapy, there did not appear to be an increased risk of AKI (OR, 3.16; 95% CI, 0.67–14.91; adjusted OR, 2.50; 95% CI, 0.41–15.44). The authors speculated that given the limited number of patients in the pooled analysis and the wide CI, this finding could be the result of a type II error. Other factors that may influence the incidence of AKI, such as duration of vancomycin exposure, concomitant use and/or duration of other nephrotoxic agents, hypotension or shock, and i.v. contrast dye exposure, were not consistently reported across all studies and therefore could not be evaluated. Relevant clinical outcomes such as mortality, need for renal replacement therapy, and LOS were also not assessed in this study. The authors concluded that the incidence of AKI is higher in patients receiving VPT combination therapy and that this risk should be considered when selecting antibiotic regimens. EM pharmacist take away The combination of vancomycin and piperacillin/tazobactam resulted in an increased risk of AKI compared to vancomycin without piperacillin/tazobactam. This trend was also observed in subgroup analyses accounting for age, other antibiotics used, and study quality. Additional factors potentially associated with AKI, such as concomitant use of nephrotoxic agents (ie, i.v. contrast media) and hypotension or shock were not evaluated. Mullins et al. Comparison of the nephrotoxicity of vancomycin in combination with cefepime, meropenem, or piperacillin/tazobactam: A prospective, multicenter study.53 This was the first prospective, multicenter, observational study evaluating the incidence of AKI in patients receiving VPT (n = 94) compared to vancomycin with cefepime or meropenem (VC/VM) therapy (n = 148). AKI was defined as a minimum 1.5-fold increase in serum creatinine (SCr) within the first 7 days of antibiotic therapy. Adult patients receiving 72 or more hours of both vancomycin and piperacillin/tazobactam, cefepime, or meropenem therapy were included. Those who had chronic kidney disease or evidence of AKI prior to receiving antibiotics, had vancomycin concentrations of <10 mg/L, were switched between β-lactam antibiotics, or experienced cardiac arrest prior to antibiotic therapy were excluded. Baseline demographics and vancomycin dosing (weight-based dose, duration, and minimum and maximum concentrations) were similar between groups. The incidence of AKI was higher in the VPT group compared to the VC/VM group (29.8% vs 8.8%, P < 0.001) during the prespecified interim analysis, and the study was terminated early. This same trend was noted when individually comparing VPT to VC (29.8% vs 5.9%, P < 0.001) but not VPT to VM (29.8% vs 14.9%, P = 0.054), which could be due to lower VM usage (47 of 148 patients). The mean maximum SCr was higher in those receiving VPT compared to VC/VM (1.4 mg/dL vs 1.0 mg/dL, P < 0.001), and 56% of patients who developed AKI never returned to baseline. Three patients in the VPT group required renal replacement therapy compared to none in the VC/VM group (3.2% vs. 0%, P = 0.057). Independent predictors of AKI were determined to be concomitant use of loop diuretics (OR, 3.27; 95% CI, 1.42–7.53) and vasopressors (OR, 5.04; 95% CI, 1.66–15.35), as well as vancomycin concentrations of >30 mg/L (OR, 13.33; 95% CI, 3.13–56.77). The authors concluded that use of the VPT combination does increase the risk of AKI compared with other broad-spectrum antibiotics. Interestingly, despite the use of broad-spectrum antibiotics, only one-third of patients met sepsis criteria, with the majority of infections involving the respiratory system or skin and/or skin structures. It is important for the EM pharmacist to recognize the increased risk of AKI associated with this commonly used empiric broad-spectrum antibiotic regimen and to collaborate with EM clinicians to use a patient-specific approach to antimicrobial regimen selection, with consideration of risk factors for nosocomial pathogens, local resistance patterns, severity of illness, and other patient-specific characteristics (ie, recent antibiotic use, colonization, comorbidities) to prevent unnecessary harm. EM pharmacist takeaway Higher rates of AKI were noted in patients receiving vancomycin and piperacillin/tazobactam therapy compared to vancomycin with cefepime or meropenem. Independent predictors of AKI were found to be concomitant use of loop diuretics or vasopressors and vancomycin concentrations of >30 mg/L. Oritavancin/dalbavancin Lodise et al. Economic impact of oritavancin for the treatment of acute bacterial skin and skin structure infections in the emergency department or observation setting: cost savings associated with avoidable hospitalizations.54 Acute bacterial skin and skin structure infections (ABSSSIs) account for a large portion of infections managed by EM clinicians. The recently approved long-acting glycopeptides oritavancin and dalbavancin offer a simplified 1- or 2-time dosing regimen for parenteral antibiotics while avoiding hospital admission. Unfortunately, the costs of these agents have limited their use for ED “treat and release” patients as an alternative to oral antibiotics. This investigation was a cost-minimization analysis of use of oritavancin in the outpatient setting (ED and observation unit) compared to in-hospital management with vancomycin i.v. for ABSSSI. Patients were included in this retrospective, observational study if they had no or few comorbidities (defined using Charlson Comorbidity Index [CCI] of 0 or 1) without any life-threatening signs of infection (ie, necrotizing fasciitis, bacteremia, neutropenia, sepsis and systemic inflammatory response syndrome). Patients were further subgrouped based on the absence or presence of systemic symptoms. Hospital LOS, hospitalization costs, medications, laboratory, diagnostic, and therapeutic services were database elements included in the analysis. The Premier Research Database was used to capture 53,545 patients who had received vancomycin for ABSSSI on day 1 or 2 of hospitalization. The majority of patients with a CCI of 0 did not have symptoms (62.3% vs 7.4%). This same trend was also observed in patients with a CCI of 1 (26.3% vs 4%). The cost associated with vancomycin (mean, $6,512) was significantly higher than oritavancin (ED: $3,409; observation unit: $4,220). In a variety of cost comparison models accounting for location (ED vs observation), CCI classification, and absence vs presence of symptoms, oritavancin was associated with cost savings each time. A sensitivity analysis found that even using oritavancin in the observation unit (costlier than ED), up to 23% of patients could still be hospitalized while maintaining budget-neutrality compared to inpatient vancomycin therapy. While the results of this study are promising, it is important to recognize that oritavancin reimbursement and vancomycin-associated costs may differ in real-world scenarios, thus affecting overall cost savings and decreasing the budget-neutrality threshold for subsequent hospitalization. Also, it is impossible to say that these patients were only hospitalized for vancomycin therapy and that outpatient oritavancin would have been clinically appropriate, even though information on severity of illness was used in the model. Also, if outpatient management was appropriate, it is uncertain if oral antibiotics could have been used. More literature illustrating institution-specific patient identification for oritavancin or dalbavancin therapy, use implementation, and costs would be helpful in identifying real-world utility and cost impact. EM pharmacist takeaway Oritavancin and dalbavancin provide a potential alterative to inpatient management of uncomplicated ABSSSIs but are high-cost agents. Using a cost-minimization model, there was an overall cost reduction with oritavancin compared to vancomycin therapy in the ED and observational unit settings. More real-world experience is needed to identify true utility and cost impact. Fluoroquinolones and adverse effects Tandan et al. Adverse events of fluoroquinolones vs. other antimicrobials prescribed in primary care: A systematic review and meta-analysis of randomized controlled trials.55 Fluoroquinolones (FQs) have been frequently used in the ED and outpatient settings to treat a variety of infections because of their broad-spectrum coverage and oral availability. Due to widespread use, increased resistance has been observed, limiting their utility. Additionally, postmarketing safety research has led FDA to institute black box warnings for FQs regarding the risk of irreversible joint, tendon, and central nervous system (CNS) adverse effects. This systematic review and meta-analysis evaluated the incidence of adverse effects (GI, CNS, and skin-related) in patients receiving oral FQs in primary care settings in comparison to other antibiotic therapies. A total of 38 studies were included, providing data for 17,735 patients. Ciprofloxacin was the most used FQ, followed by moxifloxacin and norfloxacin. FQs were most often compared to amoxicillin/clavulanic acid, TMP/SMX, clarithromycin, cefuroxime, and fosfomycin. The most commonly reported adverse effects were nausea, vomiting, diarrhea, headache, dizziness, and rash. Overall, there was no difference in total number of adverse effects reported in patients receiving FQs compared to other antibiotics and placebo (OR, 1.07; 0.97–1.18, I2 = 74.7%). However, subgroup analyses found significant increases in CNS and GI adverse effects with FQ therapy (CNS: OR, 1.40, 1.12–1.75, I2 = 0%; GI: OR, 1.20; 1.06–1.36; I2 = 80%). There were no differences in skin-related adverse effects between groups. Of all antibiotics studied, there were higher rates of discontinuation secondary to FQ-related adverse effects (OR, 1.19; 1.00–1.42; I2 = 5%). Despite these findings, there are several limitations with this review. All studies included reported adverse effects as secondary outcomes and reporting rates were low. Likewise, significant heterogeneity in both antibiotics and dosing regimens between studies existed, which may introduce bias towards use of particular agents and/or doses. However, these findings provide information on higher rates of CNS and GI adverse effects with FQs. Another limitation is that only GI adverse effects, but not specifically C. difficile infection, was investigated, as this has been frequently associated with FQs. Fluoroquinolones have been linked to a variety of unique adverse effects, as they induce activity of matrix metalloproteinases, resulting in the breakdown of both collagen and other structural components. By this proposed mechanism, FQs have been implicated in tendon rupture and a possible increased risk of aortic aneurysm or dissection. A systematic review of 16 observational studies found a higher risk of any tendon disorder (adjusted ORs ranged from 1.1 to 1.7) and Achilles tendon rupture (adjusted ORs ranged from 1.1 to 7.1) in those taking FQ, and one study in this review demonstrated much greater risk of tendon disorders with FQ use compared to cephalosporin use (relative risk [RR], 6.29; 95% CI, 2.27–17.46).56 Factors associated with increased risk of Achilles tendon rupture were older age (>60 years), higher FQ dose, and concomitant use of corticosteroids. A retrospective cohort study compared the incidence of aortic aneurysm or dissection between FQs (n = 360,088) and amoxicillin (n = 360,088) using propensity scores accounting for demographics, medical history, concomitant use of other medications, and measures of health utilization.57 Although the risk of aortic aneurysm or dissection was significantly increased amongst the FQ group compared to the amoxicillin group (1.2 vs 0.7 episodes per 1,000 person years; HR, 1.66; 95% CI, 1.12–2.46), this appears to be influenced by aortic aneurysm (HR, 1.90; 95% CI, 1.22–2.96) as there was not an increased risk of aortic dissection (HR, 0.93; 95% CI, 0.38 to 2.29). In 2013, FQ prescribing information was updated to include warnings regarding risk of peripheral neuropathy as a result of data from the FDA adverse event reporting system and case reports. A pharmacoepidemiologic, case-controlled study in US men (45–80 years of age) was conducted using insurance claims data to identify both peripheral neuropathy and FQ use.58 Between 2001 and 2011, a total of 6,226 cases were identified and matched with 24,904 controls. Patients receiving any oral FQs within 1 year were more likely to be diagnosed with peripheral neuropathy than those who did not receive FQs (RR, 1.30; 95% CI, 1.21–1.40). This risk increased for patients actively receiving FQ therapy (RR, 2.07; 95% CI, 1.56–2.74). As a result of the potential complications outlined above, the use of FQs as first-line agents for many common infections is discouraged unless alternative therapy is not feasible. It is important for EM pharmacists to understand these data, the FDA warnings, and black box information in the prescribing information, as they have a crucial role in educating clinicians on these risks and developing guidance and clinical decision tools for alternative antibiotics with less potential complications to treat a variety of disease states managed in the ED. EM pharmacist takeaway There is a higher risk of adverse drug events with FQ therapy compared to other antibiotics. Specifically, there are higher rates of CNS and GI side effects and newer literature demonstrating increases in tendon disorders, peripheral neuropathies, and aortic aneurysms. In general, use of FQs should be limited to scenarios where alternative therapy is not feasible. Sexually transmitted diseases Workowski et al. Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines.59 Sexually transmitted diseases (STDs) continue to increase in prevalence and remain a common reason for patients to seek care in the ED. The EM pharmacist is frequently involved in treatment recommendations and process development related to the management of patients with STDs or those potentially exposed through sexual assault. The CDC guidelines are an important reference as they contain general management recommendations in addition to information for special patient populations, including pregnant patients, victims of sexual assault, pediatric patients, and those with antimicrobial allergies. With the emergence of antimicrobial-resistant Neisseria gonorrhoeae, FQs are no longer recommended as first-line therapies in the United States, leaving cephalosporins as the sole class of antimicrobials available for treatment. However, cephalosporin MICs have been increasing across various parts of the world, leading to concerns about cephalosporin treatment failures. As a result, the recommended dose of ceftriaxone has been increased from 125 mg i.m. to 250 mg i.m.. Ceftriaxone also remains the preferred cephalosporin due to its ability to achieve high bactericidal levels of drug in the blood. Dual therapy for gonococcal infections is also recommended in an attempt to slow cephalosporin resistance. Azithromycin is the preferred second antimicrobial agent due to its compliance advantages (given as a single dose) and overall lower resistance compared to tetracyclines. Dual therapy with gentamicin 240 mg i.m. and azithromycin 2000 mg p.o. is also recommended to prevent macrolide resistance for patients who have severe beta-lactam allergies. Similarly, increasing trichomoniasis treatment failures have also been observed with single dose metronidazole therapy. Data from one multicenter, open-label RCT found a lower rate of positive tests for Trichomonas vaginalis after treatment with metronidazole 500 mg orally twice daily for 7 days compared to the single dose metronidazole 2,000 mg orally (11% vs 19%, P < 0.0001) in female patients.60 Although not yet endorsed by the CDC guidelines as first-line therapy, these results should be considered when treating patients empirically; this regimen also treats bacterial vaginosis. The treatment recommendations for the majority of other STDS, such as syphilis and chlamydia, remain unchanged from previous CDC STD guidelines. Current CDC recommendations for postexposure prophylaxis against human immunodeficiency virus (HIV), either from occupational or nonoccupational exposure, include emtricitabine/tenofovir/disoproxil fumarate 200 to 300 mg daily plus raltegravir 400 mg orally twice daily or dolutegravir 50 mg daily for 28 days.61 However, dolutegravir is no longer recommended in the first trimester of pregnancy or in nonpregnant women at risk of pregnancy (ie, sexually active and not using effective birth control methods) after increases in neural tube defects were observed.61 A review article focused on STD management from the EM pharmacist perspective is a good resource to use in addition to the CDC guidelines as it provides treatment recommendations focused on the ED perspective, evidenced-based information to help address commonly encountered questions from EM clinicians, updates from the 2015 CDC publication, and outlines the pharmacist role.62 EM pharmacist takeaway The CDC STD guidelines serve as an important reference for EM pharmacists. Updates include dual therapy for gonococcal infections, alternative trichomoniasis treatment strategies, and possible birth defects observed with dolutegravir use in pregnancy. This guideline contains information about treatment management as well as information for special populations such as pregnant patients, patients with drug allergies, pediatric patients, and patients who need HIV postexposure prophylaxis. MISCELLANEOUS Esophageal foreign body impaction Bodkin et al. Effectiveness of glucagon in relieving esophageal foreign body impaction: a multicenter study.63 Glucagon may be used for the management of esophageal foreign body impaction (EFBI) due to its effects as a smooth-muscle relaxant in decreasing lower esophageal sphincter tone. The efficacy of this approach is difficult to study since overall treatment is often multimodal, involving use of carbonated beverages and medications such as benzodiazepines, sublingual nitroglycerin, nifedipine, and proteolytic enzymes in addition to glucagon. Spontaneous resolution may also occur; that coupled with patient-specific factors potentially affecting success and medication costs of glucagon or endoscopy makes this treatment controversial. Overall, 133 glucagon doses (median dose, 1 mg i.v.) administered for EFBI to 127 patients were evaluated in this retrospective study across 2 EDs. Glucagon-related resolution of EFBI occurred in only 18 cases (14.2%). There was no difference in rates of resolution of EFBI when comparing patients who received glucagon (n = 127) to a small control group (n = 29): 14.2% and 10.3%, respectively, P = 0.59. Vomiting as an adverse event occurred in 13%, which was lower than rates reported in other studies. The majority of patients (58%) received adjunctive therapy, primarily benzodiazepines and nitrates. The authors concluded that despite its routine use in ED, glucagon is not advantageous for EFBI. One strength of this study compared to other reports is that the definition for glucagon-related success was patient-reported symptoms within 60 minutes, a time frame more reflective of the pharmacokinetics of the agent. The authors noted that glucagon use was routine within their respective institutions for most EFBI; this minimizes potential treatment bias, but the reported success rates may not correlate to rates at other institutions, where the decision to use glucagon (or not) may be based more on patient-specific factors (eg, type of EFBI or known esophageal abnormality). EM pharmacist takeaway Glucagon therapy has a low success rate when used for routine management of EFBI and is of no significant benefit in EFBI resolution. There are also notable risks of adverse effects like vomiting when glucagon therapy is used. Ketamine for agitation Riddell et al. Ketamine as a first-line treatment for severely agitated emergency department patients.64 This prospective, single-center, observational study evaluated 98 adult ED patients presenting with acute agitation (considered “highly aroused” or “violent” prior to ketamine administration) and compared agitation scores at 5, 10, and 15 minutes. Patients fell into 5 groups: ketamine (n = 24), midazolam (n = 19), lorazepam (n = 33), haloperidol (n = 14), benzodiazepine plus haloperidol (n = 10). Medication doses and routes of administration were at the discretion of the prescriber and were variable. Mean (range) doses were as follows: ketamine i.v., 0.9 (0.3–2.2) mg/kg; ketamine i.m., 3 (0.9–4) mg/kg; midazolam i.v., 3 (1–4) mg; midazolam i.m., 2.3 (1–4) mg; lorazepam i.v., 1.9 (1–4 mg); lorazepam i.m., 2.4 (2–4) mg; and haloperidol i.m., 5.7 (5–10) mg. The most common route of administration in all except haloperidol was i.v.. There were significantly more patients that were no longer agitated in the ketamine group compared to all other medication groups at all time points (P = 0.001, P ≤0.001, P = 0.032). The mean time to agitation control was shorter with ketamine use (6.6 [SD, 8.7] minutes, compared to 13 to 23 minutes in the other groups). This study was unique in that it explored the use of ketamine as a first-line agent for patients in the ED setting rather than for refractory patients or in the prehospital setting. Also, only 2 patients in the ketamine group and 1 in each other group were intubated; this was significantly less than figures reported for another study of use of ketamine 5 mg/kg i.m. in the prehospital setting for this indication, in which 28 of 49 patients (57%) were intubated.65 Despite low patient numbers in each group, there was a significant difference, potentially indicating a large treatment effect. However, the study design is critical to consider; physicians collected outcomes data and data collection was not blinded, potentially biasing results. Also, there was variability in dosing and route of administration, complicating data interpretation. The greatest confounder was that prehospital treatment was not considered. Some of these patients may have been treated with 1 or more of the study agents prior to arrival in the ED (although this could not have included ketamine); if treatment was successful, that might have influenced prescribing and, potentially, treatment success or failure after ED arrival. Moreover, the study population included a high percentage of methamphetamine abusers, which might have limited external validity. Despite its multiple confounders, this study provides support for use of ketamine as a therapeutic option. In the treatment of a complex clinical presentation with various etiologies, the availability of multiple potential agents with different mechanisms of action is advantageous. EM pharmacist takeaway Ketamine used as a first-line sedating agent in agitated ED patients significantly reduced agitation at 5, 10, and 15 minutes relative to midazolam, lorazepam, or haloperidol. However, a number of study confounders and design limitations may limit the application of results to a broad ED population. Linder et al. Ketamine for the acute management of excited delirium and agitation in the prehospital setting.66 This systematic review of the literature sought to explore available data for the use of ketamine for the acute management of excited delirium and agitation, specifically in the prehospital setting. The authors identified 10 articles on studies including a total of 418 patients. Two studies compared ketamine to haloperidol, and the other studies were retrospective chart reviews or case series evaluating ketamine dose and route and effects on sedation. Comparing ketamine 5 mg/kg i.m. with haloperidol 5 to 10 mg i.m. (with or without a benzodiazepine and/or diphenhydramine), ketamine achieved faster sedation (5 minutes vs 17 minutes), required less redosing, and did not affect prehospital on-scene time, but the intubation rate was 39% with ketamine compared to 4% with haloperidol in one study. Overall, the most common dose and route of ketamine was 5 mg/kg i.m., although others such as 4 mg/kg i.m. and 0.25–2 mg/kg i.v. or intraosseous (including 0.25–0.5 mg/kg dose followed by an infusion) were efficacious. Rates of intubation ranged from 6% to 63% (most intubations occurred in the ED and not the prehospital setting), and other adverse effects, such as hypoxia (23%), cardiovascular effects (22%), hypersalivation (8%-38%), emergence reaction (10%-23%), and vomiting (6%-14%) were reported. The largest challenge with this review is that all but one study was retrospective; hence the methodology was not ideal, limiting potential inferences. However, conducting prospective, blinded studies is difficult in this setting and with this patient population. This article provides a review of the proposed pharmacology of ketamine in this setting as well as a sample prehospital protocol for management of excited delirium based on available data. Ketamine provides an attractive option for excited delirium due to its quick onset of action and low likelihood of precipitating prehospital intubation. This review provides the best available information for EM pharmacists to assist prehospital personnel in developing education and protocols for ketamine use. EM pharmacist takeaway Ketamine, administered via the i.m., i.v., or intraosseous routes, is a reasonable option for the management of excited delirium in the prehospital setting due to its quick sedating effects. Sickle cell disease Afenyi-Annan et al. Managing acute complications of sickle cell disease. In: Evidence-Based Management of Sickle Cell Disease.67 Patients with sickle cell disease can present to the ED with several disease-related complications. This is an evidence-based guideline from the National Heart, Lung, and Blood Institute. A methodology team conducted a literature review and then developed recommendations in conjunction with an expert panel or through consensus building by experts from the American Pain Society and other groups. The authors note the paucity of published data regarding pain management for vaso-occlusive crisis secondary to sickle cell disease. The need for rapid pain assessment and treatment is emphasized, with treatment options including NSAIDs for mild to moderate pain and i.v. or subcutaneous opioids for severe pain. The author recommend individualized prescribing and monitoring protocols to promote rapid, effective, and safe management, as well as attentive reevaluation of therapy to assess the need for therapy escalation. Classic treatments like oxygen supplementation and fluid resuscitation should be considered. Management of sickle cell disease–related complications such as acute stroke, acute chest syndrome, and priapism is detailed. In summary, exchange transfusions are recommended for acute stroke following advanced imaging for diagnosis, i.v. cephalosporin and an oral macrolide in addition to oxygen, red cell transfusion if the hemoglobin concentration is less than 9 g/dL; exchange transfusions are recommended for acute chest syndrome; and aggressive hydration, analgesia, and urology intervention are recommended for priapism lasting 4 hours or longer. EM pharmacist takeaway Vaso-occlusive crisis manifesting as acute pain is a common sickle cell disease complication. NSAIDs for mild to moderate pain, opioids for severe pain, hydration, and supplemental oxygen if oxygen saturation is less than 95% on room air should be initiated as soon as possible. Brandow et al. Impact of emergency department care on outcomes of acute pain events in children with sickle cell disease.68 This secondary analysis of a previously published study involving 204 patients with sickle cell disease ranging in age from 4 to 21 years evaluated the impact of ED acute pain management on outcomes such as hospital LOS and change in health-related quality of life (HRQL). ED management with regard to route, dose, and timing of opioid administration was evaluated. Specifically, time to first i.v. opioid dose (within 60 minutes vs >60 minutes), total initial opioid dose (highest and lowest tertiles), and time to first oral opioid dose (within 24 hours vs >24 hours) were evaluated. Earlier oral opioid administration was strongly correlated with shorter LOS (r = 0.61, P < 0.01); however, this was not evident with i.v. opioid administration. Higher initial opioid doses were weakly correlated with longer LOS (r = 0.34, P < 0.01), and both higher initial opioid doses and oral opioids initiated within 24 hours of presentation were significantly associated with larger mean improvement in HRQL. This study addresses both a qualitative healthcare outcome and patient-reported outcome, reinforcing the importance of assessing patient experience during management of acute pain crisis. All patients evaluated in this study had “severe” pain and required hospitalization due to failed outpatient therapy. Patient characteristics that may have influenced opioid administration via different routes were not investigated further. All patients ultimately received i.v. opioids in the ED prior to inpatient administration, which limits any conclusions regarding the best pain management strategy for adequate efficacy and prevention of admission. Notably, only 54% of patients reported receiving opioids at home prior to seeking ED treatment. This trial demonstrated that ED management of acute pain events in sickle cell disease may influence LOS, and is hypothesis generating for patient-centered methods to optimize opioid use and timing in this population. EM pharmacist takeaway ED management of acute pain events in pediatric sickle cell disease may influence hospital LOS, but the optimal pharmaceutical approach to treatment remains unclear. NEUROLOGY Acute ischemic stroke Powers et al. 2018 Guidelines for the early management of patients with acute ischemic stroke. Stroke 2018: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.69 These guidelines are the much-anticipated update to 2013 guidelines regarding the treatment of adult patients with acute ischemic stroke (AIS). Recommendations for prehospital care, urgent and emergency evaluation and treatment with i.v. and intraarterial therapies, and approaches used during the first 2 weeks of management of this patient population are discussed. There are several notable revisions and new recommendations important for the EM pharmacist. First, although the primary goal of achieving door-to-needle time of 60 minutes or less in patients treated with i.v. alteplase continues to be the standard, new recommendations suggest a goal of 45 minutes may be reasonable. Additional recommendations are made regarding telestroke care and remote consultation for alteplase administration. This guideline update clarifies that blood glucose is the only laboratory assessment that must precede the initiation of i.v. alteplase; all other laboratory assessments should not delay initiation. Recommended blood pressure goals are not changed; hypotension and hypovolemia should be corrected to maintain systemic perfusion. Qualifications for i.v. alteplase therapy remain largely unchanged; however, recommendations regarding eligibility are less stringent. Two important changes are that the expanded criteria previously used in the ECASS-III trial to exclude some patients presenting within the 3- to 4.5-hour alteplase treatment window (age of >80 years; taking warfarin, regardless of INR; combined history of diabetes mellitus and previous ischemic stroke; and NIH Stroke Scale score of >25) were removed, and use of teleplase in those patients is now considered safe. Also, patients taking thrombin inhibitors or factor Xa inhibitors can receive alteplase as long as the last dose was not within the previous 48 hours and all laboratory tests are normal. The updated guidelines also recommend i.v. alteplase for patients with sickle cell disease who present with an AIS. Recommendations for symptomatic ICH within 24 hours and orolingual angioedema following i.v. alteplase are provided. Substantial challenges with guideline interpretation and implementation of i.v. alteplase therapy per these updated recommendations include a dearth of new data from prospective RCTs and a heavy reliance on scientific statements and retrospective database analysis to support recommendations. EM pharmacist takeaway The only required laboratory value prior to i.v. alteplase is glucose. Previous exclusion criteria for patients with AIS presenting within the 3- to 4.5-hour treatment window have been removed, and those who have not taken thrombin or factor Xa inhibitors in the previous 48 hours are eligible for i.v. alteplase. Campbell et al. Tenecteplase vs alteplase before thrombectomy for ischemic stroke.70 Administration of i.v. alteplase for stroke requires a complex administration process with a bolus dose and infusion over 60 minutes. There are potential pharmacologic advantages to tenecteplase; its longer half-life allows for a single bolus administration, which can result in quicker time to total dose administration, and its greater fibrin specificity can potentially lower the incidence of bleeding complications. Consequently, with tenecteplase use there is a potential for improved reperfusion and clinical and functional outcomes. This randomized, multicenter, open-label trial evaluated 202 patients with AIS presenting within 4.5 hours of symptom onset who were eligible to undergo thrombectomy. Patients were randomly assigned to receive either tenecteplase 0.25 mg/kg i.v. (maximum dose, 25 mg) or alteplase 0.9 mg/kg i.v. (maximum dose, 90 mg) before thrombectomy. Patients who received tenecteplase had a higher incidence of reperfusion compared to alteplase (22% vs 10%, P = 0.002) and improved 90-day modified Rankin scale scores (P = 0.04), with no significant difference in bleeding outcomes. As only patients with large-vessel occlusions were included, the study population represented a small portion of AIS patients. A subsequent study to evaluate patients not eligible for thrombectomy is planned. One critical issue that needs resolution is identifying the optimal dose of tenecteplase in this setting. In this study a dose of 0.25 mg/kg was used, whereas other researchers have studied doses of 0.1 mg/kg and 0.4 mg/kg.71,72 Nevertheless, tenecteplase is an attractive option whose use has the potential to yield logistical advantages in the ED setting (ie, in managing patients being transported for thrombectomy) as well as in the prehospital setting (ie, in managing patients being transferred to a stroke center). EM pharmacist takeaway Tenecteplase may represent the future of i.v. thrombolytic therapy for AIS, perhaps providing logistical advantages and the potential for reduced adverse effects. Intracranial hemorrhage Qureshi et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage.73 In the multicenter, open-label Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 trial, investigators randomly assigned 1,000 patients presenting with ICH and a Glasgow Coma Score of ≥5 to intensive SBP control with a target of 110 to 139 mm Hg or standard treatment with a target of 140 to 179 mm Hg. Blood pressure control was maintained with i.v. nicardipine. The rate of occurrence of the primary outcome of death or disability was not significantly different between the 2 groups, and the trial was stopped early for futility reasons. There was also no significant difference in the incidence of serious adverse events within 72 hours between the 2 groups. There was, however, a significantly higher rate of renal adverse events within 7 days in the intensive-treatment group compared with the standard treatment group (9% vs 4%, P = 0.002). This study was prompted by the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT)-2 trial, in which patients were randomly assigned to intensive or standard treatment groups (SBP targets of <140 mm Hg and <180 mm Hg, respectively) and there was a nonsignificantly lower rate of death or disability in the intensive treatment group.74 The rationale for the different outcomes in the 2 trials largely hinges on the actual implementation of the blood pressure parameters. In the ATACH-2 trial the mean SBP in the first 2 hours was 128.9 mm Hg in the intensive treatment group and 141.1 mm Hg in the standard treatment group, with both values being within the groups’ respective target ranges. In the INTERACT2 study, however, the mean SBP was 150 mm Hg in the intensive treatment group and 164 mm Hg in the standard treatment group, with the former value missing the assigned group target (<140 mm Hg). Both groups in the INTERACT2 study, therefore, had SBP values similar to those in the standard treatment group in the ATACH-2 study (140–179 mm Hg). There were also several methodological and baseline characteristic differences that may have contributed to the discordant results. Nevertheless, a lower blood pressure target is not always beneficial in this population and may negatively impact end-organ function. The ATACH-2 investigators concluded that treatment to achieve a target SBP of 140 to 179 mm Hg is as effective as treatment to achieve lower blood pressure targets in improving functional outcomes in this population. EM pharmacist takeaway The optimal target blood pressure for ICH remains debatable, and a collective discussion with your EM interdisciplinary team is recommended to develop a consensus target range SBP for antihypertensive therapy that is below 180 mm Hg. Hemphill et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.75 This guideline is an update of a previous version published in 2010 providing recommendations for the diagnosis and treatment of spontaneous ICH. Specifically, regarding the restoration of hemostasis, these guidelines state that preferential use of PCCs over FFP combined with i.v. vitamin K should be considered, and they do not recommend the use of recombinant activated factor VII (rFVIIa). The authors note that while FFP is effective, the time involved in thawing and the large volume of FFP that often required substantially limit the utility of FFP when a rapidly available, low-volume, and therapeutically equivalent product is available. These recommendations are based largely on results of a multicenter open-label trial involving 202 patients with major bleeding requiring VKA reversal (98 received 4F-PCC and 104 received FFP), in which hemostasis at 24 hours occurred at rates of 72% and 65% and INR of ≤1.3 at 30 minutes occurred in 62% and 10% of patients treated with 4F-PCC and FFP, respectively; 17 rates of thromboembolic events were similar (7.8% vs 6.4%). Limitations of these and similar data are that the endpoints focused on time to INR reversal compared to clinical efficacy outcomes, and hemostasis endpoints were not evaluated at the bedside but by an adjudication board. Despite the ability of rFVIIa to normalize INR measurements (calculated on the basis of FVII-sensitive prothrombin time), it lacks factors II, IX, and X and cannot be recommended over PCC. For reversal of direct thrombin and factor Xa inhibitors, the authors recommend treatment with FEIBA, other PCCs, or rFVIIa, depending on the specific agent involved. The authors note that preliminary data indicate that FEIBA or rFVIIa may be better for reversal of direct thrombin inhibitors, while other PCCs may be better for reversal of factor Xa inhibitors. It should be cautioned that this guideline was published prior to the availability of drug-specific reversal agents (idarucizumab and andexanet alfa). Activated charcoal may be considered if dabigatran, apixaban, or rivaroxaban was ingested less than 2 hours prior to presentation (the previously recommended limit was 4 hours). In the absence of platelet function analysis, platelet transfusions are not recommended for patients with a history of antiplatelet use. Lastly, the previous practice of administering rFVIIa for treatment of ICH unrelated to anticoagulant use is not recommended, as data are inconclusive and there is potential for harm. Lowering blood pressure to 140 mm Hg is safe and may yield improved functional outcomes. At the time of writing, results from the ATACH-2 trial were not published, and the recommendations discussed here were primarily based on INTERACT2 trial data. Additional recommendations are avoidance of hyperglycemia or hypoglycemia (although no specific range is recommended), maintenance of normothermia, and treatment of seizures with antiseizure drugs (no specific drug recommendations). The guidelines also recommend against corticosteroid treatment for elevated intracranial pressure (ICP) due to the absence of benefit and potential for adverse effects. While guidelines form some of the strongest support for clinical practice standards, it is important to recognize the date range of the literature review on which the authors’ recommendations were based. As mentioned, these guidelines do not reflect results of the ATACH-2 trial, the Neurocritical Care Society’s guideline for reversal of antithrombotics in intracranial hemorrhage, and the 2017 American College of Cardiology expert consensus decision pathway on management of bleeding in patients on oral anticoagulants.16,73,76 EM pharmacist takeaway PCCs are recommended for anticoagulation reversal of VKA-associated ICH. Avoiding glucose derangements, maintaining normothermia, and treating seizures are recommended, and use of rFVIIa to treat ICH unrelated to anticoagulation or corticosteroids is not recommended. Recommendations regarding reversal of DOACs and blood pressure lowering should be interpreted within the context of subsequent landmark trials and guidelines. Status epilepticus Huff JS et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures.77 This ACEP policy is a revision of a 2004 policy regarding the evaluation and management of adult patients with seizures in the ED and was also endorsed by the Emergency Nurses Association. The policy addresses many aspects of ED seizure management, an area not typically covered by other guidelines. A low-level recommendation that EM physicians do not need to initiate antiepileptic medications in the ED for patients experiencing their first provoked or unprovoked seizure is provided. EM physicians may initiate or defer antiepileptic medication therapy in patients experiencing their first unprovoked seizure who have a remote history of brain disease or injury. Admission is not required following the first unprovoked seizure as long as the patient returns to baseline status in the ED. The largest portion of this policy discusses which agents are recommended for patients with generalized convulsive status epilepticus refractory to optimal benzodiazepine dosing. However, the optimal benzodiazepine agent, route, and dosing for initial therapy for generalized convulsive status epilepticus in the ED is not discussed or defined in this policy. Regarding the selection of additional antiepileptic agents following benzodiazepines, the authors provide a level B recommendation for i.v. phenytoin, fosphenytoin, or valproate and a level C recommendation for i.v. levetiracetam, propofol, or barbiturates in those for whom optimal benzodiazepine therapy has failed. The authors acknowledge that valproate may have some advantages over phenytoin or fosphenytoin with regard to fewer adverse effects. Existing data are insufficient to support a stronger recommendation for levetiracetam, although various small, retrospective studies have indicated that it may be an efficacious intervention. Unclear etiology, concomitant pharmacotherapy, and medical history are challenges when treating treatment-refractory status epilepticus in the ED. While the literature remains far more robust for older agents like phenytoin, fosphenytoin, and valproate compared to newer agents like levetiracetam, this should not prevent clinicians from tailoring medication selection based on individual patient characteristics to avoid potential drug-drug or drug-disease interactions. EM pharmacist takeaway Not all patients presenting with their first seizure need to be admitted to the hospital or initiated on antiepileptic medications. Use of older agents like phenytoin, fosphenytoin, and valproate is supported by a higher-level recommendation than use of newer agents like levetiracetam in status epilepticus refractory to treatment with benzodiazepines. Brophy et al. Guidelines for the evaluation and management of status epilepticus.78 This is the first edition of these guidelines from the Neurocritical Care Society regarding management of acute status epilepticus in critically ill patients. It is comprehensive not only in its review of the literature but also in its clear and evidence-supported definitions, classifications, and evaluations of status epilepticus. Etiologies, diagnostic workups, and prognosis are all discussed and reviewed. Treatment options for the acute management of status epilepticus, as well as optimal dosing and routes of administration and administration considerations, are all discussed. Lorazepam is the preferred i.v. benzodiazepine (0.1 mg/kg up to 4 mg repeated every 5–10 minutes), midazolam is preferred for i.m. (0.2 mg/kg up to 10 mg), intranasal (0.2 mg/kg), or buccal (0.5 mg/kg) administration, and diazepam is preferred for rectal administration. Some EDs may not maintain rectal diazepam stock, and i.m. administration is preferred in patients without i.v. access. Available evidence supports the use of i.v. phenytoin or fosphenytoin (20 mg/kg; an additional 5–10 mg/kg may be given), phenobarbital (20 mg/kg; an additional 5–10 mg/kg may be given), and valproate (20–40 mg/kg; an additional 20 mg/kg may be given) as first-line antiepileptic agents; i.v. levetiracetam (20–60 mg/kg) may be used. That said, all of these treatments were given the same class IIb category recommendation by the authors. Management of treatment-refractory status epilepticus is reviewed, and the administration of a continuous infusion of midazolam, pentobarbital, or propofol is recommended. Alternative therapies for refractory status epilepticus include ketamine and corticosteroids, and nonpharmacologic agents may include vagal nerve stimulation, ketogenic diets, hypothermia, and electroconvulsive therapy. From an ED management perspective, this guideline is particularly useful because of its detailed review of initial benzodiazepine therapy, including maximum doses per administration, as well as adult and pediatric weight-based dosing for all agents. Administration recommendations are also exceedingly useful when helping to develop detailed guidance for nursing colleagues. EM pharmacist takeaway The optimal benzodiazepine, dose, and route should be selected for each patient in order to ensure termination of status epilepticus across all age groups. Phenytoin or fosphenytoin, phenobarbital, valproate, and levetiracetam are recommended first-line antiepileptic agents for status epilepticus refractory to benzodiazepines. Migraine Orr et al. Management of adults with acute migraine in the emergency department: The American Headache Society evidence assessment of parenteral pharmacotherapies.79 This evidence assessment sought to answer the question of which injectable medications are first-line therapies for adults who present to the ED with an acute migraine and to determine if parenteral corticosteroids prevent recurrence of migraine in adults who are discharged from the ED. The authors reviewed 68 RCTs that evaluated 28 different injectable medications and concluded that i.v. metoclopramide (10–20 mg), i.v. prochlorperazine (10 mg), and subcutaneous sumatriptan (6 mg) should be offered to adult patients who present to the ED with acute migraine. Dexamethasone (the ideal dose could not be determined; 10–24 mg is typical) is recommended to prevent recurrence, but the risk of treatment-related adverse effects needs to be evaluated on a patient-by-patient basis. The authors concluded that i.v. morphine, hydromorphone, and lidocaine should be avoided in adult patients who present to the ED with acute migraine. Based on the currently available evidence, no recommendations were made for dihydroergotamine, ketamine, magnesium, or propofol. The greatest strength of this review was the systematic and very thorough exploration of the literature that was conducted, with initial identification of 2,050 studies. A significant limitation was that only 19 of the 68 included studies were rated as having a low risk of bias, resulting in no “level A-must offer” recommendations and potentially confounding the results. Some studies evaluating the use of sumatriptan were conducted outside of the ED setting, limiting external validity. Although sumatriptan is recommended as an agent that should be offered to patients with migraine, the reviewed studies indicated that it is most effective if administered very early after onset, which can be challenging in an ED. EM pharmacist takeaway: Metoclopramide and prochlorperazine are first-line agents for patients presenting to the ED with acute migraine. Opioid therapy should be avoided. Patniyot et al. Acute treatment therapies for pediatric migraine: a qualitative systemic review.80 This systematic review of 31 studies of pediatric patients presenting to an ED or outpatient acute care setting sought to evaluate the safety and efficacy of available acute treatments for migraine or benign primary headache. Ibuprofen (10 mg/kg), prochlorperazine (0.15 mg/kg up to 10 mg) and certain triptan medications (almotriptan, rizatriptan, zolmitriptan nasal spray, sumatriptan nasal spray, and combination sumatriptan/naproxen) were deemed the most effective and safest agents. Acetaminophen was considered less effective than ibuprofen, and i.v. fluids, chlorpromazine, valproate, injectable sumatriptan, and i.v. dihydroergotamine were considered probably effective. There was insufficient evidence to recommend propofol, magnesium, or bupivacaine. The strength of this literature evaluation was the authors’ thoroughness and detailed review, with 410 studies initially screened for inclusion; however, only 17 of the included 31 studies were RCTs. Also, available studies were strongly weighted towards triptan medications, with 14 studies pertaining to their use. EM pharmacist takeaway Ibuprofen, prochlorperazine, and triptan medications are the most effective and safest agents for the management of pediatric migraine. PHARMACY SERVICES AND PATIENT SAFETY Position statements and guidelines Eppert et al. ASHP guidelines on emergency medicine pharmacist services. 81 These guidelines provide the framework for the role of an EM pharmacist. Focused on establishing best practices for EM pharmacist services and suggesting goals for providing services to meet institution-specific needs, these guidelines were developed based on primary literature, therapeutic and practice guidelines, national standards, and consensus of EM pharmacist experts. The document describes 2 levels of services: essential (core) and desirable. It is noted that the level of service may vary between different institutions. Continuous EM pharmacist coverage (24 hours a day and 7 days per week) is described as optimal but also must be individualized to suit institutional and ED needs and limited resources. Essential direct patient care roles are described as resuscitation, bedside patient care evaluation and medication order review targeting high-risk medications and procedures, documentation, medication information, therapy monitoring, and medication procurement and preparation. Essential administrative roles include optimization of medication and patient safety, leadership and professional service provision, and involvement in quality improvement initiatives and emergency preparedness. Care of boarding patients, education, and research and scholarly activity are listed as desirable roles. One limitation of these guidelines is the lack of description of necessary skills and training of an EM pharmacist specialist; however, these guidelines were developed prior to the proliferation of advanced training programs. In the past decade, this pharmacist specialty has grown significantly, as have the levels and types of services provided. An update to these guidelines is in development to better reflect current EM pharmacist specialist roles. EM pharmacist takeaway Essential and desirable EM pharmacist roles are described. These guidelines provide the framework for EM pharmacist services and should be referenced to prioritize services in the ED during pharmacy service development or optimization. American College of Emergency Physicians. Clinical pharmacist services in the emergency department.82 Farmer et al. The role of clinical pharmacists in the emergency depart- ment.83 Emergency medicine pharmacist recognition and support extends beyond pharmacist organizations, with both ACEP and the American College of Medical Toxicology (ACMT) having published supportive statements. In 2015, ACEP recognized EM pharmacists as critical members of the interdisciplinary EM team with regard to ensuring effective, safe, and efficient medication use during patient care decisions, resuscitation, and transitions of care.82 ACEP advocates for dedicated pharmacists in the ED, an environment for EM pharmacist training and pharmacist participation in EM-related research. Also, in a 2017 published statement of support ACMT highlights the positive impact EM pharmacists have on outcome measures such as timely medication administration during critical illness and time-dependent emergencies, optimization of therapy related to patient-specific medication selection considering evidence-based medicine and national quality standards, medication safety through prescribing error interventions, recognition of adverse drug events, improvement in transitions of care, cost avoidance through error reduction, quality improvement and attainment of quality standards, prevention of readmissions, and patient satisfaction.83 Support from these organizations solidifies the importance of EM pharmacists as part of the interdisciplinary EM team and defines their role for nonpharmacist colleagues. EM pharmacist takeaway Both ACEP and ACMT have published statements supporting inclusion of EM pharmacists on the interdisciplinary EM team. These support statements help advance the EM pharmacy specialty and can be used to support EM pharmacist services or service expansion. Update on EM clinical pharmacy practice Thomas et al. A national survey of emergency pharmacy practice in the United States.84 This large, national survey of 187 EM pharmacists conducted in 2015 provides the most recent comprehensive information on the clinical, educational, and administrative activities of EM pharmacists in community and academic medical centers. All respondents reported weekday EM pharmacy services and 64.8% reported some weekend coverage. Nine or more hours of EM pharmacist coverage on weekdays and on weekends was reported by 68.4% and 48.9% of respondents, respectively. The most frequent coverage hours on both weekdays and weekends were 1 PM to midnight. Clinical activities like pharmacotherapy and toxicology consultation, drug information requests, patient education, and culture follow-up accounted for the greatest share of time commitment by EM pharmacists (25%; interquartile range [IQR], 15%-40%), followed by emergency response (15%; IQR, 10%-20%) and prospective order review (15%; IQR, 5%-25%), medication history/reconciliation (10%; IQR, 5%-25%), teaching (didactic education of prehospital providers, EM clinicians, and nurses; pharmacy student and resident training; and bedside education of the EM team) (10%; IQR, 5%-15%), and administrative (5%; IQR, 3%-10%) and scholarly (0%; IQR 0%-5%) activities. Further description of these activity areas is provided in this article, which can be a good resource for new or growing EM pharmacy programs to reference and use in targeting initiatives. Most respondents (77.8%) reported some pharmacist involvement in medication history/reconciliation activities, but only 4.7% reported that pharmacists were routinely responsible for these tasks for most ED patients. When respondents were asked if this activity should be lessened for pharmacists, most agreed that it should. It is highlighted by the authors that there seems to be a gap in visions of responsibilities between hospital administrators and pharmacists practicing in the ED, and this is an important area to address in the development of clinical pharmacist roles in the ED. Overall, these data suggest a shift to increased EM pharmacist involvement in clinical activities as opposed to inventory management. EM pharmacy services data representing community and academic centers (previous reports focused on academic centers) strengthen the generalizability of the survey results. EM pharmacist takeaway Clinical activities, emergency response, and prospective order review account for the greatest amount of time commitment for EM pharmacists. Findings from this survey can be used as a peer comparison to guide optimization and expansion of EM pharmacist service activities. Roman et al. Roles of the emergency medicine pharmacist: a systematic review.85 Comparative studies reporting patient outcomes from EM pharmacist team integration or interventions in the general ED setting or trauma center were targeted for this systematic review. In total, 15 studies met the inclusion criteria: 6 studies of outcomes related to trauma or resuscitation (time to post–rapid sequence intubation analgesia and sedation, time from arrival to analgesia, and change in pain score), stroke (door-to-needle time), or MI (time from door to cardiac catheterization laboratory arrival and/or balloon insertion); 5 studies of outcomes related to culture follow-up (incidence and time to regimen revision, time to review and/or notification, and readmission occurrence); 2 studies of outcomes related to on medication histories and pharmacist-generated home medication ordering (errors and discrepancies); and 2 studies of outcomes related to HCAP (appropriate antimicrobial regimen, dose, and time to antibiotics) and appropriate phenytoin loading doses, respectively. All studies showed positive patient outcomes for the various endpoints described above. Methodological strengths were the comprehensive literature review and blinded review for inclusion. Studies with descriptive results were excluded, but only involvement in sepsis management was not captured by the inclusion strategy. Many of the reviewed studies were retrospective studies but still provided necessary data support for evolving EM pharmacist roles that improve patient outcomes and show the value of creating these positions. EM pharmacist takeaway Studies focused on trauma or resuscitation, culture surveillance and follow-up, and AIS and MI team response, among other practice areas, have shown improved patient outcomes with EM pharmacist participation. This systematic review provides a summation of these studies necessary to help justify and expand EM pharmacist services. This document can also be used to direct EM pharmacist services to those areas in which they can have the greatest impact. EM pharmacist–related medication safety Rothschild et al. Medication errors recovered by emergency department pharmacists.86 Patanwala et al. A prospective, multicenter study of pharmacist activities resulting in medication error interception in the emergency department.87 The ED practice environment is vulnerable to medication errors. Two prospective studies were able to assess the impact of EM pharmacists on patient safety. Rothschild et al86 conducted an observational study at 4 academic medical center EDs in which pharmacy residents observed 787 hours of EM pharmacist order review. Care was provided by the EM pharmacist to 6,471 patients, and 17,320 medication orders were reviewed. A total of 504 medication errors were intercepted by EM pharmacists (a rate of 7.8 errors per 100 patients or 2.9 per 100 medications). Most intercepted errors were potential adverse drug events (90% did not reach the patient) and were classified as serious (48%) or significant (36%). As expected, antimicrobials, CNS agents, and anticoagulation and thrombolytic agents accounted for the majority of involved medications. The multicenter design (albeit including only academic centers), use of observers to perform data collection, and use of case reviewers to individually review and classify suspected errors were strengths of this study. However, this study did not assess the impact of EM pharmacists on patient safety outside of medication error review and did not describe other EM pharmacist activities associated with medication error intervention. As a result, Patanwala et al designed a study to capture not only the rate of error interception but also the EM pharmacist activities that led to the recovered errors.87 Four geographically diverse sites, including academic and community medical centers, were represented in this study. A total of 1,000 EM pharmacist hours were captured, and 16,446 patients presented to the EDs during the study period. As in the study of Rothschild et al, medication errors collected were independently reviewed; there were 364 confirmed medication errors. Interestingly, most of the errors were captured during consultative activities (51.4%) or medication order review (34.9%). Also, 82.4% of errors were caught in the prescribing phase, and 32.7% involved verbal orders. The results of this study established that the physical presence of pharmacists in the ED and their involvement in consultative activities are associated with the most impact related to medication error intervention. In both of these studies, data were collected as a convenience sample and EM pharmacists were not blinded to the study goals and may have been more diligent during study periods in order to achieve a higher medication error recovery rate. Nonetheless, these studies provide robust data describing the role of the pharmacist as it relates to reducing medication errors in the ED. EM pharmacist takeaway EM pharmacists reduce medication errors in the ED, and these studies provide important support for justification or expansion of services. Further, they describe that pharmacists’ physical presence in the ED, as opposed to involvement from a remote location, is most impactful for medication error reduction. Pevnick et al. Improving admission medication reconciliation with pharmacists or pharmacy technicians in the emergency department: a randomised controlled trial.88 This was an RCT comparing the accuracy of medication histories taken in the ED by pharmacists, by pharmacy technicians, or by standard processes. The sample included complex patients being admitted from the ED. Patients with 10 or more chronic prescriptions, complex disease states (eg, heart failure or transplant), or high-risk or narrow therapeutic index medications (eg, insulin or anticoagulants) and patients presenting from a skilled nursing facility were targeted. In all study arms the usual approach to obtaining a medication history was used first, with several process variations (electronic health record information, ED nurse–obtained medication history, and patient- and/or caregiver-provided written information or medication bottles); the initially obtained histories served as a control. Patients were then screened and randomly assigned to the 3 intervention arms for compilation of a best possible admission medication history. Reference standards for detection of admission medication history errors were obtained in all intervention arms by expert pharmacists (based on previous experience) following admission. These histories were more comprehensive since they began with the initial admission medication history and often contained new information available after admission (eg, medication lists or documentation of improved mental status) and information on errors identified during clinical care. The primary outcome was mean severity-weighted admission medication history score. Errors identified between the intervention and control admission medication histories and the reference standard were then rated as significant, serious, or life-threatening and assigned weights of 1, 4, and 9, respectively. A total of 278 patients were assessed. The performance of both pharmacy groups (pharmacists and pharmacy technicians) was better than the usual care approach. Mean (SD) numbers of admission medication history errors per patient were 1.4 (1.9), 1.5 (2.1), and 8 (5.6) in the pharmacist, technician, and usual care groups, respectively (P < 0.0001), with mean (SD) severity-weighted scores of 4.1 (6.8), 4.1 (7.0), and 23 (16.1), respectively. Similarly, mean (SD) numbers of admission order errors per patient were 0.6 (1.1), 0.6 (1.1), and 3.2 (2.9) in the pharmacist, technician, and usual care groups, respectively (P < 0.0001), with mean (SD) severity-weighted scores of 1.5 (2.9), 1.2 (2.5), and 6.9 (7.2), respectively. There were no statistically significant between-group differences in the rate of LOS or readmission within 30 days, but the rate was approximately 10% lower in both pharmacy arms vs the usual care group. The authors concluded that pharmacists and technicians reduced admission medication history and order errors by over 80%; there was a consistent positive effect by pharmacists and technicians when controlling for error severity and patients lost to follow-up. One key finding of this study was that pharmacy technicians can accurately obtain a medication history from complex patients in the ED setting. This has implications for pharmacy practice in the ED because it provides evidence to support pharmacists transitioning to more of a supervisory capacity with regard to medication history taking. Increased utilization of pharmacy extenders such as technicians and pharmacy students may be a suitable cost-effective strategy to improve safety during this important transition of care. EM pharmacist takeaway Pharmacists and pharmacy technicians provide more accurate medication histories than are obtained via standard processes in the ED. Pharmacist extenders should be considered for ED medication history-taking activities. ED antimicrobial stewardship Losier et al. A systematic review of antimicrobial stewardship interventions in the emergency department.89 Antimicrobials are routinely prescribed for a variety of infectious disease states in the ED, and reducing inappropriate use is necessary to preserve antimicrobial effectiveness. There are also patient safety concerns due to the risks of allergic reactions and other adverse effects. The ED has traditionally been a difficult area to target for antimicrobial stewardship (AS) given the need for quick decision making, often with minimal information. But arguably, the empiric decision is the most important as it influences continued therapy in both the outpatient and inpatient settings. Emergency department AS efforts have been described and include incorporation of EM pharmacists to lead or support AS interventions, culture surveillance and follow-up programs, prospective audit with intervention and feedback, education of EM staff, guideline and clinical pathway development, clinical decision support systems, clinical justification requirements for antimicrobials, formulary restriction, rapid diagnostic testing, shortening of duration of therapy, dose optimization, and ED antibiogram development.90 This systematic review identified 43 studies evaluating ED antimicrobial stewardship interventions that improve patient outcomes and decrease consequences of antimicrobial use. The most common interventions were patient or clinician education or clinical pathway or clinical decision support implementation alone or in combination (19 studies). Adherence to guidelines, appropriateness of prescribing, and decreased antimicrobial use were the most frequent interventions evaluated. Five studies showed improved patient outcomes related to ED or hospital LOS, reduced hospital admissions of low-risk patients, ICU admission, ED returns and/or readmission, and mortality. In 13 studies, pharmacist involvement was described, most often in relation to pharmacist-managed culture surveillance and follow-up, and compared to other programs; the studies showed that pharmacist involvement resulted in improvement in time to review, increases in appropriate prescribing or interventions to reduce inappropriate therapy, and reduction in ED returns and/or readmissions. Among the included studies, 2 were RCTs—one evaluating CAP pathway implementation aimed at reducing hospital LOS and the other evaluating a 16-hospital implementation of a respiratory tract infection pathway along with education at 16 hospitals that promoted appropriate antibiotic use and ultimately reduced overall antibiotic use. Many of the studies included were small, retrospective, and lacked randomization, but this review provides an inclusive evaluation of all ED-targeted AS initiatives. Further research is needed to measure effects of these initiatives on patient outcomes. This is a key publication to assist EM pharmacists with developing AS activities. EM pharmacist takeaway The most common AS interventions in the ED are focused on clinician education or clinical decision support (or both). EM pharmacist involvement is most fully described in relation to ED culture surveillance and follow-up. This document can help EM pharmacists target ED-based AS interventions for maximum impact on patient outcomes. RESPIRATORY CARE Acute severe asthma Su et al. Intravenous and nebulized magnesium sulfate for treating acute asthma in children: a systematic review and meta-analysis.91 Magnesium sulfate has several purported mechanisms in the management of acute asthma. As an adjunct to standard therapy, magnesium may enhance relaxation of bronchial smooth muscles and inhibit release of both acetylcholine and histamine as a means to mitigate common signs and symptoms associated with this condition. Ten randomized trials were included in this systematic review and meta-analysis focused on pediatric patients with moderate to severe asthma. Six studies evaluated i.v. magnesium (n = 165, with 160 controls) and 4 evaluated nebulized magnesium (n = 433, with 437 controls). Doses ranged from 25 to 100 mg/kg (maximum of 2 g and median of 40 mg/kg) administered over 20 to 35 minutes for i.v. therapy and at a dose of approximately 150 mg for nebulizer therapy. Treatment with i.v. magnesium was associated with an improvement in pulmonary function (standard mean difference, 1.94; 95% CI, 0.80–3.08, P = 0.0008) and reduced hospital admissions (RR, 0.55; 95% CI, 0.31–0.95, P = 0.03); these benefits not seen with nebulized magnesium administration. The authors reported that i.v. magnesium may be a reasonable adjunctive therapy for pediatric moderate to severe asthma and may decrease hospital admissions. An important consideration when interpreting this analysis is that pulmonary function outcome measures, bronchodilator therapy, corticosteroid regimens, and other cointerventions were variable. Further, there is no consensus regarding optimal i.v. magnesium dosing. This analysis does not provide insights on adult management, although i.v. magnesium is recommended for adults with a peak expiratory flow of <50% best or predicted to have poor response to initial bronchodilator therapy per British Thoracic Society/Scottish Intercollegiate Guideline Network guidelines.92 EM pharmacist takeaway With its bronchodilatory effects, i.v. magnesium is recommended as an adjunctive agent for moderate to severe pediatric asthma exacerbation in the ED, and its use may lead to potential avoidance of inpatient admission. Kirkland et al. Intramuscular vs oral corticosteroids to reduce relapses following discharge from the emergency department for acute asthma.93 Corticosteroids are often used in the management of moderate to severe acute asthma. The authors of this systematic review and meta-analysis evaluated 9 studies of single-dose i.m. corticosteroid therapy (n = 402) vs a short course of oral corticosteroids (n = 402) prior to ED discharge in both adult and pediatric patients. All pediatric patients received i.m. dexamethasone, while adults received dexamethasone, methylprednisolone, betamethasone, or triamcinolone (median dose, 78 mg of methylprednisolone equivalents; range, 40–120 mg). In all pediatric studies oral prednisone/prednisolone was used as the comparator, while adult studies involved use of oral prednisone, methylprednisolone, or dexamethasone. Overall, there were minimal differences in pulmonary function and incidence of relapse between the i.m. and oral treatment groups; fewer adverse events were reported in the i.m. corticosteroid group. Based on the low to moderate quality of evidence identified in this analysis, there is insufficient evidence to determine whether i.m. corticosteroids are more or less effective than oral corticosteroid therapy in these patient populations. There were many analytical limitations, including the lack of standardization of corticosteroid product and dose and oral therapy duration, differing dose adjustment strategies (taper vs no taper), varying definitions of postdischarge relapse, and inconsistent cointerventions (although most were standardized). In the ED, it is often more convenient to provide a single therapeutic dose rather than discharge patients with a prescription, as there are a variety of barriers to patients getting prescriptions filled as well as unknown regimen adherence. Nonetheless, this analysis provides reasonable evidence to support a single i.m. dose of corticosteroid therapy if corticosteroids are being considered as part of acute asthma management. EM pharmacist takeaway A single i.m. dose of corticosteroid therapy may be reasonable to consider as an alternative to a short course of oral corticosteroids in the management of adult or pediatric acute asthma exacerbations in the ED. Chronic obstructive pulmonary disease Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management and prevention of COPD, GOLD94 These recently updated guidelines provide recommendations for acute exacerbation and maintenance management of chronic obstructive pulmonary disease (COPD), definitions for acute respiratory failure (non–life-threatening and life-threatening), and indications for hospitalization. Though the majority of COPD exacerbations can be managed in the outpatient setting with the help of COPD action plans that include corticosteroids and antibiotics, it is important for EM pharmacists to understand pharmacotherapeutic management for patients with COPD who present to the ED. Short-acting β 2-agonists (delivered nebulized or with a metered-dose inhaler) every hour for 2 to 3 doses (recommended over continuous administration) and then every 2 to 4 hours, with or without short-acting anticholinergics and prednisone 40 mg daily for 5 days to shorten recovery time and improve forced expiratory volume, are recommended. The authors also review the controversy surrounding antibiotic use, provide discussion on the use of biomarkers to evaluate patients for airway infection, and support antibiotic use for 5 to 7 days when patients have at least 2 of the 3 clinical signs of bacterial infection (increased dyspnea, increased sputum volume, and sputum purulence). A review of newer pharmacotherapy treatment options and directions for future research are also provided. EM pharmacist takeaway Short-acting β 2-agonists and a short course of steroids are recommended for patients with COPD exacerbations presenting to the ED. A short course of antibiotics should only be used in select patients. SHOCK Advanced cardiac life support Link et al. Part 7: Adult advanced cardiovascular life support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care.95 Callaway et al. Part 8: Post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care.96 These guidelines update the previous 2010 AHA guidelines on cardiopulmonary resuscitation (CPR) and emergency cardiovascular care and is focused on changes to advanced cardiac life support (ACLS), in-hospital cardiac arrest (IHCA), OHCA, and targeted temperature management (TTM). Specific updates related to ACLS medications focus on the use and timing of epinephrine administration and vasopressin. Data from several large observational studies evaluating timing of epinephrine administration in patients with IHCA and OHCA (with both nonshockable and shockable rhythms) were used to guide recommendations. In patients with nonshockable rhythms, early administration of epinephrine (ie, within 1 to 3 minutes of CPR initiation for IHCA and within 10 minutes of EMS-initiated CPR for OHCA) increased rates of ROSC, survival to hospital discharge, survival at 1 month, and good neurologic outcome. The same recommendation cannot be translated to shockable rhythms, as epinephrine use along with early defibrillation could not be determined. Vasopressin was removed from all algorithms due to the lack of improved outcomes in terms of achieving ROSC, discharge with a good neurologic outcome (cerebral performance category of 1 or 2), or survival to hospital admission or discharge. As an adjunct to epinephrine and vasopressin therapy in IHCA, corticosteroids have been found to increase ROSC and survival to discharge with a good neurologic outcome compared to outcomes with epinephrine alone97; this is thought to be due to a corticosteroid-induced reduction of proinflammatory cytokines and decreased vasodilation. With the removal of vasopressin, it is difficult to interpret the medication bundle used in these studies: methylprednisolone 40 mg i.v. once (with hydrocortisone administered for 7 days and then tapered) along with epinephrine 1 mg i.v. and vasopressin 20 units i.v. every cycle. AHA does give the use of steroids with epinephrine a weak recommendation, but more studies are needed to investigate the outcomes associated with this regimen. This update of the AHA ACLS guideline recommends TTM at 32oC to 36oC for a minimum of 24 hours in both IHCA and OHCA. Data detailing these recommendations are included later in this section. The ACLS guidelines are updated every 5 years, with the next update expected in 2020. Although not included in these AHA guideline updates and outside of our inclusion date range, we would be remiss to not discuss the most recent AHA update related to antiarrhythmic use during and immediately after cardiac arrest.98 Previously amiodarone (5 mg/kg up to 300 mg for the first dose, 150 mg for the second) was the preferred antiarrhythmic agent; however, lidocaine (1–1.5 mg/kg for the first dose, 0.5–0.75 mg/kg for the second) may also be considered in patients with shockable rhythms unresponsive to defibrillation, particularly in witnessed arrests where time to medication administration is shorter. The authors acknowledge there is a lack of evidence regarding long-term survival with use of these agents but felt that short-term outcomes of antiarrhythmic use (improved survival to hospital admission and improved survival to hospital discharge), as documented in the ROC-ALPS study, warranted the recommendation.99 Magnesium is not recommended during cardiac arrest unless there is evidence of torsades de pointes. Although β-adrenergic agents are thought to reduce ischemic injury and have membrane-stabilizing effects, their use within the first hour after ROSC is not recommended owing to a lack of supporting evidence. The authors state that β-blocker use may precipitate hemodynamic instability and exacerbate heart failure and may therefore be hazardous. Lidocaine is not routinely recommended in the first hour after ROSC; however, it may be considered in the prehospital setting to manage recurrent VF or pulseless VT (pVT). Regardless of these medication recommendations, it is known that early, high-quality CPR, with minimal interruptions, timely defibrillation when appropriate, and good teamwork, provide the greatest survival impact. EM pharmacist takeaway Epinephrine i.v. is recommended for ACLS in patients with nonshockable and shockable rhythms; specifically, early administration in patients with nonshockable rhythms is associated with ROSC, survival to hospital discharge, survival at 1 month, and a good neurologic outcome. Both amiodarone and lidocaine are options for patients with shockable rhythms refractory to defibrillation. Magnesium is not recommended unless the rhythm is torsades de pointes, and β-blockers or lidocaine are not recommended in the first hour after ROSC. Pediatric advanced life support De Caen et al. Part 12: Pediatric advanced life support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care.100 This guideline update from AHA addresses fluid resuscitation, atropine use during endotracheal intubation, and antiarrhythmic medications for VF or pVT. In the setting of shock, an initial i.v. fluid bolus of 20 mL/kg for infants and children is recommended, and reassessment should be conducted after each bolus. Routine use of atropine as premedication for emergent intubation in critically ill infants and children is no longer recommended. However, in patients at higher risk for bradycardia (eg, when succinylcholine is used), atropine at a dose of 0.02 mg/kg may be considered, although the authors acknowledge there are limited data to support this recommendation. For the first time since the 2005 guidelines, either amiodarone 5 mg/kg or lidocaine 1 mg/kg in addition to epinephrine 0.01 mg/kg i.v. every 3 to 5 minutes for shock-refractory VF and pVT are recommended (on the basis of new pediatric observational data). Epinephrine alone is still recommended in patients with nonshockable cardiac rhythms. EM pharmacist takeaway Intravenous fluid administration and epinephrine i.v. are recommended during pediatric cardiac arrest. Amiodarone or lidocaine can be used in patients with shockable rhythms refractory to defibrillation. Atropine is no longer recommended as premedication for intubation unless the patient is at higher risk for bradycardia. Epinephrine in cardiac arrest Perkins et al. A randomized trial of epinephrine in out-of-hospital cardiac arrest: PARAMEDIC2 Trial.101 This multicenter, randomized, double-blind, placebo-controlled trial assessed the role of epinephrine in patients with out-of-hospital cardiac arrest receiving ACLS. It was the largest such trial to date, with 8,014 patients (age ≥16 years) included. In the trial, conducted in the United Kingdom, patients were randomly assigned to receive epinephrine 1 mg i.v. every 3 to 5 minutes or a normal saline bolus; both groups also received standard care. Rather than evaluating short-term primary outcomes such as ROSC or survival to ED or hospital admission, the investigators evaluated long-term outcomes such as 30-day survival (the primary endpoint), survival to hospital discharge with favorable neurologic outcome (modified Rankin scale score of ≤3), survival to hospital admission, and survival and neurologic outcome at hospital discharge and at 3 months, which strengthens their publication. Patients experiencing cardiac arrest due to trauma, anaphylaxis, or asthma or who received any epinephrine before the trial-trained paramedic arrived were excluded. Epinephrine improved the rate of 30-day survival relative to placebo use (3.2% vs 2.4% [OR, 1.39; 95% CI, 1.06–1.82; number needed to treat, 125), but there was no significant between-group difference at 3 months. Much higher percentages of patients who received epinephrine had ROSC in the field and/or were admitted to the hospital (36.3% vs 11.7% and 23.8% vs 8.0%, respectively). However, among those who survived to hospital discharge there was no significant difference in the rate of favorable neurologic outcome (2.2% vs 1.9% with placebo use; OR, 1.18; 95% CI, 0.86–1.61) or survival at 3 months, and a higher proportion of patients in the epinephrine group had severe neurologic impairment at hospital discharge (modified Rankin scale score of 4 or 5): 31% vs 17.8%. This was a well-done RCT in a difficult patient care setting. It was the largest trial of its kind to date, there was an attempt to obtain data regarding quality of CPR (although yield was poor), and outcomes were assessed by research paramedics blinded to treatment assignments, all of which were strengths. Among the study limitations, aspects of hospital-based care were not defined in the trial protocol (eg, TTM, hemodynamic support, ventilator criteria), no other epinephrine doses or frequencies were evaluated, patients’ baseline neurologic status was not known, the overall survival rate was lower than anticipated (potentially affecting the number of patients needed in the study sample), and median time to ambulance arrival was 6.6 minutes, with an additional 13.8 minutes to drug administration. Delayed medication administration is a common problem in OHCA trials making it difficult to determine actual treatment effect. EM pharmacist takeaway This is the only trial that has shown a survival benefit with use of epinephrine in OHCA, but these findings are limited by the lack of favorable neurologic outcomes. Targeted temperature management Geocadin et al. Practice guideline summary: Reducing brain injury following cardiopulmonary resuscitation: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology.102 This guideline provides recommendations to decrease brain injury in patients with OHCA who are comatose following ROSC. Three major recommendations were provided: (1) In patients with an initial rhythm of VF or pVT, therapeutic hypothermia (32oC-34oC for 24 hours) improves survival and functional neurologic outcome (a level A recommendation based on the highest level of evidence); (2) if the initial rhythm is VF, pVT, PEA, or asystole, TTM (36oC for 24 hours and temperature maintenance below 37.5oC until 72 hours) is thought to be as effective as therapeutic hypothermia and offers an alternative (a level B recommendation); and (3) for an initial rhythm of PEA or asystole, therapeutic hypothermia possibly improves survival and functional neurologic outcome and should be offered (a level C recommendation). It is important to note that prehospital cooling measures were not shown to confer benefit when compared to TTM after hospital arrival (high level of evidence). Pharmacotherapeutic therapies such as Co-enzyme Q10 are addressed in this guideline as well. An unresolved question that warrants additional investigation is determination of the ideal temperature to achieve best outcomes. EM pharmacist takeaway TTM is recommended for patients with ROSC following VF, pVT, PEA, or asystolic arrest. Although the strongest evidence of improved survival and functional neurologic outcomes with use of TTM is for VF or pVT arrest, there is evidence supporting TTM following PEA and asystole and it should be offered. Nielsen et al. Targeted temperature management at 33°C vs 36°C after cardiac arrest.103 In 2002, two small trials established therapeutic hypothermia as a best-practice management strategy for patients presenting with OHCA and an initial rhythm of VT or VF. Compared with normothermic postresuscitation care, attainment of a therapeutic temperature goal (33°C in one study and 32–34°C in the other) was associated with increased survival and improved neurologic outcome in both studies. These articles are detailed in the aforementioned 2011 “Key Articles and Guidelines” paper.1 Because therapeutic hypothermia management is resource intensive, this follow-up trial was conducted to determine if it is truly necessary to target these lower temperatures. Over 900 patients with both shockable and nonshockable initial rhythms were included in this multicenter, randomized, open-label controlled trial comparing outcomes with attainment of a target of 33°C vs a target of 36°C. Standard mechanisms of cooling were used in each group to achieve and maintain the desired temperatures for 36 hours and then maintain temperatures at 37.5°C until 72 hours. Mortality rates were similar in the 2 groups at the end of the trial (mean follow-up period, 256 days): 50% with targeting of 33°C and 48% with targeting of 36°C, and there were no significant between-group differences in terms of neurologic outcome, as evaluated using cerebral performance categories and modified Rankin score. Although this was a large, well-designed trial, there are many potential confounders during cardiac arrest and the post-ROSC period. Treatment teams were not blinded, whether or not bystander CPR was performed was unclear, and patient recruitment was less selective (ie, patients with all initial rhythm types were included) than for the 2002 trials, potentially impacting the results. Because ICU management has evolved, it is possible that the incremental benefit of this singular intervention may have been reduced. EM pharmacist takeaway There was no difference in mortality or neurologic outcomes with TTM targeted to 33°C vs 36°C in patients with shockable and nonshockable initial cardiac rhythms. Septic shock The PRISM investigators. Early, goal-directed therapy for septic shock—a patient-level meta-analysis.104 Three different randomized, controlled, open-labeled trials (the ProCESS [Protocolized Care for Early Septic Shock] trial, ARISE [Australasian Resuscitation in Sepsis Evaluation], and the ProMISe [Protocolised Management in Sepsis] trial) sought to compare the early-goal directed therapy (EGDT) protocol, published in 2001, to current practices for management of septic shock.105-108 The EGDT protocol is a 6-hour resuscitation bundle focused on optimizing central venous pressure, arterial blood pressure, central venous oxygen saturation, and hemoglobin level to enhance tissue oxygenation. This goal is accomplished through administration of fluids, vasopressors, inotropes, and red blood cell transfusions. At the time of publication, sepsis-related mortality was high, and time-sensitive EGDT was associated with a 16% absolute mortality reduction (from 46.5% to 30.5%).108 Due to its inherent complexity and requirement of invasive monitoring, EGDT has not been universally adopted. The lack of adoption was the impetus for the 3 aforementioned trials.105-107 Inclusion criteria for severe sepsis and septic shock (including a lactate concentration of 0.4 mg/dL [in SI units, >4 mmol/L]) were similar in all 3 trials and in the study by Rivers et al108 that led to EGDT protocol development, with the exception of fluid volume administered in the setting of refractory hypotension (1 L in the new trials and 20–30 mL/kg in the EGDT protocol trial). The ARISE and ProMISe trials had 2 arms: a treatment arm (in which patients received treatment similar to EGDT) and a usual resuscitation arm.105,106 The ProCESS trial had 3 arms (treatment, usual resuscitation, and protocolized standard therapy), with all care provided by a designated team, as in the study of Rivers et al.108 No significant between-group differences in either in-hospital or 90-day mortality were found in any of the 3 trials. Mortality was lower than anticipated in all 3 studies and lower than both arms of the trial of Rivers et al. This finding could be explained by a seemingly more severely ill population in the trial of Rivers et al (as indicated by those patients’ overall higher lactate and lower central venous oxygen saturation relative to values in the 3 more recent studies) and the advancement of sepsis management over the past 15 years, including more timely recognition of sepsis, early fluid resuscitation and antibiotics, and lung-protective ventilation strategies, all of which may have had a favorable effect on mortality. The Protocolized Resuscitation in Sepsis Meta-Analysis (PRISM) of individual patient data (not average results) was performed to evaluate important treatment effects in subgroups or settings that may not have been identified due to the heterogeneity of patients who develop septic shock and variability in usual care across hospitals.104 This meta-analysis was planned a priori by individual study investigators before inclusion of any patients in the 3 trials discussed above to enable analysis of pooled data to determine the effect of EGDT vs usual care on 90-day mortality and other clinical and economic outcomes across prespecified subgroups delineated by patient demographics, preexisting conditions, and severity of illness and care delivery characteristics (time from ED presentation to randomization and first antimicrobial, time of day of randomization, and intensity of care related to use of fluids and/or vasopressors in usual care). A total of 4,211 patients admitted to 138 international hospitals from March 2008 through July 2014 were included in the meta-analysis. Overall, 90-day mortality did not differ with use of EGDT vs usual care (OR for death, 0.97; 95% CI, 0.82–1.14; P = 0.68), nor did the likelihood of survival to 1 year (HR, 0.98; 95% CI, 0.86–1.11; P = 0.75). Patients in the EGDT groups tended to have a shorter ED LOS, longer ICU LOS, and more cardiovascular support. EGDT conferred no benefit in patients with severe septic shock; mortality was higher among those with severe chronic liver disease and lower in those with severe chronic respiratory disease. There were no significant between-group differences in care delivery characteristics despite large variabilities in vasopressor and fluid use in the usual care group. The authors describe these results as a more granular evaluation of data from the ARISE, ProMISe, and ProCESS trials that confirm that the EGDT bundle is not superior to usual care, although optimal fluid and vasopressor regimens, the role of hemodynamic monitoring, and optimal resuscitation goals are still unknown. A strength of this meta-analysis is that it was planned by the original EGDT protocol investigators prior to the RCTs, and therefore the designs of the trials and endpoints were similar. It is important for EM pharmacists to understand these trials and the history of EGDT and how it has impacted usual care. In the ED, care can be streamlined and not delayed for invasive monitoring. EM pharmacist takeaway Clinicians’ focus should be on early identification of severe sepsis and septic shock and prompt fluid resuscitation and use of antibiotics and vasopressors. Invasive monitoring is not necessary to guide sepsis management in the ED. Levy et al. The Surviving Sepsis Campaign bundle: 2018 update.109 Every four years the Surviving Sepsis Campaign updates its guidelines to accelerate and streamline the delivery of initial sepsis care. The updated bundle includes identification of sepsis; determination of lactate concentration (remeasure if >0.22 mg/dL [in SI units, >2 mmol/L]); blood culture collection prior to administration of broad-spectrum antibiotics; administration of crystalloid resuscitation 30 mL/kg i.v. (can use ideal body weight in obesity) for hypotension or a lactate concentration of ≥ 0.44mg/dL [4 mmol/L]; and, if the patient is hypotensive during or after fluid resuscitation, vasopressors to maintain a mean arterial pressure (MAP) of ≥65 mm Hg. Previously these steps of sepsis management were described in 3- and 6-hour bundles, but the latest edition of the guidelines has been confronted with major criticism because these steps were combined into a 1-hour bundle with no new evidence to support this change. Chief concerns regarding the 1-hour bundle include the fact that thoughtful clinical decision making is nearly impossible in this time frame, and there may be negative effects from aggressive fluid resuscitation in patients with end-stage renal disease or heart failure, as well as unwanted effects of unnecessary antibiotics or vasopressors. Nevertheless, many hospitals and even states (eg, New York) are mandating these measures, with time zero beginning either at ED triage or when clinical indicators of sepsis or septic shock are reported in the patient medical record. EM pharmacist takeaway Lactate measurements, blood culture collection, and administration of fluids, antibiotics, and vasopressors are part of the 1-hour sepsis management bundle. EM pharmacists should understand these measures to prioritize direct patient care of these patients and can be instrumental in developing processes aimed at meeting these treatment goals. Cardiogenic Shock van Diepen et al. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association.110 In 2017 the AHA released a single clinical resource document that housed a summary of the epidemiology, pathophysiology, and in-hospital best practices for management of cardiogenic shock. For acute coronary syndrome–associated cardiogenic shock, an early revascularization plan with either PCI or coronary artery bypass grafting is recommended. In facilities that cannot accomplish an invasive approach in a timely fashion, fibrinolysis should be available. Norepinephrine is recommended as the vasopressor of choice as it is associated with fewer arrhythmias in the cardiogenic shock population. Other management strategies endorsed are temporary mechanical circulatory support through use of an intra-aortic balloon pump or venoarterial extracorporeal membrane oxygenation (ECMO) as needed. Long-term durable mechanical circulatory support should be a means for bridge therapy to meaningful recovery or transplantation. EM pharmacist takeaway In the event of delay to invasive revascularization in patients with acute coronary syndrome–associated cardiogenic shock, a fibrinolytic agent should be administered. Also, norepinephrine is the vasopressor of choice for most shock states, including cardiogenic shock. Schumann et al. Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome.111 This Cochrane review was conducted to assess the efficacy and safety of inotropic and vasodilative medications in patients with cardiogenic shock or low cardiac output syndrome due to acute MI, heart failure, or cardiac surgery. Thirteen RCTs met the selection criteria. Comparator arms were levosimendan vs dobutamine, enoximone vs placebo, epinephrine vs norepinephrine/dobutamine, amrinone vs dobutamine, dopexamine vs dopamine, enoximone vs dopamine, and nitric oxide vs placebo. When compared to dobutamine, levosimendan was found to reduce short-term mortality (RR, 0.60; 95% CI, 0.37–0.95), but the evidence was of low quality and this finding has not been confirmed on long-term follow-up. In all other comparison arms, inotropic agents’ effects on short-term mortality were considered to be uncertain (low-quality evidence). Considering the limited evidence, there is no formal recommendation for the ideal inotropic agent or vasodilatory strategy in this patient population. Also, levosimendan may not be as readily available as other options in the ED. The authors advise that it may be more appropriate to research therapeutic use of inotropics and the impact of timing of inotropic administration on survival rates rather than looking for the “best” medication for hemodynamic support. EM pharmacist takeaway There is no formal recommendation for use of a specific inotropic agent and vasodilator strategy in patients with cardiogenic shock or other low-cardiac-output syndromes. Early stabilization of hemodynamics may be more critical than identifying an ideal inotropic agent. Anaphylaxis/angioedema Simons et al. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.112 This update from the World Allergy Organization is intended to strengthen the current international consensus on the management of anaphylaxis based on new research findings from 2014–2015. In addition to guidance on patient risk factors, amplifying cofactors in anaphylaxis, triggers, diagnosis, and the role of laboratory testing, the updated guidelines state that early use of epinephrine remains the first-line therapy, as it is the only medication shown to reduce hospitalization (when given prior to ED arrival) and death by relieving airway edema, reducing hypotension from distributive shock, increasing inotropy and chronotropy, causing bronchodilation, and decreasing mediator release. Emphasis is placed on prompt recognition as well as the route of epinephrine administration (i.m. preferred over i.v.). In this guideline update, the authors reviewed a single-center retrospective observational cohort study of epinephrine safety in 573 consecutive patients treated for anaphylaxis.113 Only 4 of 316 patients (1.3%) in the i.m. group had a cardiac adverse event (ischemia, angina, or hypertension), compared to 3 of 30 patients (10%) in the i.v. group (arrhythmia and/or ischemia). Four epinephrine overdoses occurred in the i.v. group (resulting from administration of a >100-µg bolus followed by doses of 0.5 mg or 0.75 mg in 2 patients and 1 mg in 2 patients), and 3 of these overdoses were associated with cardiac adverse effects. Histamine H1 and H2 inhibitors and glucocorticoids (to prevent biphasic reactions) are recommended as supportive care and not initial treatment as they are not lifesaving. Interestingly in relatation to ED management, the guidelines do not recommend prolonged monitoring in patients with food-induced anaphylaxis, as biphasic episodes are less likely to occur in those patients as opposed to those with unknown triggers or with hypotension. EM pharmacist takeaway Epinephrine i.m. continues to be first-line therapy and is the only medication shown to be lifesaving in the management of anaphylaxis. Histamine H1and H2inhibitors and glucocorticoids are recommended for supportive care, but their use should not delay administration of epinephrine. Sinert et al. CAMEO study group. Randomized trial of icatibant for angiotensin-converting enzyme inhibitor-induced upper airway angioedema.114 This phase III trial was a follow-up to a previous multicenter, randomized, phase II study comparing the selective bradykinin B2 receptor antagonist icatibant (30 mg subcutaneously) to standard therapy (prednisolone plus clemastine) for the treatment of angiotensin-converting enzyme (ACE) inhibitor–induced angioedema. In the phase II trial, which involved 27 patients (13 who received icatibant and 14 who received standard), time to resolution of edema was quicker (8 hours [IQR, 3–16 hours] vs 27 hours [IQR, 20–48 hours]), time to symptom relief onset was shorter (median, 2 hours vs 11.7 hours), and 38% of patients in the icatibant group vs 0% in the standard therapy group had complete resolution of edema at 4 hours.115 This small evaluation was limited by sample size, lack of a safety evaluation, inclusion of patients with mild baseline disease severity, and lack of diversity (Caucasian only), and about one-third of patients had previously experienced ACE inhibitor–induced angioedema events. The phase III trial was also a multicenter trial. Patients were randomly assigned to treatment with icatibant 30 mg subcutaneously (n = 61) or placebo use (n = 60) for ACE inhibitor–induced angioedema; unlike in the phase II trial, all had moderate to severe disease.114 All patients could receive conventional medications (eg, antihistamines, corticosteroids, epinephrine), and over 90% received at least one of these medications prior to the study drug. The phase III trial also differed from the phase II trial in its primary endpoint; in the phase III trial the primary endpoint was time from drug administration to meeting discharge criteria (ie, the earliest time that difficulty breathing and difficulty swallowing were absent and voice change and tongue swelling were mild or absent). Secondary endpoints included time to onset of symptom relief, occurrence of airway intervention, hospital admission, and symptomatic treatment after drug administration. The authors reported no significant differences between the icatibant and placebo groups in any of the endpoints; time to meeting discharge criteria was 4 hours, and time to resolution of symptoms was approximately 2 hours in both groups. Relative to the phase II study, the phase III study had a more diverse patient population, including a high proportion (69%) of black or African American patients, who are known to have a higher sensitivity to bradykinin, and involved a more realistic treatment scenario wherein conventional therapies were permitted and endpoints were assessed frequently using validated criteria and rating scales designed for clinically relevant application to the ED setting. It is important to note that this study did not include rapidly worsening patients or those requiring immediate intubation; these are often the types of cases in which EM clinicians might consider use of icatibant. EM pharmacist takeaway Icatibant for ACE inhibitor–induced angioedema does not improve times to discharge and resolution of symptoms compared to placebo use or conventional medication management. Resolution of ACE inhibitor–induced angioedema occurs over a long period of time (hours), and there are no rapid-acting medication interventions known to prevent intubation in a rapidly declining patient. Push-dose pressors Holden et al. Safety considerations and guideline-based safe use recommendations for “bolus-dose” vasopressors in the emergency department.116 This was not a systematic review but rather a summary of clinical, pharmacologic, operational, and safety-related considerations with use of bolus-dose vasopressors in the ED. The authors searched peer-reviewed medical literature databases as well as Google and Google Scholar to identify free open-access medical education articles and documents pertaining to bolus-dose administration of vasopressors, or “push-dose pressors.” The authors concluded, citing a lack of safety and outcomes data, that the push-dose method provides no benefit over vasopressor infusions or other management strategies in the ED. However, they did not advocate for or against use of the method; instead they focused on how to safely implement this treatment in accordance with best practices. There are unique challenges in the ED setting compared to the OR setting, where the practice of push-dose vasopressor administration originated. These challenges are mostly related to the ED being a high-acuity, overcrowded, chaotic environment that is often understaffed and may not be conducive to push-dose pressor preparation; it is also a high-risk environment for medication dose or administration errors. In order to safely administer bolus-dose vasopressors in the ED, a standardized dose calculation, drug dilution, and dose titration method is recommended. Also, an interdisciplinary assessment considering the risks, benefits, and safety of this practice should be completed before implementation. EM pharmacist takeaway There are no outcome data to support push-dose administration vs continuous infusion of vasopressors. If clinicians are considering the use of the push-dose method, an assessment of risks, benefits, and safety is necessary; development of a standardized process to ensure safe preparation and ED availability of push-dose pressors is also advised. SUBSTANCE ABUSE Emerging drugs of abuse Tait et al. A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment.117 This systematic literature review describes the clinical presentation and management of patients following synthetic cannabinoid exposure. A total of 106 studies were included, accounting for more than 4,000 patient cases (mostly young males presenting with nausea/vomiting, agitation, and tachycardia). Tachycardia was present in 33% to 75% of cases and oftentimes accompanied by hypertension. Hot showers were reported to confer nausea/vomiting relief similar to that seen with cannabinoid hyperemesis. Although paranoia and anxiety are observed with cannabis use, synthetic cannabinoids appear to enhance psychiatric adverse effects, leading to severe agitation and new-onset psychosis (hallucinations, catatonic features, and self-harm). Unlike cannabis, synthetic cannabinoids have been associated with more severe, life-threatening conditions such as seizures (4%-15% of cases), AKI (16 cases), cardiac symptoms (3 cases), cerebral ischemia, and fatal arrhythmias. Death occurred in 26 patients (25%). Supportive care is the mainstay of therapy and typically includes i.v. fluids, oxygen, and benzodiazepines to control agitation or treat seizures. Although these more serious manifestations are less common, EM pharmacists should be aware of them so they escalate the level of treatment as appropriate. EM pharmacist takeaway Unlike cannabis, synthetic cannabinoids can be associated with tachycardia, hypertension, severe agitation, seizures, and other less common severe adverse effects. Therapy should be escalated as appropriate and includes i.v. fluids, oxygen, and benzodiazepines. Smith et al. Gabapentin misuse, abuse, diversion: a systematic review.118 Gabapentin is a γ-aminobutryic acid (GABA) analog that can increase GABA and decrease glutamate concentrations and was thought to have no abuse potential (does not bind to GABAA or GABAB receptors). It has been increasingly prescribed as an opioid-sparing adjunct for neuropathic pain, acute pain management, and postsurgical pain. This systematic review describes 23 case studies and 11 epidemiologic reports from 7 countries from 1993 to 2015 of patients with overdose or withdrawal symptoms presenting to a hospital (general or psychiatric) or clinic (general or substance abuse). From these reports it was identified that more female patients and those with a history of or current substance misuse (not associated with alcohol abuse) misuse gabapentin. Gabapentin was also represented in drug-related deaths, impaired driving cases, and postmortem reports. One report found that 1.1% of a United Kingdom–based sample reported ever misusing gabapentin. Doses for misuse and abuse range from 900 to 3,600 mg/d (therapeutic doses) to supratherapeutic doses. In one report of 162 opioid-dependent US patients, 22% had a prescription for gabapentin, of whom 40% indicated they had taken more than the prescribed dose. Gabapentin misuse is related to recreational use, self-harm, or self-medication, and effects are described as including euphoria, sedation, relaxation, and/or calmness similar but not as strong as effects of opioid use. It is reported that these effects can be achieved with gabapentin alone or with concomitant use of other drugs (eg, buprenorphine/naloxone, methadone, baclofen, quetiapine, alcohol, cocaine). Other reported effects include improved sociability; “highs” like those induced by marijuana, cocaine, amphetamine, and MDMA; dissociation; increased energy and/or focus, and improved quality of sleep. The quality of the data included in this review is low, but the data are impactful. Considering the current drug overdose epidemic, it is important to recognize emerging drugs of abuse, not only for management of patients in the ED but also for development of strategies to provide optimal pain management. EM pharmacist takeaway Gabapentin misuse is on the rise, and the drug’s availability is increasing as it is being used more often as an opioid-sparing analgesic agent for neuropathic, acute, and postsurgical pain. Gabapentin is frequently misused because of its pleasurable CNS effects. Recognition of this phenomenon and understanding which populations are at risk for gabapentin misuse is important for the EM pharmacist when developing optimal pain management strategies. Wu et al. Clinical review: loperamide toxicity.119 Although this is a clinical review, the authors felt it was important to provide a resource to describe the increasing misuse and abuse of loperamide that occurs due to its low cost, ease of access, and opioid properties. Loperamide abuse was first reported in 2005, and in a 5-year interval from 2010 to 2015 there were 1,736 intentional exposures reported to the National Poison Data System (underreporting is likely). Used clinically as an antidiarrheal agent, loperamide is a phenylpiperidine opioid (similar to meperidine) that slows GI transit time via stimulation of µ receptors in the intestinal tract. The maximum recommended daily dose for this indication is 16 mg; however, doses of 200 to 400 mg have been reported in patients presenting with loperamide toxicity. Also it is imperative to recognize that loperamide pharmacokinetics is heavily influenced by P-glycoprotein, and it is a cytochrome P-450 (CYP) 3A4 and CYP2C8 substrate. Therefore, plasma concentrations can be additionally elevated due to genetic polymorphisms or intentional or nonintentional P-glycoprotein drug-drug interactions, resulting in central opioid effects. Since loperamide blocks both potassium and sodium channels, cardiac toxicity may manifest in the setting of supratherapeutic concentrations, namely QT interval prolongation (more commonly, potassium channel blockade occurs at lower concentrations) and QRS complex widening. Supportive care is indicated for loperamide toxicity, although activated charcoal may be used if administered within 2 to 4 hours of ingestion, and naloxone can be administered in the setting of respiratory depression. Low doses of naloxone (0.01–0.04 mg) are recommended to restore respirations while preventing opioid withdrawal. If QT interval prolongation is noted (prolongations up to 704 milliseconds have been reported), hypokalemia and hypomagnesemia should be corrected, and if QRS widening (values up to 200 milliseconds have been reported) occurs, sodium bicarbonate (1–2 mEq/kg) is indicated, although it is unclear if these measures will improve cardiac conduction in cases of loperamide toxicity. Intravenous lipid emulsion therapy may be an option given the lipophilicity of loperamide. EM pharmacist take away Loperamide misuse can cause serious cardiac effects like QT prolongation and, to a lesser degree, QRS complex widening. EM pharmacists must be aware of how to manage loperamide toxicity, and this a good reminder to investigate abuse of and/or exposure to both nonprescription and prescription medications during patient evaluation. Alcohol withdrawal Mo et al. Barbiturates for the treatment of alcohol withdrawal syndrome: a systematic review of clinical trials.120 There has been a resurgence in use of barbiturates as an option for alcohol withdrawal. Although benzodiazepines have been the mainstay of treatment, some patients develop tolerance (GABA receptor desensitization) over time and may not respond to treatment, even at high doses. Barbiturates are an attractive option since they are rapid acting (5 minutes), with a long duration of action (a half-life of 53–140 hours). They also potentiate the effects of GABA by binding to GABAA receptors, increasing the movement of chloride through sustained channel opening, and the presence of GABA, often depleted in alcoholism, is not necessary for activity. This systematic literature review evaluated the safety and efficacy of barbiturates compared with benzodiazepine therapy for the treatment of alcohol withdrawal syndrome in the acute care setting. Seven articles were included; only 3 reported on RCTs, but most studies discussed had a sample size greater than 100 patients and were of higher quality. One RCT described in this review found that a single dose of phenobarbital (10 mg/kg i.v.) administered in the ED at the discretion of the EM clinician along with symptom-triggered lorazepam therapy, as compared to use of lorazepam alone, reduced the ICU admission rate (8% vs 25%) and resulted in lower usage of lorazepam continuous infusions (4% vs 31%).121 Another RCT evaluated an alternative phenobarbital dosing strategy (260 mg i.v. followed by 130 mg), but found no benefits in terms of symptom control, disposition, or LOS. The authors concluded that none of the studies demonstrated inferiority of either barbiturates or benzodiazepines and that both had comparable safety profiles and were well tolerated. Phenobarbital alone or combined with benzodiazepines had a greater benefit in more severe forms of withdrawal, may lead to favorable additive clinical effects, and is an option for patients refractory to high-dose benzodiazepines. These data are limited by the lack of consistent measurement of alcohol withdrawal symptoms. Also, variation in barbiturate doses, timing of administration, and combination with benzodiazepines limit these findings. No serious side effects were noted in this review, but clinicians should be cognizant that combining barbiturates with benzodiazepines or alcohol may enhance CNS depression and hypotension. This paper provides a much-needed review and analysis of a common disease state in many EDs that is very challenging to manage, particularly in light of drug shortages that may limit therapeutic options. EM pharmacist takeaway Phenobarbital alone or combined with benzodiazepines is an effective option for the management of alcohol withdrawal syndrome. Patients with a high risk of moderate or severe alcohol withdrawal may benefit from a front-loaded phenobarbital strategy. Flannery et al. Unpeeling the evidence for the banana bag: evidence-based recommendations for the management of alcohol-associated vitamin and electrolyte deficiencies in the ICU.122 Use of several i.v. vitamins and electrolytes at varying doses prescribed in combination, often referred to as a “banana bag” or “rally pack,” has been a mainstay of supportive treatment for chronic alcohol use disorder, not only in the ED setting but also in critical care and internal medicine. This systematic review sought to explore thiamine, folic acid, magnesium, multivitamin, and i.v. fluid deficiencies in the context of alcohol use disorder treatment. As expected, assessment and replacement of thiamine for prevention and treatment of Wernicke’s encephalopathy was determined to be the most important intervention in critically ill patients with chronic alcohol use disorder. Folic acid and magnesium may warrant supplementation (weak evidence), but there are no published data to support routine supplementation of multiple vitamins or any electrolytes. It is suggested to abandon the banana bag and provide appropriate doses of each individually. The traditional banana-bag dose of thiamine (100 mg) is grossly insufficient relative to the dosage of 200 to 500 mg i.v. every 8 hours recommended for Wernicke’s encephalopathy. Magnesium sulfate (64 mg/kg), folic acid (400–1,000 µg), and dextrose-containing fluids instead of normal saline (if alcoholic ketoacidosis is suspected) are recommended. This article provides an important discussion regarding the traditional teaching that thiamine should be administered prior to dextrose to prevent precipitation of Wernicke’s encephalopathy. Thiamine is needed in the Krebs cycle for anaerobic glycolysis (conversion of glucose, a cofactor for pyruvate, to usable energy in the form of ATP). Thiamine depletion inhibits this pathway and also causes lactic acidosis from the accumulation of toxic intermediates, resulting in neurologic damage (mental status changes and/or confusion, ataxia, and vision changes). The theoretical concern is that a dextrose and/or glucose load would exhaust any small thiamine stores remaining, causing the conversion of pyruvate to acetyl coenzyme A to shut down, further limiting glycolysis and the link to the Krebs cycle and resulting in cell death. One small case series (4 patients receiving large-volume and prolonged dextrose infusions) published in 1981 is often cited in regards to this phenomenon.123 Due to limited evidence from research in humans, most clinicians advocate not withholding dextrose because hypoglycemia, which is more common, is more of an actual risk. This article provides a thorough review of the literature and the pathophysiological concepts that underpin vitamin nad electrolyte deficiencies in chronic alcohol use disorder. It addresses a largely unmet need in the literature to bring a commonly used, costly, and time-consuming practice under the microscope to assess its actual clinical benefit. EM pharmacist takeaway In the setting of vitamin deficiency secondary to chronic alcohol use, available evidence supports only repletion of thiamine, folic acid, and magnesium. The administration of the banana bag should be abandoned. Opioid use disorder treatment/harm reduction D’Onofrio et al. Emergency department-initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial.124 This was a clinical trial involving 329 opioid-dependent patients who were treated at an urban teaching hospital ED. Patients were randomly assigned to one of 3 groups: (1) screening and referral to treatment (referral, n = 104); (2) screening, brief intervention, and facilitated referral to community-based treatment services (brief intervention, n = 111); and (3) screening, brief intervention, ED-initiated treatment with buprenorphine (8 mg on day 1 and 16 mg on days 2 and 3), and referral to primary care for 10-week follow-up (buprenorphine, n = 114). ED-initiated buprenorphine treatment significantly increased the rate of engagement in addiction treatment (78% vs 37% for the referral group and 45% for the brief intervention group), reduced self-reported illicit opioid use, and decreased the use of inpatient addiction treatment services compared to referral or brief intervention alone. However, the buprenorphine group did not demonstrate a significant decrease in rates of positive urine testing for opioids and HIV infection risk. This study is very impactful because it was the first to evaluate all 3 strategies against one another in a randomized fashion. However, these results may be difficult to generalize since the most successful strategy was the combination of buprenorphine with weekly or biweekly office-based treatment by physicians and nurses using established procedures for 10 weeks. It is difficult to ascertain if buprenorphine therapy alone could yield similar positive results. A subsequent publication evaluated cost-effectiveness aspects of these data from the perspective of a healthcare system through analysis of self-reported 30-day assessment data for patient engagement in formal addiction treatment and opioid-free days.125 Even under the most conservative assumptions regarding willingness-to-pay, ED-initiated buprenorphine treatment was more cost-effective than referral or brief intervention. Because this cost analysis included office-based costs in addition to hospital-based care costs (including ED visits), institution of this practice could provide a direct cost benefit to both the ED and patient. While this finding is compelling, it should be noted that some costs were estimated retrospectively and patients were only assessed at 30 days post randomization. Linkage to care for opioid use disorder and treatment of opioid withdrawal are challenging problems to address in EDs across the nation. Such a program in the ED provides an option for patients and hospitals with limited inpatient resources. The US Department of Health and Human Services defines such a program and approach to the treatment of substance use disorders as medication-assisted treatment (MAT). As such, it is subject to specific federal legislation, regulations and guidelines. Therefore, in order to write a prescription for buprenorphine a practitioner must receive training and apply to prescribe and dispense under the Drug Addiction Treatment Act of 2000, but exemptions allow EM clinicians to administer a single dose of buprenorphine for the relief of withdrawal symptoms in the ED while arranging referral for ongoing treatment. Strategies for use of single, higher doses of buprenorphine (16–32 mg) have been described recently.126 Such programs in the ED could help expand options for this patient population to receive much-needed treatment. EM pharmacist takeaway Administration of buprenorphine in the ED is effective for management of opioid withdrawal and may serve as a point of access to care for definitive treatment of opioid use disorder. Dwyer et al. Opioid education and nasal naloxone rescue kits in the emergency department.127 The ED is an ideal location to target for implementation of harm reduction strategies, such as opioid overdose education and naloxone rescue kits, due to patient accessibility. A telephone survey of at-risk patients who were seen at an academic, urban, level I trauma center ED is described. Patients received either opioid overdose education (~5 minutes) or opioid overdose education and naloxone distribution (a free nasal naloxone kit dispensed under a standing order) from an ED-based licensed alcohol and drug counselor. A total of 359 patients received overdose education only, and 56 received education and naloxone. Patients were seen in the ED from January 2011 through February 2012, and research assistants contacted patients from March through October 2012 to answer survey questions related to demographics, overdose education, naloxone history, personal or witnessed overdose history, overdose risk knowledge retention, and self-reported opioid use in the previous 30 days (the median time from ED visit to survey was 12 months). Fifty-one of 415 patients (12%) completed the survey; 73% (n = 37) received education plus a naloxone kit, and 14 (27%) received education only. There were no statistical between-group differences in the answers to the survey questions. Approximately 35% in both groups described use of illicit opioids within 30 days prior to the survey, but a higher percentage of patients in the education-only group reported nonfatal overdose (29% vs 19%). Among the 27 patients who reported witnessing an overdose, a higher proportion of those in the education and naloxone group called 911 (74% vs 38%) and/or administered naloxone (32% vs 0%). Also, 54% of patients (n = 20) still had the ED-distributed naloxone kit in their possession at the time of the survey. This is a difficult population to study, as evidenced by low number of patients researchers were able to contact following ED visits. The results of this study are limited by the open-label design, nonrandomized nature of the intervention, and elapsed time between intervention and follow-up, and it is difficult to draw meaningful conclusions due to the small number of patients surveyed. Regardless, this is a practice being implemented in many centers, and this study is the first to attempt to systematically evaluate its impact on this vulnerable and growing population. EM pharmacist takeaway The provision of education and naloxone kits to this vulnerable population is a feasible and potentially lifesaving harm reduction intervention. Coffin et al. Cost-effectiveness of distributing naloxone to heroin users for lay overdose reversal.128 With the increasing distribution of naloxone to individuals at risk for opioid overdose in the community, the investigators developed an analytical model to compare the cost-effectiveness (from the societal perspective) of distribution of naloxone to 20% of heroin users with no distribution using epidemiologic data. They described absolute and relative overdose death rates with and without naloxone distribution and expressed cost-effectiveness in costs, quality-adjusted life-years (QALY), and incremental costs per QALY gained. In their hypothetical model, naloxone distribution increased cost by $53 (95% CI, $3-$156) but prevented 1 death for every 227 naloxone kits distributed (95% CI, $71-$716), and increased QALY by 0.119 (95% CI, 0.017–0.378), for an incremental cost-effectiveness ratio of $438 (95% CI, $48-$1,706). Even in sensitivity analyses and a “worst-case” scenario evaluation, naloxone distribution was cost-effective based on accepted thresholds. As this analysis was limited by the absence of actual patient data, and the target population consisted of only heroin users, it does not represent the full spectrum of opioid use disorder or those at risk for an opioid-related adverse event. Also, the model was designed to be biased against the hypothesis that naloxone distribution would be beneficial, so the actual benefit may be underestimated. Although many assumptions went into this model due to the lack of published data on this topic at the time it was developed, even under conservative assumptions naloxone distribution was expected to reduce mortality and be cost-effective, a finding that lends support to this harm reduction strategy. EM pharmacist takeaway Naloxone dispensing is expected to not only reduce mortality associated with opioid overdose but also be cost-effective from the societal perspective. TOXICOLOGY Dart et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care.129 A wide range of expert clinicians were included on this consensus panel to provide guidance regarding antidotes that must be stocked and related issues (necessary quantity on hand and acceptable timeframe for delivery). The panel employed a multiphase approach wherein a standardized search strategy and evidence-based review of each relevant peer-reviewed publication was compiled into a comprehensive evaluation for each antidote. The evaluation and the resulting expert recommendation was brought to the full panel, and an iterative process was used to reach consensus. During the full panel presentation, effectiveness of the antidote, medical benefits vs potential risk, appropriate time to availability (immediate use or available within 60 minutes), and dose requirements in obesity (>100 kg) were discussed. Consensus was defined as agreement of at least 75% of the panel members, with no votes of “strong disagreement.” In total, 2,447 articles were used to draft a guidance and recommendation statement, and 44 antidotes (with 23 immediately available, 14 available within 1 hour, and 7 stocked but not available in 1 hour) were recommended for stocking in hospitals that accept emergency care patients. In scenarios where multiple antidotes may be used (eg, toxic alcohol exposure, cyanide toxicity, VKA reversal) the panel recommended a preferred agent. The minimum stock quantity needed to treat a 100-kg patient for either 8 or 24 hours was provided, but the panel recommended that the specific amount a hospital should stock be individualized by performing a hazard vulnerability assessment for each antidote. The methodology for this document is strong, and considerations were taken to prevent bias in the final recommendations. This is a key reference for EM pharmacists, as they are often consulted to help guide these recommendations at the hospital or healthcare system level. EM pharmacist takeaway This article provides pharmacist guidance in regards to both managing various toxicologic emergencies (regarding preferred antidote, dosing, and timeliness) as well as antidote stocking in hospitals. Acetylcysteine Bateman et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomized controlled trial.130 Acetaminophen ingestion is a leading cause of acute liver failure and one of the most common toxicities seen in the ED. Intravenous N-acetylcysteine (NAC) remains the mainstay of treatment, but the regimen is complicated by the need for 3 different weight-based infusions and varying infusion rates. Such variation can be associated with medication errors and/or administration errors and potential adverse events and may extend hospital LOS. This was a double-blind, multicenter, randomized study to assess whether a simplified i.v. NAC regimen, antiemetic pretreatment with ondansetron, or both could reduce adverse effects in patients presenting within 8 hours with acetaminophen toxicity. Patients receiving N-acetylcysteine were categorized into a modified group (initial dosage of 100 mg/kg over 2 hours followed by 200 mg/kg over 10 hours) or a standard group (150 mg/kg over 15 minutes followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours). Patients were also randomly assigned to receive ondansetron pretreatment (4 mg i.v.) or a placebo within both the modified and standard groups. A total of 39 of 108 patients (36%) in the modified protocol, compared to 71 of 109 patients (65%) in the standard regimen group reported emesis or retching or needed a rescue antiemetic (OR, 0.26; 97.5% CI, 0.13–0.52; P < 0.001). Ondansetron pretreatment (45 of 109 patients, 41%) also significantly reduced emesis, retching, and/or need for a rescue antiemetic compared to placebo use (65 of 108 patients, 60%) (OR, 0.41; 97.5% CI, 0.2–0.8; P < 0.003). Those who received the modified regimen and ondansetron (n = 54) reported the least amount of nausea, vomiting, and/or retching within 12 hours of NAC initiation. Hepatotoxicity was not evaluated, but only 1 patient died (20 days following ingestion due to malignancy). Importantly, 31 patients in the standard group had a severe anaphylactoid reaction, compared to 5 who received the modified regimen. There was a significantly lower rate of delays in therapy and an overall shorter average hospital LOS with use of the modified regimen (5% vs 12% [P = 0.002] and 1 day vs 2 days [P <0.001], respectively). However, there were no significant differences in the numbers of medication errors reported. Although the study was not powered to detect noninferiority, the results of use of the modified NAC regimen appear to be promising. Potentially, the reported effect size would not have been as great in the United States. During study recruitment newly issued United Kingdom guidance recommended the threshold for treatment based on the 4-hour acetaminophen concentration treatment line be changed from 150 µg/mL to 100 µg/mL, and 18% to 25% of patients in each study group had a concentration of 100 to 149 µg/mL. These patients would not have received NAC in the United States and, one could argue, did not necessarily need NAC treatment. Other limitations of the study were that many patients (n = 1,170) were excluded for several factors, including staggered overdose (multiple ingestion times), intoxication, unreliable history, and vomiting at the time of randomization. Although these factors likely did not affect the outcomes due to the randomized nature of the study, the applicability of the results to patients without a single, acute ingestion cannot be inferred. Likewise, it is important to note that the standard NAC regimen used in this study was different than the traditional 3-bag NAC regimen used in the United States (with the initial infusion administered over 15 minutes instead of 1 hour). There is no evidence that the higher maximum concentration achieved by infusion of the initial bag over 15 minutes improves outcomes but may increase the risk of regardless of these limitations, a 2-bag regimen administered over 12 hours could potentially allow for a shorter therapy regimen, with less vomiting and anaphylactoid reactions, less interruptions or delays in therapy, and a shorter LOS than are seen with use of a 3-bag, 21-hour regimen. EM pharmacist takeaway The modified regimen of NAC (initial infusion of 100 mg/kg i.v. over 2 hours followed by 200 mg/kg i.v. over 10 hours) was demonstrated to be associated with lower rates of nausea and/or vomiting, retching, anaphylactoid reactions, and interruptions in therapy and shorter LOS, with no hepatotoxicity differences, compared to use of the standard 3-bag, 21-hour NAC regimen. However, these benefits in reported in the United Kingdom would likely be less pronounced in the United States, as large proportions of patients in each group (18%-25%) had a 4-hour acetaminophen concentration of 100 to 149 µg/mL and likely would not have received NAC in the United States. Schmidt et al. Fewer adverse effects associated with a modified two-bag intravenous acetylcysteine protocol compared to a traditional three-bag regimen in paracetamol overdose.131 As in the study by Bateman et al, these investigators sought to evaluate a less complex i.v. NAC administration regimen. This was a retrospective before-and-after study investigating nonallergic anaphylactoid reactions (NAARs) associated with a modified 2-bag regimen (200 mg/kg over 4 hours followed by 100 mg/kg over 16 hours) vs the traditional 3-bag regimen (described above) among patients presenting with acetaminophen toxicity. A total of 493 patients (64%) received the 2-bag i.v. NAC regimen, while 274 (36%) received the 3-bag regimen. The mean acetaminophen concentration was approximately 225 µg/mL (in SI units, 1,410 mmol/L), with a large SD value (approximately 98 mg/dL, or 882 mmol/L). The overall incidence of NAARs was 9%, with a lower rate in the 2-bag vs 3-bag group (4% vs 17%, P < 0.001). This difference was also observed in subgroup analyses that accounted for weight, gender, age, and nature of acetaminophen ingestion (acute or repeated). Further, there was no difference in hepatoxicity rates between the groups (4% in both). Patients who received the 2-bag regimen also had a lower rate of severe symptoms (eg, hypotension, respiratory distress, edema) (0.6% vs 4%, P = 0.003) and cutaneous symptoms (2% vs 14%, P ≤ 0.001). Notably, there were fewer interruptions or delays in therapy with the 2-bag regimen (rate, 5% vs 12%, P = 0.002). Although this study assessed whether delays occurred as a result of reactions or adverse events, it is worth mentioning that coordination of the 3-bag regimen can be difficult in the ED and during transitions of care due to location changes, which can cause delays in therapy as well, making a simplified regimen attractive. Due to the retrospective nature of this study, it is possible that NAARs thought to be more mild or unrelated to NAC may not have been documented and were therefore underreported. Lastly, the investigators noted that in Denmark full-dose NAC is initiated in most patients with toxic acetaminophen ingestion. Since there is an association with lower acetaminophen concentrations and more NAC adverse effects, including patients with less severe toxicity actually would have improved the sensitivity of these results. EM pharmacist takeaway A nontraditional NAC regimen (200 mg/kg over 4 hours followed by 100 mg/kg over 16 hours) can be appealing secondary to ease of administration and may reduce NAARs and decrease interruptions or delays in therapy, without increasing hepatotoxicity. Physostigmine Arens et al. Safety and effectiveness of physostigmine: a 10-year retrospective review.132 Physostigmine is a reversible acetylcholinesterase inhibitor used for anticholinergic toxicity–related agitation and hyperthermia, but concerns with seizures, bradycardia, and asystole in tricyclic antidepressant overdose have limited routine use of physostigmine for this purpose. However, a report published by the California poison control agency noted an increase in use from 2003 to 2012. Data from 191 patients, all having at least 1 symptom of anticholinergic delirium (eg, agitation, altered mental status, hallucinations), were included in this report. At the time, the California poison control agency did not have a specific protocol, but a more conservative physostigmine regimen (0.5–1 mg every 5–10 minutes up to a maximum of 2 mg over the first hour) was often recommended. Physostigmine administration (median dose, 1–1.4 mg) resulted in improvement or resolution of symptoms in 73% of patients, 44% of whom required no additional physostigmine, benzodiazepines, or neuroleptics. Repeat physostigmine doses were administered in 69 patients (36%). Adverse effects were documented in 9 patients (4.7%): emesis (n = 4); QTc prolongation not associated with arrhythmia (n = 2); seizure (n = 2), with one case involving ingestion of multiple agents known to cause seizures and the other reported in a patient who had seizures prior to physostigmine administration; and death thought to be unrelated to physostigmine (n = 1). The authors concluded that physostigmine was effective and safe at doses of ≤2 mg. However, because these data were extracted from poison center records, there was the potential for missing information related to both efficacy and safety given that patients were followed remotely by the poison center staff. Also, over one-third of patients ingested an anticholinergic plant rather than a prescription medication, and it was identified that the physostigmine dose required to manage botanical ingestion was lower than that required after ingestion of other substances. In light of increasing physostigmine use, it is imperative for the EM pharmacist to fully understand dosing and administration strategy and the drug’s adverse effect profile. Although outside of our key article inclusion time, a recent publication reported results of a prospective study performed at 3 US state poison centers that evaluated a treatment algorithm recommending administration of physostigmine i.v. (1–2 mg [0.02 mg/kg], with a maximum of 0.5 mg for patients 2–12 years of age) over 5 to 10 minutes for those with anticholinergic toxicity, HR of ≥60 beats/min, and no QRS prolongation.133 A total of 154 patients, primarily with exposures to antihistamines, analgesics, and antipsychotics, received poison center consultation, with physostigmine administration recommended for 81% (37% received physostigmine). Patients treated with physostigmine were more likely to have delirium control (79%) than those who were not (36%), with no difference in adverse effects; these results were similar to the findings in this retrospective review. EM pharmacist takeaway Physostigmine is an effective and safe treatment option in the setting of anticholinergic toxicity–related agitation and hyperthermia. Total doses of ≤2 mg appear to ameliorate symptoms, with most patients requiring only a single dose, and the overall incidence of adverse events is low. Patients with a significant or progressing conduction block (which can be seen in tricyclic antidepressant exposure) or significant bradycardia should not receive physostigmine. High-dose insulin euglycemia Cole et al. High dose insulin for beta-blocker and calcium channel-blocker poisoning.134 High-dose insulin euglycemia (HDIE), or hyperinsulinemia euglycemia therapy (HIET), is recommended in the treatment of β-blocker and CCB overdoses. During normal conditions the myocardium catabolizes free fatty acids for energy expenditure, but during shock induced by β-blocker and/or CCB overdose the myocardium utilizes carbohydrates as an alternative energy source. Insulin facilitates utilization of carbohydrates, leading to improvement in myocardial metabolism and sustained positive inotropic effects, and also attenuates toxin-induced glucose dysregulation and impaired peripheral uptake. Little published evidence on HDIE administration and place in therapy (eg, before or after vasopressor therapy) is available. This single–poison center, retrospective review sought to describe case characteristics (HDIE doses, concomitant therapies, and outcomes) and adverse events associated with HDIE treatment with insulin (≥0.5 units/kg/h) for β-blocker and CCB overdoses from 2000 to 2016. A total of 199 patients were included, and the majority of overdoses involved β-blockers (44%), followed by a combination of β-blockers and CCBs (23%), nondihydropyridine CCBs (22%), and dihydropyridine CCBs (11%). At the time of HDIE initiation, the median heart rate was 62 beats/min (range, 12–128 beats/min) and the median SBP was 80 mm Hg (range, 40–223 mm Hg). The median weight-based insulin bolus dose was 1 unit/kg (range, 0.5–10 units/kg), and the median insulin infusion was 1 unit/kg/h (range, 0.22–10 units/kg/h), with a median peak dose of 8 units/kg/h. The median duration of HDIE was 2 days (range, 1–7 days), and hypokalemia (potassium concentration of <3.5 mEq/L) and hypoglycemia (more common with β-blocker overdose and with a lower concentration of dextrose-containing fluids) were common, occurring in 29% and 32% of patients, respectively. Many patients received vasopressors, most often norepinephrine, but due to the retrospective nature of this study, the initiation and timing could not be assessed. Cardiac arrest occurred in 21% of patients, and 16% of patients died. Although there were several limitations to this study related to its retrospective nature, it provided guidance on the dose of insulin (1–10 units/kg/h), need for dextrose-containing fluids, and close monitoring and management of potassium and glucose levels when HDIE is used for β-blocker and CCB overdose. Because of concerns with fluid overload with standard insulin and dextrose concentrations during HDIE management, EM pharmacists should use the results of this review to understand this therapy and be integrally involved developing processes for the safe use of these products. EM pharmacist takeaway High-dose insulin facilitates utilization of carbohydrates in the setting of β-blocker or CCB overdose, improves myocardial metabolism, and produces inotropic effects. HDIE is being increasingly used in severe overdose, and it is important for the EM pharmacist to develop safe processes for use of concentrated insulin and dextrose products, dosing and monitoring recommendations, and adjunctive therapy recommendations to prevent hypoglycemia and manage hypokalemia. Digoxin-specific antibody fragments Chan et al. Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1).135 This prospective observational study included patients with chronic digoxin toxicity, defined as a digoxin concentration of >2.6 nmoL/L (although 1 patient with a concentration of 2.3 nmol/L was included), and arrhythmias, hyperkalemia, or renal failure, who were evaluated to determine clinical response to digoxin-specific antibody fragments (digoxin-Fab). Patients with acute-on-chronic toxicity were excluded. Chronic digoxin toxicity is less predictable, as it can be confounded by underlying diseases like cardiovascular disease and renal dysfunction, and serum concentrations may not be reflective of the total body burden due to tissue accumulation. Rehydration and treatment of an underlying condition, like renal failure, is imperative in addition to use of digoxin-Fab in cases of life-threatening toxicity. Theoretically, a reduced dose of antidote should be warranted in patients receiving prolonged digoxin therapy because less digoxin is in the central circulation. Patients enrolled were identified through the New South Wales Poisons Information Centre from September 2013 through February 2015. During the study period, 36 patients with chronic digoxin toxicity were treated with anti-digoxin Fab (median age, 78 years; median daily digoxin dose, 125 µg; median digoxin concentration, 4.7 nmol/L [range, 2.3–11.2 nmol/L]). Prior to treatment with anti-digoxin Fab, the median heart rate was 49 beatss/min and the most common arrhythmias were slow atrial fibrillation or junctional rhythms. The median total digoxin concentration was 4.7 nmol/L and the median potassium concentration was 5.3 mmol/L prior to digoxin-Fab administration. Of the 36 patients enrolled, 10 received 1 vial of anti-digoxin Fab (median digoxin level, 3.9 nmol/L), 16 patients received 2 vials (median digoxin level, 5.2 nmol/L), and 10 received 3 or more vials (median digoxin level, 4.8 nmol/L). After antidote administration, the median change in heart rate was 8 beats/min (Pearson correlation, 0.13; P = 0.44), but greater improvements were observed with a larger number of vials (4.5 beats/min vs 10 beats/min vs. 17.3 beats/min). The median decrease in potassium concentration was 0.3 mmol/L, which did not appear to correlate with antidote administration (Pearson correlation, 0.21; P =0.21). All GI symptoms (nausea, vomiting, diarrhea) improved. Free digoxin concentrations following digoxin-Fab administration decreased to 0 nmol/L (range, 0–1.2 nmol/L), but antidote administration, in almost all patients, did not correlate with significant clinical symptom improvement. There were confounding factors that could have explained the discrepancies in clinical response (eg, other medications that the patients were taking at home or receiving concomitantly, such as vasopressors). Unfortunately, there was not a subgroup analysis to compare the effects of antidote administration on clinical outcomes in patients with significant digoxin levels (>5 nmol/L). The authors concluded that 1 to 2 vials of anti-digoxin Fab appear to be effective in reducing the free digoxin concentration in chronic toxicity; however, the impact on clinical outcomes may be lacking. EM pharmacist takeaway In patients with chronic digoxin toxicity and significant bradycardia, arrhythmias, or hyperkalemia, it appears that 1 to 2 vials of anti-digoxin Fab (in addition to the management of any underlying conditions) may be enough to reduce digoxin free concentrations while improving heart rate and GI symptoms. However, more data on clinical outcomes are needed. Hauptman et al. Digoxin toxicity and use of digoxin immune fab.136 This retrospective cohort study was performed over a 5-year period (2007–2011) using the Premier Perspective Comparative Hospital Database to describe the patient population that presented with digoxin toxicity and compare those who received and did not receive treatment. The study specifically looked at clinical outcomes (ie, LOS, cost of hospitalization, and in-hospital mortality). Review of the database identified 19,543 hospitalizations coded for digoxin toxicity. A total of 5,004 patients (20%) received digoxin-Fab, and a majority were 65 years of age or older. Independent, significant predictors for digoxin-Fab use were suicidal intent (OR, 3.7), arrhythmia (OR, 3.6), hyperkalemia (OR, 2.4), acute renal failure (OR, 2.1), and emergent admission (OR, 1.7). Most often digoxin-Fab (median, 3 vials) was administered on hospital day 1 or 2 and, interestingly, there were no significant differences in in-hospital mortality or LOS between patients who received digoxin-Fab and those who did not. Based on the results of this study and given its retrospective design, it is still unclear whether digoxin-Fab is associated with better outcomes in the elderly population. The study helped to delineate the patient population in which digoxin-Fab is most often administered and indicated that often it is specialists who tend to use it more than generalists when patients present with acute signs of digoxin toxicity (eg, those with arrhythmias and hyperkalemia). EM pharmacist takeaway Further research is needed to determine whether the use of digoxin-Fab improves clinical outcomes in patients with digoxin toxicity and to identify which patient populations may best benefit from its administration. Antivenom Bush et al. Comparison of F(ab’)2vs Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial.137 Fab antivenom (CroFab, ovine) has been the mainstay of treatment in the United States for Crotalinae envenomation. Unfortunately, recurrence of coagulopathy can occur due to differences in pharmacokinetics between the venom and antivenom. F(ab’)2 (Anavip, equine) has been shown in studies from Africa and Asia to be more effective at restoring coagulability. The primary difference between Fab and F(ab’)2 is the number of antigen-binding portions (ie, Fab is monovalent whereas F(ab’)2 is divalent and has 2 antigen-binding portions). This prospective, multicenter, randomized clinical trial conducted in the United States compared the development of late coagulopathy (platelet counts of <150,000 cells/mm3 or a fibrinogen concentration of <150 mg/dL occurring from the end of the maintenance dose to day 8, or use of antivenom to treat a coagulation abnormality up to study day 5) among patients treated with F(ab’)2 or Fab antivenom. Patients were randomly assigned to one of the following treatment groups: F(ab’)2 for initiation and maintenance (n = 41), F(ab’)2 for initiation and placebo for maintenance (n = 41), and Fab for initiation and maintenance (n = 41). Ten vials of F(ab’)2 or 5 vials of Fab were administered over an hour every 2 hours until initial control was achieved (no further progression of local injury, with coagulation serum levels normal or returning towards normal) for initiation. Maintenance doses were 4 vials of F(ab’)2, 250 mL of normal saline, or 2 vials of Fab administered every 6 hours for 3 doses. Demographics were similar between the groups, including snake bite severity score, bite to antivenom start time, and platelet and fibrinogen levels. Patients in both F(ab’)2 groups had less frequent late coagulopathies than those in the Fab-only group (10% [F(ab’)2/F(ab’)2] vs 5% [F(ab’)2/placebo] vs 30% [Fab/Fab]). There were fewer adverse effects (eg, pruritus, nausea, rash) in the F(ab’)2/placebo group than the other 2 groups (81.4% vs 64.9% vs 80.5%), but there were more adverse events categorized as severe in the group that received F(ab’)2 for both initiation and maintenance, although these events were deemed unrelated to the study drug after assessment. One patient in the Fab/Fab group experienced multicomponent coagulopathy recurrence and persistence (ecchymosis, an intrajugular i.v. site bleed, and a 10-g drop in hemoglobin on days 2, 6, and 11, respectively). Numbers of acute serum reactions or serum sickness were similar (1 in each group). The authors describe the absolute risk reduction and calculated that 4 to 5 patients would need to be treated with F(ab’)2 to observe less late coagulopathies. Study results were also indicative of maintenance doses not being needed with this product. There was a disproportionate number of children in the F(ab’)2/F(ab’)2 group, but the authors stated that the risks of late coagulopathies in children and adults are similar and that this imbalance did not affect their overall findings. FDA approved F(ab’)2 only for rattlesnake (genus Crotalus) bites based on these data, but there were 13 patients with copperhead or water moccasin (genus Agkistrodon) venom exposure who received F(ab’)2. EM pharmacist takeaway The use of F(ab’)2 antivenom appears to result in less late coagulopathy development relative to use of the traditional Fab antivenom. This article also highlights that maintenance therapy with F(ab’)2 antivenom may not be needed. Pharmacists working in the ED should understand the key differences between the 2 antivenom products and assist in determining formulary management. TRAUMA Tranexamic Acid Roberts et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.138 Roberts et al. Antifibrinolytic drugs for acute traumatic injury.139 Tranexamic acid is a lysine analog that inhibits fibrinolysis and is therefore thought to reduce bleeding in those with traumatic injury and/or hyperfibrinolysis. This mechanism, in addition to the known attenuation of inflammatory responses, may be beneficial following traumatic injury. Early in-hospital administration of tranexamic acid (1 g i.v. over 10 minutes followed by 1 g i.v. over 8 hours) in patients with trauma-induced hemorrhage was found to reduce the death rate when compared to standard-of-care treatment (14.5% vs 16%; RR, 0.91; 95% CI, 0.85–0.97; P = 0.0035) in the CRASH-2 trial; an RCT involving 20,211 adult trauma patients in 274 hospitals in 40 countries.140 The CRASH-2 trial has been criticized for its study design (eg, use of uncertainty principle for randomization), lack of modern trauma systems and resuscitation strategies at many of the study sites, lack of laboratory monitoring of coagulation function and collection of injury severity score, and underreporting of adverse effects. Also, the target population consisted of trauma patients with a significant hemorrhage, but only half of the patients required a blood transfusion and less than half had SBP of <90 mm Hg or HR of >110 beats/min. The first key article was a post hoc exploratory analysis of the CRASH-2 data to examine the time to treatment effect of TXA on death due to bleeding.138 Compared to placebo recipients, patients treated within an hour of injury had a 32% relative reduction in mortality (RR, 0.68; 95% CI, 0.57–0.82; P < 0.0001), while patients treated within 1 to 3 hours of injury had a 21% relative reduction in mortality (RR, 0.79; 95% CI, 0.64–0.97; P = 0.03). However, patients treated with tranexamic acid more than 3 hours after injury had a 44% relative increase in mortality (RR, 1.44; 95% CI, 1.12–1.84; P = 0.004). The cause for this increase is unknown; however, it is postulated that since there was no difference in all-cause mortality when tranexamic acid was administered beyond 3 hours, the patients who died from bleeding might have died from a non–bleeding-related cause. The second key article is a recent systematic review and meta-analysis that sought to evaluate the effect of antifibrinolytics on mortality, adverse events, need for surgical intervention, blood transfusion, and blood volume requirements in patients with acute traumatic injury.139 However, only 2 RCTs involving tranexamic acid use were included, and patients from the CRASH-2 trial accounted for 99% of the included patients. Mortality (RR, 0.90; 95% CI, 0.85–0.97; P = 0.003) and risk of death from bleeding (RR, 0.85; 95% CI, 0.76–0.96; P = 0.0077) or MI (RR, 0.61; 95% CI, 0.40–0.92; P = 0.02) were all reduced in those who received tranexamic acid compared to those who did not. There were no significant between-group differences in death from other causes; the incidence of PE, stroke, or vascular occlusion; blood transfusion requirements; or volume of blood transfused. Since both of these studies primarily used CRASH-2 data, inherently the findings are limited by the same major concerns with the CRASH-2 trial. From these data it seems that tranexamic acid may have the most benefit in trauma patients with bleeding. If the decision to use tranexamic acid is made, these data indicate that administration should be as soon as possible from the time of injury to provide the greatest benefit. EM pharmacist takeaway Tranexamic acid may reduce mortality in traumatic injury patients with bleeding; however, the available literature has a number of limitations. When tranexamic acid is used, administration should occur as soon as possible after injury and within 3 hours. Morrison et al. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study.141 The MATTERs trial investigators attempted to further define the traumatic injury population that would most benefit from tranexamic acid in the periresuscitation period. While this was a retrospective trial and focused on military casualties, it included a more targeted patient population (those who received at least 1 unit of packed red blood cells [pRBCs] within 24 hours of admission) and recorded coagulation function (PT and aPTT) and thromboembolic events. An absolute risk reduction of 6.5% for in-hospital mortality was found in patients who received tranexamic acid (n = 293; mortality, 17.4%) compared with those who did not (n =603; mortality, 23.9%) (P = 0.03). Mortality at 48 hours was also significantly reduced; however, there was no difference in mortality at 24 hours. Patients requiring a massive transfusion (MT) (≥10 units of pRBCs within 24 hours) had the most benefit from tranexamic acid vs no tranexamic acid (in-hospital mortality, 14.4% vs 28.1%, P = 0.004). The incidence of thromboembolic events was increased with tranexamic acid vs no tranexamic acid (DVT, 2.4% vs 0.2%; PE, 2.7% vs 0.3%; P = 0.001 for both comparisons). This study was limited by the retrospective design, external validity based on injury mechanism, differences between the military and civilian populations, dosing based on clinician discretion, and clinical practice guidelines implemented during the study period possibly introducing variations in tranexamic acid use. However, this study provides further evidence that tranexamic acid may reduce mortality in specific bleeding trauma populations, especially those requiring MT. EM pharmacist takeaway Bleeding trauma patients requiring transfusion and specifically those requiring MT appear to have the greatest mortality benefit from tranexamic acid administration. More data are required to determine the thromboembolic risk of tranexamic acid use in this population. El-Menyar et al. Efficacy of prehospital administration of tranexamic acid in trauma patients: a meta-analysis of the randomized controlled trials.142 Early in-hospital administration of tranexamic acid in patients with trauma-induced hemorrhagic shock reduces the risk of death and is a cost-effective intervention.143 Given the time-dependent effect of antifibrinolytic therapy, prehospital administration of tranexamic acid has been explored, and this meta-analysis includes the findings of 2 studies. Both studies included in this meta-analysis compared outcomes in patients who received prehospital tranexamic acid (n = 386) relative to control or propensity-matched patients (n = 383). Patients were deemed candidates for tranexamic acid based on signs of hemorrhagic shock following blunt or penetrating trauma, SBP of <90 mm Hg at the scene of injury or during transport, sustained injury of <3 hours, high risk of significant hemorrhage, or at the discretion of the EM clinician. There was a statistically significant reduction in 24-hour mortality in the intervention group (OR, 0.49; 95% CI, 0.28–0.85), as well as a nonsignificant reduction in 30-day mortality (OR, 0.86; 95% CI, 0.56–1.32) and thromboembolic events (OR, 0.74; 95% CI, 0.27–2.07). Limitations of this analysis included a lack of documentation of exact causes of death; in addition, the time of administration and doses of tranexamic acid were not available, and the volumes of blood products transfused in either group were not noted. Even considering these limitations, this analysis suggests that mortality at 24 hours may be decreased with prehospital tranexamic acid use; however, the effect of tranexamic acid on prolonged survival and the risk of thromboembolic complications must be explored further. Trials of prehospital tranexamic acid therapy are currently ongoing and will help inform future practice. EM pharmacist takeaway Prehospital administration of tranexamic acid for trauma-induced hemorrhagic shock within 3 hours of injury is likely a valuable intervention. Ongoing studies to confirm the feasibility and safety of this practice are needed. Massive transfusion and coagulopathy management Holcomb et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: The PROPPR randomized clinical trial.144 Massive hemorrhage is a leading cause of death in trauma patients. Damage control resuscitation (DCR) has been adopted in many civilian centers as an attempt to reduce mortality. This study sought to determine the effectiveness and safety of a 1:1:1 transfusion ratio compared with a 1:1:2 transfusion ratio in patients with trauma who were predicted to receive a MT. Patients were randomly assigned to receive plasma, platelets, and pRBCs in a 1:1:1 (n = 338) or 1:1:2 (n = 342) ratio. There was no significant difference in mortality rates at 24 hours (12.7% and 17.0% in the 1:1:1 and 1:1:2 groups, respectively; P = 0.12) or at 30 days (22.4% and 26.1%, respectively; P = 0.26.) However, exsanguination as the cause of death in the first 24 hours occurred at a lower rate in the 1:1:1 group (9.2%) vs the 1:1:2 group (14.6%) (difference, –5.4%; 95% CI, −10.4% to –0.5%; P = 0.03), and more patients achieved anatomic hemostasis in the 1:1:1 group (86.1% vs 78.1%, P = 0.006). The overall rate of complications (eg, acute respiratory distress syndrome, multiple organ failure, VTE, sepsis, transfusion-related complications) was high (89%); however, complications and safety outcomes did not differ significantly between groups. Since there was no difference in the primary outcome but differences in important secondary outcomes, it can be presumed that this study was not powered to detect a small effect size. Other limitations included the inability to independently examine effects of plasma and platelets and unblinding once the transfusion containers were opened; in addition, patients with nonsurvivable brain injury were not excluded (only those with devastating injuries and expected to die within 1 hour were excluded). Overall this article supports a key component of DCR for severely injured trauma patients. EM pharmacist takeaways High ratio composition transfusion (1:1:1) is associated with lower risks of death from exsanguination in the first 24 hours and hemostasis. This article provides support for important key components of modern transfusion practices for severely injured trauma patients. It is important for the EM pharmacist to understand this practice to support the trauma team during DCR. Cannon et al. Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Association for the Surgery of Trauma.145 This guideline was developed to address key components of DCR, typically performed within the ED and ICU settings. Following systematic review of 37 studies and meta-analysis of 31 studies, the task force recommended using a MT/DCR protocol and a high ratio of plasma and platelets to pRBCs for patients with severe trauma. Decreased mortality was described with use of an MT/DCR protocol vs no protocol (OR, 0.61; 95% CI, 0.43–0.87; P = 0.006) and when high ratios of plasma and platelets to pRBCs vs a low ratio transfusion composition were used (ORs, 0.60 [95% CI, 0.46–0.77; P < 0.001] and 0.44 [95% CI, 0.28–0.71; P = 0.0003] for plasma:pRBC and platelet:pRBC, respectively). The task force was unable to make recommendations for or against use of rFVIIa and tranexamic acid for patients with severe trauma based on their literature evaluation and methodology. They concluded there is no clear mortality benefit of rFVIIa but that when given early in resuscitation it may decrease the need for MT (optimal dosing and timing of administration relative to blood transfusion is unknown), and they provided a conditional recommendation for in-hospital use of tranexamic acid early (within 3 hours) in the management of severely injured adult trauma patients. No conclusions related to thromboembolic events were made for either rFVIIa or tranexamic acid. Overall this guideline answers some important questions related to trauma resuscitation and uses Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology in addition to meta-analysis, which strengthens the recommendations. One limitation is that these recommendations are specific to patients with severe trauma, defined by the guideline committee as severely injured patients at risk of death from hemorrhage, and do not provide guidance on management of other trauma populations. EM pharmacist key takeaway MT/DRC protocols and high ratios of plasma and platelets to pRBCs are associated with decreased mortality in severely injured trauma patients. Clear recommendations for rFVIIa or tranexamic acid use cannot be provided, but these agents may be beneficial in certain populations. The thromboembolic risk of rFVIIa or tranexamic acid use in severely injured trauma patients is unknown. Joseph et al. Prothrombin complex concentrate vs fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference?146 Fresh frozen plasma provides coagulation factors and facilitates volume expansion during trauma resuscitation, but it has been associated with delays in coagulopathy reversal. Prothrombin complex concentrates are an alternative option that provide concentrated clotting factors and, theoretically, rapid reversal of coagulopathy. This retrospective analysis of a prospectively maintained database included 252 coagulopathic trauma patients (INR of ≥1.5). Propensity score matching was utilized to compare those who received 4F-PCC plus FFP (n = 63) or FFP (n = 189) in a 1:3 ratio. PCC in addition to FFP was used since patients still required volume expansion and PCC alone has a low overall volume. The PCC/FFP group had a faster time to INR correction (mean [SD], 394 [311] minutes vs 1,050 [1,126] minutes; P = 0.001), reduced pRBC infusion requirements (6.6 [4.1] units vs 10 [8.3] units, P = 0.001), and a reduced overall dose of FFP (2.8 [1.8] units vs 3.9 [1.3] units, P = 0.01). There was no significant difference in thromboembolic complications, and mortality was lower in the PCC/FFP group (23% vs 28%, P = 0.04). Overall, use of PCC in addition to FFP in coagulopathic trauma patients more rapidly corrected INR and reduced blood product requirements. It is important to note that there was not a PCC utilization protocol; use was determined at clinicians’ discretion, thereby introducing selection bias. Also, INR was used as a surrogate for coagulopathy rather than viscoelastic tests (thromboelastography [TEG] or thromboelastometry [ROTEM]); this may not provide an accurate assessment of overall coagulation status, since INR is calculated using PT, which is FVII sensitive. Lastly, volume of crystalloids administered was not reported, and an assessment of the influence of dilutional coagulopathy was not performed. This study provided promising results with the use of PCC in combination with FFP in the resuscitation of coagulopathic trauma patients, but prospective studies should be performed to further understand the role of PCC in conjunction with FFP and its effect on mortality. EM pharmacist takeaway PCC may be a therapeutic addition to FFP in the management of trauma-induced coagulopathy to rapidly correct INR and reduce the overall volume of pRBCs and FFP required. Future studies are needed to better define who may benefit from PCC and its place in therapy and to assess its mortality benefit and safety profile. Schöchl et al. Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy vs standard fresh frozen plasma-based therapy.147 Trauma-induced coagulopathy is not well understood, but hemostatic derangements in activated protein C, tissue factor, coagulation factors, platelet function, and fibrinogen are all possible contributors. Common coagulation measures like PT, INR, and activated partial thromboplastin time lack accuracy in the trauma setting. Viscoelastic tests that measure the ability of whole blood samples to form a clot may be useful to guide resuscitation efforts, help rapidly correct coagulopathy in trauma, and reduce the need for allogeneic blood products such as pRBCs and platelets. This retrospective analysis compared trauma patients (n = 80) who received ROTEM-guided fibrinogen concentrate (≥1 g) and/or PCC (≥500 units) and no FFP with 601 patients from a European trauma registry who received FFP (≥2 units) and no fibrinogen concentrate or PCC. Baseline demographic data differed between the groups with regard to mechanism of trauma, but the average trauma injury severity scores were similar. The median dose of fibrinogen concentrate was 6 g (IQR, 3–9 g), and the median 4F-PCC dose was 1,200 units (IQR, 0-2,400 units). The median FFP administration was 6 units (IQR, 4–10 units). In the fibrinogen/PCC group and the FFP group, 71% and 97% of patients received a pRBC transfusion and 9% and 44% required platelets, respectively. This was a single-center retrospective study, with incomplete data, that lacked a safety evaluation, had potential reporting bias from the European trauma registry, only evaluated blood transfusion during the ED stay and surgery (not the complete ICU or hospital stay), and used a fibrinogen concentrate product not available in the United States. But it showed that viscoelastic tests may be a useful tool to guide resuscitation strategies. Prospective studies are necessary to confirm the findings of this study and to address the rates of thromboembolic complications. Nevertheless, TEG or ROTEM are being used more frequently, and the EM pharmacist should understand the tests, interpretation, and possible clinical implications. EM pharmacist takeaway Viscoelastic tests (TEG and ROTEM) provide a more functional assessment of clot formation compared to INR, PT, or platelet count and are valuable tools that may be used in goal-directed coagulation management in trauma patients. Prospective studies are needed to assess ease of use and describe efficacy and safety outcomes following product administration guided by TEG in this population. Traumatic brain injury Carney et al. Guidelines for the management of severe traumatic brain injury.148 The fourth edition of this guideline provides detailed recommendations regarding (1) treatment interventions, such as decompressive craniotomy, prophylactic hypothermia, hyperosmolar therapy, cerebrospinal fluid drainage, ventilation therapies, anesthetics, analgesics and sedatives, steroids, nutrition, infection prophylaxis, DVT prophylaxis, and seizure prophylaxis; (2) ICP, cerebral perfusion, and advanced cerebral monitoring recommendations; and (3) blood pressure, ICP, cranial perfusion pressure (CPP), and advanced cerebral monitoring thresholds—all specific to the care of patients with severe traumatic brain injury (TBI). The interdisciplinary group used a standardized process for systematic review and synthesis, assessed all included studies for potential bias, and graded the final recommendations based on level of evidence. There are several consensus statements that are important to the EM pharmacist or involve medication management. Hyperosmolar therapy may lower ICP, but a specific agent (mannitol or hypertonic saline) could not be recommended. Both are thought to reduce blood viscosity, improve microcirculatory flow, and decrease blood volume. Patient-specific factors, including blood pressure, should be considered with agent selection. High-dose barbiturates are recommended for burst suppression to prevent elevated ICP or for ICP control in patients refractory to maximum therapy, but high-dose propofol to control ICP is not recommended. High-dose steroids are not recommended as they are associated with increased mortality, and early seizure prophylaxis (within 7 days of injury) with phenytoin is recommended (there was insufficient evidence to recommend levetiracetam over phenytoin), but prophylaxis to prevent late posttraumatic seizures is not recommended. Many of these recommendations are unchanged from the third edition of the guideline. The guideline provides comprehensive reviews and summarizes the literature assessed. EM pharmacist takeaway This guideline provides important pharmacologic recommendations for patients with severe TBI. Mannitol or hypertonic saline can be used for hyperosmolar therapy, and phenytoin remains the recommended agent for early posttraumatic seizure prophylaxis. Patanwala AE et al. Succinylcholine is associated with increased mortality when used for rapid sequence intubation of severely brain injured patients in the emergency department.149 Patients with severe TBI needing airway protection require intubation to reduce the risk of hypoxemia and secondary brain damage. Succinylcholine remains a commonly used neuromuscular blocking agent (NMBA) for rapid sequence intubation (RSI) within the ED, but its use may be associated with a transient increase in ICP that can worsen cerebral hypoxemia. The mechanism for this phenomenon is not completely understood. This retrospective cohort study of 233 patients from a single, urban academic medical center compared in-hospital mortality in patients with TBI who underwent RSI with either succinylcholine (n = 149) or rocuronium (n = 84). Patients were stratified as having low- or high-severity head injuries based on the Abbreviated Injury Severity score. The in-hospital mortality rates were 14% and 44% in the low- and high-severity subgroups of the succinylcholine group, respectively (difference, 30%; 95% CI, 14%-46%). In patients who received rocuronium, the in-hospital mortality rates were 22% and 23% in the low- and high-severity groups, respectively (difference, 1%; 95% CI, 18%-20%). In multivariate analysis, succinylcholine vs rocuronium use was independently associated with increased mortality in high-severity patients (OR, 4.1; 95% CI, 1.18–14.12). The authors concluded that succinylcholine use in RSI in patients with severe TBI was associated with increased mortality. It may not be possible to discriminate which patients are most likely to benefit from avoidance of succinylcholine at the time of intubation in the ED. Regardless, based on the overall mortality of 23% in both low- and high-severity groups, it seems that rocuronium could be used for all TBI patients. It is important to recognize that neurologic assessment would be impaired for up to 30 to 60 minutes with rocuronium use. Study limitations included the possibility of selection bias. For example, comorbidities and need for postintubation neurologic assessment could influence the choice of NMBA for RSI. Also, hypotension is known to be associated with worse outcomes in TBI and occurred more often in the succinylcholine group. However, the authors conducted a multivariate analysis to adjust for some potential confounders. Information such as NMBA dosing and use of other medications known to effect ICP were not reported. The study was not designed to stratify by severity of head injury a priori, which could have impacted statistical power. These data indicate an important potential association, and prospective trials are needed to confirm these findings. EM pharmacist takeaway Succinylcholine was associated with higher in-hospital mortality in patients with severe head injury. These data provide guidance on who may benefit from succinylcholine avoidance during RSI after TBI. More data is needed to determine what specific severe head injury populations may benefit from succinylcholine avoidance. Zeiler FA et al. The ketamine effect on ICP in traumatic brain injury.150 This was a qualitative systematic literature review conducted with the primary goal of evaluating ketamine-related effects on ICP in TBI patients. Secondary outcomes included ketamine-related effects on CPP, MAP, patient outcomes, and adverse effects. A standardized literature search strategy was used, and strength of the evidence was determined using Oxford criteria and GRADE methodology. A total of 7 prospective studies were included (156 patients were studied), 4 of which were randomized controlled studies, with 2 studies focused on pediatrics (all providing low-quality evidence). Dosing and administration method used (continuous infusion or bolus) were heterogeneous, and all studies included no more than 30 patients. Ketamine administered as a bolus dose failed to produce ICP increases, and there was a trend toward an ICP reduction (3 studies) and increased CPP (1 study; mean CPP increased by 4 mmHg and mean MAP decreased by 4 mm Hg). Continuous infusion of ketamine did not affect ICP (4 studies) and increased CPP and MAP (2 studies). Non–clinically significant tachycardia occurred in 2 patients and was the only adverse effect reported. Although the evidence was of low quality, it indicated that ketamine does not increase ICP in patients already intubated. These data are limited by the aforementioned heterogeneity, low level of evidence, small sample sizes, and concomitant sedative medications. It is important to recognize that the patients included in this systematic review were not representative of all patients presenting to EDs, where this question often arises. Bolus doses were administered in already-intubated patients for anticipated stimulation, but this is dissimilar to usual practice in the ED RSI population. Nevertheless, these data support other evidence indicating that ketamine use in the TBI population is not associated with detrimental ICP changes. EM pharmacist takeaway Ketamine is not associated with elevations in ICP in the TBI population. The EM pharmacist should be comfortable recommending this agent when it is clinically appropriate or when other options may be contraindicated or less preferred. Conclusion Emergency medicine is an area of practice in which clinicians will continue to encounter a vast spectrum of disease state management challenges and diverse patient populations. It is imperative for the EM pharmacist to stay up to date with the ever-evolving body of primary literature and international and national guidelines. As this is becoming increasingly difficult, this article provides useful highlights and discussion relevant to the EM pharmacist. Disclosures The authors have declared no potential conflicts of interest. References 1. Thomas MC , Acquisto NM, Patanwala AE, et al. Key articles and guidelines for the emergency medicine pharmacist . Pharmacotherapy . 2011 ; 31 : 454e - 491e . Google Scholar Crossref Search ADS WorldCat 2. Centre for Evidence-Based Medicine . Oxford Centre for Evidence-based Medicine – levels of evidence (March 2009). www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed May 21, 2018 . 3. Stephens RJ , Ablordeppey E, Drewry AM, et al. Analgosedation practices and the impact of sedation depth on clinical outcomes among patients requiring mechanical ventilation in the ED: A cohort study . CHEST . 2017 ; 152 : 963 - 971 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Devlin JW , Skrobik Y, Gelinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU . Crit Care Med . 2018 ; 46 : e825 - e873 . Google Scholar Crossref Search ADS PubMed WorldCat 5. Barnett ML , Olenksi AR, Jena AB. Opioid prescribing by emergency physicians and risk of long-term use . N Engl J Med . 2017 ; 376 : 663 - 673 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Shah A , Hayes CJ, Martin BC. Characteristics of initial prescription episodes and likelihood of long-term opioid use - United States, 2006–2015 . MMWR Morb Mortal Wkly Rep. 2017 ; 66 : 265 - 269 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Jeffery MM , Hooten WM, Hess EP, et al. Opioid prescribing for opioid-naive patients in emergency departments and other settings: Characteristics of prescriptions and association with long-term use . Ann Emerg Med . 2018 ; 71 : 326 - 336.e19 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Oliveira JE , Silva L, Scherber K, et al. Safety and efficacy of intravenous lidocaine for pain management in the emergency department: a systematic review . Ann Emerg Med . 2018 ; 72 : 135 - 144 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Makhoul T , Kelly G, Schult RF, Acquisto NM. Intravenous lidocaine for renal colic in the emergency department (ED) . Am J Emerg Med . 2019 ; 37 : 775 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Pathan SA , Mitra B, Straney LD, et al. Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial . Lancet . 2016 ; 387 : 1999 - 2007 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Afshar K , Jafari S, Marks AJ, et al. Nonsteroidal anti-inflammatory drugs (NSAIDs) and non-opioids for acute renal colic . Cochrane Database Syst Rev . 2015 ; 6 : CD006027 . OpenURL Placeholder Text WorldCat 12. Holdgate A , Pollock T. Nonsteroidal anti-inflammatory drugs (NSAIDS) versus opioids for acute renal colic . Cochrane Database Syst Rev . 2004 ; 1 : CD004137 . OpenURL Placeholder Text WorldCat 13. Motov S , Yasavolian M, Likourezos A, et al. Comparison of intravenous ketorolac at three single-dose regimens for treating acute pain in the emergency department: a randomized controlled trial . Ann Emerg Med . 2017 ; 70 : 177 - 184 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Le May S , Ali S, Plint AC, et al. Pediatric Emergency Research Canada (PERC). Oral analgesics utilization for children with musculoskeletal injury (OUCH Trial): an RCT . Pediatrics . 2017 ; 140 : e20170186 . Google Scholar Crossref Search ADS PubMed WorldCat 15. Sin B , Wiafe J, Ciaramella C, et al. The use of intranasal analgesia for acute pain control in the emergency department: a literature review . Am J Emerg Med . 2018 ; 36 : 310 - 318 . Google Scholar Crossref Search ADS PubMed WorldCat 16. Tomaselli GF , Mahaffey KW, Cuker A, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways . J Am Coll Cardiol . 2017 ; 70 : 3042 - 3067 . Google Scholar Crossref Search ADS PubMed WorldCat 17. Sarode R , Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding . Circulation . 2013 ; 128 : 1234 - 1243 . Google Scholar Crossref Search ADS PubMed WorldCat 18. Pollack CV , Reilly PA, Ryn JV, et al. Idarucizumab for dabigatran reversal – full cohort analysis . N Engl J Med . 2017 ; 377 : 431 - 434 . Google Scholar Crossref Search ADS PubMed WorldCat 19. Connolly SJ , Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors (ANNEXA-4) . N Engl J Med . 2019 ; 380 : 1326 - 1335 . Google Scholar Crossref Search ADS PubMed WorldCat 20. Siegal DM , Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity . N Engl J Med . 2015 ; 373 : 2413 - 2424 . Google Scholar Crossref Search ADS PubMed WorldCat 21. O’Gara PT , Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction (STEMI): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines . Circulation. 2013 ; 127 : e362 - e425 . Google Scholar Crossref Search ADS PubMed WorldCat 22. Amsterdam EA , Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes (NSTEMI): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . J Am Coll Cardiol. 2014 ; 64 : e139 - e228 . Google Scholar Crossref Search ADS PubMed WorldCat 23. Pu J , Ding S, Ge H, et al. ; EARLY-MYO Investigators. Efficacy and safety of a pharmaco-invasive strategy with half-dose alteplase versus primary angioplasty in ST-segment-elevation myocardial infarction: EARLY-MYO Trial (Early routine catheterization after alteplase fibrinolysis versus primary PCI in acute ST-segment-elevation myocardial infarction) . Circulation . 2017 ; 136 : 1462 - 1473 . Google Scholar Crossref Search ADS PubMed WorldCat 24. Armstrong PW , Gershlick AH, Goldstein P, et al. ; STREAM Investigative Team. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction . N Engl J Med . 2013 ; 368 : 1379 - 1387 . Google Scholar Crossref Search ADS PubMed WorldCat 25. Kearon C , Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report . CHEST . 2016 ; 149 ( 2 ): 315 - 352 . Google Scholar Crossref Search ADS PubMed WorldCat 26. Hao Q , Dong BR, Yue J, et al. Thrombolytic therapy for pulmonary embolism . Cochrane Database Syst Rev . 2015 ;( 9 ): CD004437 . OpenURL Placeholder Text WorldCat 27. Meyer G , Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism . N Engl J Med . 2014 ; 370 : 1402 - 1411 . Google Scholar Crossref Search ADS PubMed WorldCat 28. Konstantinides SV , Vicaut E, Danays T, et al. Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism . J Am Coll Cardiol . 2017 ; 69 : 1536 - 1544 . Google Scholar Crossref Search ADS PubMed WorldCat 29. Sharifi M , Berger J, Beeston P, et al. Pulseless electrical activity in pulmonary embolism treated with thrombolysis (from the “PEAPETT” study) . Am J Emerg Med. 2016 ; 34 : 1963 - 1967 . Google Scholar Crossref Search ADS PubMed WorldCat 30. Bottiger BW , Arntz HR, Chamberlain DA, et al. Thrombolytics during resuscitation for out-of-hospital cardiac arrest . N Engl J Med . 2008 ; 359 : 2651 - 2662 . Google Scholar Crossref Search ADS PubMed WorldCat 31. Al-Khatib SM , Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary . Circulation . 2018 ; 138 : e210 - e271 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 32. Page RL , Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS guidelines for the management of adult patients with supraventricular tachycardia: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society . J Am Coll Cardiol . 2016 ; 67 : e27 - e115 . Google Scholar Crossref Search ADS PubMed WorldCat 33. January CT , Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society . J Am Coll Cardiol. 2014 ; 64 : e1 - e76 . Google Scholar Crossref Search ADS PubMed WorldCat 34. Fromm C , Suau SJ, Cohen V, et al. Diltiazem vs. metoprolol in the management of atrial fibrillation or flutter with rapid ventricular rate in the emergency department . J Emerg Med. 2015 ; 49 : 175 - 182 . Google Scholar Crossref Search ADS PubMed WorldCat 35. Ortiz M , Martín A, Arribas F, et al. Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study . Eur Heart J . 2017 ; 38 : 1329 - 1335 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 36. Alkhalili M , Ma J, Grenier S. Defining roles for pharmacy personnel in disaster response and emergency preparedness . Disaster Med Public Health Prep . 2017 ; 11 : 496 - 504 . Google Scholar Crossref Search ADS PubMed WorldCat 37. Awad NI , Cocchio C. Assessment of hospital pharmacy preparedness for mass casualty events . P T. 2015 ; 40 : 264 - 267 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 38. Narayanan N , Lacy CR, Cruz JE, et al. Disaster preparedness: biological threats and treatment options . Pharmacotherapy . 2018 ; 38 : 217 - 234 . Google Scholar Crossref Search ADS PubMed WorldCat 39. Doshi P , Potter AJ, De Los Santos D, et al. Prospective randomized trial of insulin glargine in acute management of diabetic ketoacidosis in the emergency department: a pilot study . Acad Emerg Med 2015 ; 22 : 657 - 662 . Google Scholar Crossref Search ADS PubMed WorldCat 40. Andrade-Castellanos CA , Colunga-Lozano LE, Delgado-Figuero N, et al. Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis . Cochrane Database Syst Rev. 2016 ; CD011281 . OpenURL Placeholder Text WorldCat 41. Veverka M , Marsh K, Norman S, et al. A pediatric diabetic ketoacidosis management protocol incorporating a two-bag intravenous fluid system decreases the duration of intravenous insulin therapy . J Pediatr Pharmcol Ther. 2016 ; 21 : 512 - 517 . OpenURL Placeholder Text WorldCat 42. Haas NL , Gianchandrani RY, Gunnerson KJ, et al. The two-bag method for treatment of diabetic ketoacidosis in adults . J Emerg Med. 2018 ; 54 : 593 - 599 . Google Scholar Crossref Search ADS PubMed WorldCat 43. McDonald LC , Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) . Clin Infect Dis. 2018 ; 66 : e1 - e48 . Google Scholar Crossref Search ADS PubMed WorldCat 44. Kalil AC , Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society . Clin Infect Dis . 2016 ; 63 : 1 - 51 . Google Scholar Crossref Search ADS PubMed WorldCat 45. Wang W , Chen W, Liu Y, et al. Antibiotics for uncomplicated skin abscesses: systematic review and network meta-analysis . BMJ Open . 2018 ; 8 : e020991 . Google Scholar Crossref Search ADS PubMed WorldCat 46. Vermandere M , Aertgeerts B, Agoritsas T, et al. Antibiotics after incision and drainage for uncomplicated skin abscesses: a clinical practice guideline . BMJ. 2018 ; 360 : k243 . Google Scholar Crossref Search ADS PubMed WorldCat 47. Stevens D , Bisno A, Chambers H, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America . Clin Infect Dis . 2014 ; 59 : e10 - e52 . Google Scholar Crossref Search ADS PubMed WorldCat 48. Fahimi J , Singh A, Frazee BW. The role of adjunctive antibiotics in the treatment of skin and soft tissue abscesses: a systematic review and meta-analysis . CJEM . 2015 ; 17 : 420 - 432 . Google Scholar Crossref Search ADS PubMed WorldCat 49. Cadena J , Nair S, Henao-Martinez AF, et al. Dose of trimethoprim-sulfamethoxazole to treat skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus . Antimicrob Agents Chemother . 2011 ; 55 : 5430 - 5432 . Google Scholar Crossref Search ADS PubMed WorldCat 50. Halilovic J , Heintz B, Brown J. Risk factors for clinical failure in patients hospitalized with cellulitis and cutaneous abscess . J Infect . 2012 ; 65 : 128 - 134 . Google Scholar Crossref Search ADS PubMed WorldCat 51. Reardon J , Lau TT, Ensom MH. Vancomycin loading doses: a systematic review . Ann Pharmacother. 2015 ; 49 : 557 - 565 . Google Scholar Crossref Search ADS PubMed WorldCat 52. Hammond DA , Smith MN, Li C, et al. Systematic review and meta-analysis of acute kidney injury associated with concomitant vancomycin and piperacillin/tazobactam . Clin Infect Dis . 2017 ; 64 : 666 - 674 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 53. Mullins BP , Kramer CJ, Bartel BJ, et al. Comparison of the nephrotoxicity of vancomycin in combination with cefepime, meropenem, or piperacillin/tazobactam: a prospective, multicenter study . Ann Pharmacother . 2018 ; 52 : 639 - 644 . Google Scholar Crossref Search ADS PubMed WorldCat 54. Lodise TP , Fan W, Sulham AS. Economic impact of oritavancin for the treatment of acute bacterial skin and skin structure infections in the emergency department or observation setting: cost savings associated with avoidable hospitalizations . Clin Ther. 2016 ; 38 : 136 - 148 . Google Scholar Crossref Search ADS PubMed WorldCat 55. Tandan M , Cormican M, Vellinga A. Adverse events of fluoroquinolones vs. other antimicrobials prescribed in primary care: a systematic review and meta-analysis of randomized controlled trials . Int J Antimicrob Agents . 2018 ; 52 : 529 - 540 . Google Scholar Crossref Search ADS PubMed WorldCat 56. Stephenson AL , Wu W, Cortes D, et al. Tendon injury and fluoroquinolone use: a systematic review . Drug Saf. 2013 ; 36 : 709 - 721 . Google Scholar Crossref Search ADS PubMed WorldCat 57. Pasternak B , Inghammar M, Svanström H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study . BMJ. 2018 ; 360 : k678 . Google Scholar Crossref Search ADS PubMed WorldCat 58. Etminan M , Brophy JM, Samii A. Oral fluoroquinolone use and risk of peripheral neuropathy: a pharmacoepidemiologic study . Neurology. 2014 ; 83 : 1261 - 1263 . Google Scholar Crossref Search ADS PubMed WorldCat 59. Workowski KA , Bolan GA. Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines . Clin Infect Dis . 2015 ; 61 ( suppl 8 ): S759 - S762 . Google Scholar Crossref Search ADS PubMed WorldCat 60. Kissinger P , Muzny CA, Mena LA, et al. Single-dose versus 7-day-dose metronidazole for the treatment of trichomoniasis in women: an open-label, randomised controlled trial . Lancet Infect Dis . 2018 ; 18 : 1251 - 1259 . Google Scholar Crossref Search ADS PubMed WorldCat 61. Centers for Disease Control and Prevention . Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV-United States, 2016. https://www.cdc.gov/hiv/pdf/programresources/cdc-hiv-npep-guidelines.pdf. Accessed October 2019 . 62. Mah ND , Birmingham AR, Bodkin RP, et al. Sexually transmitted infection review for the acute care pharmacist [published online ahead of print] . J Pharm Pract. 2018 : Jan 1: 897190018764567 . doi:10.1177/0897190018764567. OpenURL Placeholder Text WorldCat 63. Bodkin RP , Weant KA, Baker Justice S, et al. Effectiveness of glucagon in relieving esophageal foreign body impaction: a multicenter study . Am J Emerg Med. 2016 ; 34 : 1049 - 1052 . Google Scholar Crossref Search ADS PubMed WorldCat 64. Riddell J , Tran A, Bengiamin R, et al. Ketamine as a first-line treatment for severely agitated emergency department patients . Am J Emerg Med. 2017 ; 35 : 1000 - 1004 . Google Scholar Crossref Search ADS PubMed WorldCat 65. Cole JB , Klein LR, Nystrom PC, et al. A prospective study of ketamine as a primary therapy for prehospital profound agitation . Am J Emerg Med . 2018 ; 36 : 789 - 796 . Google Scholar Crossref Search ADS PubMed WorldCat 66. Linder LM , Ross CA, Weant KA. Ketamine for the acute management of excited delirium and agitation in the prehospital setting . Pharmacotherapy . 2018 ; 38 : 139 - 151 . Google Scholar Crossref Search ADS PubMed WorldCat 67. Afenyi-Annan A , Ballas S, Hassell K, et al. Managing acute complications of sickle cell disease . In: Evidence-based Management of Sickle Cell Disease . Bethesda, MD : National Heart, Lung, and Blood Institute ; 2014 : 31 - 54 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 68. Brandow AM , Nimmer M, Simmons T, et al. Impact of emergency department care on outcomes of acute pain events in children with sickle cell disease . Am J Hematol . 2016 ; 91 : 1175 - 1180 . Google Scholar Crossref Search ADS PubMed WorldCat 69. Powers WJ , Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke. Stroke 2018: a guideline for healthcare professionals from the American Heart Association/American Stroke Association . Stroke . 2018 ; 49 : e46 - e110 . Google Scholar Crossref Search ADS PubMed WorldCat 70. Campbell BCV , Mitchell PJ, Churilov L, et al. Tenecteplase vs alteplase before thrombectomy for ischemic stroke . N Engl J Med. 2018 ; 378 : 1573 - 1582 . Google Scholar Crossref Search ADS PubMed WorldCat 71. Parsons M , Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke . N Engl J Med . 2012 ; 366 : 1099 - 1107 . Google Scholar Crossref Search ADS PubMed WorldCat 72. Logallo N , Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomized, open-label, blinded endpoint trial . Lancet Neurol. 2017 ; 16 : 781 - 788 . Google Scholar Crossref Search ADS PubMed WorldCat 73. Qureshi AI , Palesch YY, Baran WG, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage . N Engl J Med. 2016 ; 375 : 1033 - 1043 . Google Scholar Crossref Search ADS PubMed WorldCat 74. Anderson CS , Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage . N Engl J Med . 2013 ; 368 : 2355 - 2365 . Google Scholar Crossref Search ADS PubMed WorldCat 75. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association . Stroke . 2015 ; 46 : 2032 - 2060 . Google Scholar Crossref Search ADS PubMed WorldCat 76. Frontera JA , Lewin JJ 3rd, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine . Neurocrit Care . 2016 ; 24 : 6 - 46 . Google Scholar Crossref Search ADS PubMed WorldCat 77. Huff JS , Melnick ER, Tomaszewski CA, et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures . Ann Emerg Med. 2014 ; 63 : 437 - 447 . Google Scholar Crossref Search ADS PubMed WorldCat 78. Brophy GM , Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus . Neurocrit Care . 2012 ; 17 : 3 - 23 . Google Scholar Crossref Search ADS PubMed WorldCat 79. Orr SL , Friedman BW, Christie , S, et al. Management of adults with acute migraine in the emergency department: the American Headache Society evidence assessment of parenteral pharmacotherapies . Headache. 2016 ; 56 : 911 - 940 . Google Scholar Crossref Search ADS PubMed WorldCat 80. Patniyot IR , Gelfand AA. Acute treatment therapies for pediatric migraine: a qualitative systemic review . Headache. 2016 ; 56 : 49 - 70 . Google Scholar Crossref Search ADS PubMed WorldCat 81. Eppert HD , Reznek AJ. ASHP guidelines on emergency medicine pharmacist services . Am J Health-Syst Pharm . 2011 ; 68 : e81 - e95 . Google Scholar Crossref Search ADS PubMed WorldCat 82. American College of Emergency Physicians . Clinical pharmacist services in the emergency department . Ann Emerg Med . 2015 ; 66 : 444 - 445 . OpenURL Placeholder Text WorldCat 83. Farmer BM , Hayes BD, Rao R, et al. The role of clinical pharmacists in the emergency department . J Med Toxicol . 2018 ; 14 : 114 . Google Scholar Crossref Search ADS PubMed WorldCat 84. Thomas MC , Acquisto NM, Shirk MB, Patanwala AE. A national survey of emergency pharmacy practice in the United States . Am J Health-Syst Pharm . 2016 ; 73 : 386 - 394 . Google Scholar Crossref Search ADS PubMed WorldCat 85. Roman C , Edwards G, Dooley M, Mitra B. Roles of the emergency medicine pharmacist: a systematic review . Am J Health-Syst Pharm . 2018 ; 75 : 796 - 806 . Google Scholar Crossref Search ADS PubMed WorldCat 86. Rothschild JM , Churchill W, Erickson A, et al. Medication errors recovered by emergency department pharmacists . Ann Emerg Med . 2010 ; 55 : 513 - 521 . Google Scholar Crossref Search ADS PubMed WorldCat 87. Patanwala AE , Sanders AB, Thomas MC, et al. A prospective, multicenter study of pharmacist activities resulting in medication error interception in the emergency department . Ann Emerg Med . 2012 ; 59 : 369 - 373 . Google Scholar Crossref Search ADS PubMed WorldCat 88. Pevnick JM , Nguyen C, Jackevicius CA, et al. Improving admission medication reconciliation with pharmacists or pharmacy technicians in the emergency department: a randomised controlled trial . BMJ Qual Saf . 2018 ; 27 : 512 - 520 . Google Scholar Crossref Search ADS PubMed WorldCat 89. Losier M , Ramsey TD, Wilby KJ, Black EK. A systematic review of antimicrobial stewardship interventions in the emergency department . Ann Pharm . 2017 ; 51 : 774 - 790 . OpenURL Placeholder Text WorldCat 90. May L , Cosgrove S, L’ Archeveque M, et al. Antimicrobial stewardship in the emergency department and guidelines for development . Ann Emerg Med . 2013 ; 62 : 69 - 77 . Google Scholar Crossref Search ADS PubMed WorldCat 91. Su Z , Li R, Gai Z. Intravenous and nebulized magnesium sulfate for treating acute asthma in children: a systematic review and meta-analysis . Pediatr Emerg Care. 2018 ; 34 : 390 - 395 . Google Scholar Crossref Search ADS PubMed WorldCat 92. British Thoracic Society/Scottish Guidelines Intercollegiate Network . British guideline on the management of asthma . Thorax. 2014 ; 69 :( Suppl 1 ): 1 - 192 . Crossref Search ADS WorldCat 93. Kirkland SW , Cross E, Campbell S, et al. Intramuscular versus oral corticosteroids to reduce relapses following discharge from the emergency department for acute asthma . Cochrane Database Syst Rev. 2018 ; CD012629 . OpenURL Placeholder Text WorldCat 94. Global Initiative for Chronic Obstructive Lung Disease . Global strategy for the diagnosis, management and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. www. goldcopd.org/wp-content/uploads/2016/04/GOLD-2018-WMS.pdf. Accessed August 2018 . 95. Link MS , Berkow LC, Kudenchuk PJ, et al. Part 7: adult advanced cardiovascular life support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care . Circulation . 2015 ; 132 : S444 - 464 . Google Scholar Crossref Search ADS PubMed WorldCat 96. Callaway CW , Donnino MW, Fink EL, et al. Part 8: post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care . Circulation . 2015 ; 132 : S465 - S482 . Google Scholar Crossref Search ADS PubMed WorldCat 97. Mentzelopoulous SD , Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial . JAMA . 2013 ; 310 : 270 - 279 . Google Scholar Crossref Search ADS PubMed WorldCat 98. Panchal AR , Berg KM, Kudenchuk PJ, et al. 2018 American Heart Association focused update on advanced cardiovascular life support use of antiarrhythmic drugs during and immediately after cardiac arrest . Circulation . 2018 ; 138 : e740 - e749 . Google Scholar Crossref Search ADS PubMed WorldCat 99. Kudenchuk PJ , Brown SP, Daya M, et al. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest . N Engl J Med . 2016 ; 374 : 1711 - 1722 . Google Scholar Crossref Search ADS PubMed WorldCat 100. De Caen AR , Berg MD, Chameides L, et al. Part 12: pediatric advanced life support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care . Circulation . 2015 ; 132 ( 18 suppl 2 ): S526 - S542 . Google Scholar Crossref Search ADS PubMed WorldCat 101. Perkins GD , Ji C, Deakin CD, et al. A randomized trial of epinephrine in out-of-hospital cardiac arrest: PARAMEDIC2 Trial . N Engl J Med. 2018 ; 379 : 711 - 721 . Google Scholar Crossref Search ADS PubMed WorldCat 102. Geocadin RG , Wijdicks E, Armstrong MJ, et al. Practice guideline summary: reducing brain injury following cardiopulmonary resuscitation: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology . Neurology . 2017 ; 88 : 2141 - 2149 . Google Scholar Crossref Search ADS PubMed WorldCat 103. Nielsen N , Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest . N Engl J Med . 2013 ; 369 : 2197 - 2206 . Google Scholar Crossref Search ADS PubMed WorldCat 104. The PRISM investigators . Early, goal-directed therapy for septic shock – a patient-level meta-analysis . N Engl J Med . 2017 ; 376 : 2223 - 2234 . Crossref Search ADS PubMed WorldCat 105. The ProCESS Investigators . A randomized trial of protocol-based care for early septic shock . N Engl J Med . 2014 ; 370 : 1683 - 1693 . Crossref Search ADS PubMed WorldCat 106. The ARISE Investigators and the ANZICS Clinical Trials Group . Goal-directed resuscitation for patients with early septic shock . N Engl J Med . 2014 ; 371 : 1496 - 1506 . Crossref Search ADS PubMed WorldCat 107. Mouncey PR , Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock . N Engl J Med . 2015 ; 372 : 1301 - 1311 . Google Scholar Crossref Search ADS PubMed WorldCat 108. Rivers E , Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock . N Engl J Med . 2001 ; 345 : 1368 - 1377 . Google Scholar Crossref Search ADS PubMed WorldCat 109. Levy MM , Evans LE, Rhodes A. The Surviving Sepsis Campaign bundle: 2018 Update . Crit Care Med . 2018 ; 46 : 997 - 1000 . Google Scholar Crossref Search ADS PubMed WorldCat 110. van Diepen S , Katz JN, Albert NM, et al. Contemporary management of cardiogenic shock: a scientific statement from the American Heart Association . Circulation . 2017 ; 136 : e232 - e268 . Google Scholar Crossref Search ADS PubMed WorldCat 111. Schumann J , Henrich EC, Strobl H, et al. Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome . Cochrane Database Syst Rev . 2018 ; 1 : CD009669 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 112. Simons FE , Ebisawa M, Sanchez-Borges M, et al. 2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines . World Allergy Organ J . 2015 ; 8 : 32 . Google Scholar Crossref Search ADS PubMed WorldCat 113. Campbell RL , Bellolio MF, Knutson BD, et al. Epinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine . J Allergy Clin Immunol Pract . 2015 ; 3 : 76 - 80 . Google Scholar Crossref Search ADS PubMed WorldCat 114. Sinert R , Levy P, Bernstein JA, et al. Randomized trial of icatibant for angiotensin-converting enzyme inhibitor-induced upper airway angioedema . J Allergy Clin Immunol Pract . 2017 ; 5 : 1402 - 1409 . Google Scholar Crossref Search ADS PubMed WorldCat 115. Baş M , Greve J, Stelter K, et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema . N Engl J Med . 2015 ; 372 : 418 - 425 . Google Scholar Crossref Search ADS PubMed WorldCat 116. Holden D , Ramich J, Timm E, et al. Safety considerations and guideline-based safe use recommendations for “bolus-dose” vasopressors in the emergency department . Ann Emerg Med . 2018 ; 71 : 83 - 92 . Google Scholar Crossref Search ADS PubMed WorldCat 117. Tait RJ , Caldicott D, Mountain D, et al. A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment . Clin Toxicol. 2016 ; 54 : 1 - 13 . Google Scholar Crossref Search ADS WorldCat 118. Smith RV , Havens JR, Walsh SL. Gabapentin misuse, abuse, diversion: a systematic review . Addiction . 2016 ; 111 : 1160 - 1174 . Google Scholar Crossref Search ADS PubMed WorldCat 119. Wu PE , Juurlink DN. Clinical review: loperamide toxicity . Ann Emerg Med. 2017 ; 70 : 245 - 252 . Google Scholar Crossref Search ADS PubMed WorldCat 120. Mo Y , Thomas MC, Karras GE Jr. Barbiturates for the treatment of alcohol withdrawal syndrome: a systematic review of clinical trials . J Crit Care. 2016 ; 32 : 101 - 107 . Google Scholar Crossref Search ADS PubMed WorldCat 121. Rosenson J , Clements C, Simon B, et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo controlled study . J Emerg Med . 2013 ; 44 : 592 - 598 . Google Scholar Crossref Search ADS PubMed WorldCat 122. Flannery AH , Adkins DA, Cook AM. Unpeeling the evidence for the banana bag: evidence-based recommendations for the management of alcohol-associated vitamin and electrolyte deficiencies in the ICU . Crit Care Med. 2016 ; 44 : 1545 - 1552 . Google Scholar Crossref Search ADS PubMed WorldCat 123. Watson AJ , Walker JF, Tomkin GH, et al. Acute Wernickes encephalopathy precipitated by glucose loading . Ir J Med Sci . 1981 ; 150 : 301 - 303 . Google Scholar Crossref Search ADS PubMed WorldCat 124. D’Onofrio G , O’Connor PG, Pantalon MV, et al. Emergency department-initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial . JAMA. 2015 ; 313 : 1636 - 1644 . Google Scholar Crossref Search ADS PubMed WorldCat 125. Busch SH , Fiellin DA, Chawarski MC, et al. Cost-effectiveness of emergency department-initiated treatment for opioid dependence . Addiction . 2017 ; 112 : 2002 - 2010 . Google Scholar Crossref Search ADS PubMed WorldCat 126. Herring AA , Perrone J, Nelson LS. Managing opioid withdrawal in the emergency department with buprenorphine . Ann Emerg Med . 2019 ; 73 : 481 - 487 . Google Scholar Crossref Search ADS PubMed WorldCat 127. Dwyer K , Walley AY, Langlois BK, et al. Opioid education and nasal naloxone rescue kits in the emergency department . West J Emerg Med . 2015 ; 16 : 381 - 384 . Google Scholar Crossref Search ADS PubMed WorldCat 128. Coffin PO , Sullivan SD. Cost-effectiveness of distributing naloxone to heroin users for lay overdose reversal . Ann Intern Med. 2013 ; 158 : 1 - 9 . Google Scholar Crossref Search ADS PubMed WorldCat 129. Dart RC , Goldfrank LR, Erstad BL, et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care . Ann Emerg Med . 2018 ; 71 : 314 - 325 . Google Scholar Crossref Search ADS PubMed WorldCat 130. Bateman DN , Dear JW, Thanacoody HK, et al. Reduction of adverse effects from intravenous acetylcysteine treatment for paracetamol poisoning: a randomized controlled trial . Lancet . 2014 ; 383 : 697 - 704 . Google Scholar Crossref Search ADS PubMed WorldCat 131. Schmidt LE , Rasmussen DN, Petersen TS, et al. Fewer adverse effects associated with a modified two-bag intravenous acetylcysteine protocol compared to a traditional three-bag regimen in paracetamol overdose . Clin Toxicol (Phila) . 2018 ; 156 : 1128 - 1134 . Google Scholar Crossref Search ADS WorldCat 132. Arens AM , Shah K, Al-Abri S, et al. Safety and effectiveness of physostigmine: a 10-year retrospective review . Clin Toxicol (Phila) . 2018 ; 56 : 101 - 107 . Google Scholar Crossref Search ADS PubMed WorldCat 133. Boley SP , Olives TD, Bangh SA, et al. Physostigmine is superior to non-antidote therapy in the management of antimuscarinic delirium: a prospective study from a regional poison center . Clin Toxicol (Phila ). 2018 ; 57 : 50 - 55 . Google Scholar Crossref Search ADS PubMed WorldCat 134. Cole JB , Arens AM, Laes JR, et al. High dose insulin for beta-blocker and calcium channel-blocker poisoning . Am J Emerg Med. 2018 ; 36 : 1817 - 1824 . Google Scholar Crossref Search ADS PubMed WorldCat 135. Chan BS , Isbister GK, O’Leary M, et al. Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1) . Clin Toxicol (Phila) . 2016 ; 54 : 488 - 494 . Google Scholar Crossref Search ADS PubMed WorldCat 136. Hauptman PJ , Blume SW, Lewis EF, et al. Digoxin toxicity and use of digoxin immune fab . J Am Coll Cardiol HF . 2016 ; 4 : 357 - 364 . OpenURL Placeholder Text WorldCat 137. Bush SP , Ruha A, Seifert SA, et al. Comparison of F(ab’)2 versus Fab antivenom for pit viper envenomation: a prospective, blinded, multicenter, randomized clinical trial . Clin Toxicol (Phila) . 2015 ; 53 : 37 - 45 . Google Scholar Crossref Search ADS PubMed WorldCat 138. Roberts I , Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial . Lancet . 2011 ; 17 : 1096 - 1101 . OpenURL Placeholder Text WorldCat 139. Roberts I , Shakur H, Ker K, et al. ; CRASH-2 Trial Collaborators. Antifibrinolytic drugs for acute traumatic injury . Cochrane Database Syst Rev . 2012 ; 12 : CD004896 . Update in: Cochrane Database Syst Rev . 2015 ; 5 : CD004896 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 140. CRASH-2 Trial Collaborators . Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomized placebo-controlled trial . Lancet. 2010 ; 376 : 23 - 32 . Crossref Search ADS PubMed WorldCat 141. Morrison JJ , Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) Study . Arch Surg. 2012 ; 147 : 113 - 119 . Google Scholar Crossref Search ADS PubMed WorldCat 142. El-Menyar A , Sathian B, Asim M, et al. Efficacy of prehospital administration of tranexamic acid in trauma patients: a meta-analysis of the randomized controlled trials . Am J Emerg Med. 2018 ; 36 : 1079 - 1087 . Google Scholar Crossref Search ADS PubMed WorldCat 143. Guerriero C , Cairns J, Perel P, et al. ; CRASH 2 Trial Collaborators. Cost-effectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 Trial . PLoS One . 2011 ; 6 : e18987 . Google Scholar Crossref Search ADS PubMed WorldCat 144. Holcomb JB , Tilley B, Baraniuk S, et al. ; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial . JAMA . 2015 ; 313 : 471 - 482 . Google Scholar Crossref Search ADS PubMed WorldCat 145. Cannon JW , Khan M, Raja A, et al. Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Association for the Surgery of Trauma . J Trauma Acute Care Surg . 2017 ; 82 : 605 - 617 . Google Scholar Crossref Search ADS PubMed WorldCat 146. Joseph B , Aziz H, Pandit V, et al. Prothrombin complex concentrate versus fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference? World J Surg . 2014 ; 38 : 1875 - 1881 . Google Scholar Crossref Search ADS PubMed WorldCat 147. Schöchl H , Nienaber U, Maegele M, et al. Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy . Crit Care . 2011 ; 15 : R83 . Google Scholar Crossref Search ADS PubMed WorldCat 148. Carney N , Totten AM, O’Reilly C, et al. Guidelines for the management of severe traumatic brain injury, fourth edition . Neurosurgery . 2017 ; 80 : 6 - 15 . Google Scholar Crossref Search ADS PubMed WorldCat 149. Patanwala AE , Erstad BL, Roe DJ, et al. Succinylcholine is associated with increased mortality when used for rapid sequence intubation of severely brain injured patients in the emergency department . Pharmacotherapy . 2016 ; 36 : 57 - 63 . Google Scholar Crossref Search ADS PubMed WorldCat 150. Zeiler FA , Teitelbaum J, West M, et al. The ketamine effect on ICP in traumatic brain injury . Neurocrit Care . 2014 ; 21 : 163 - 173 . Google Scholar Crossref Search ADS PubMed WorldCat © American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Key articles and guidelines for the emergency medicine clinical pharmacist: 2011-2018 update
JF - American Journal of Health-System Pharmacy
DO - 10.1093/ajhp/zxaa178
DA - 2020-08-07
UR - https://www.deepdyve.com/lp/oxford-university-press/key-articles-and-guidelines-for-the-emergency-medicine-clinical-G37BbDkOAB
SP - 1284
EP - 1335
VL - 77
IS - 16
DP - DeepDyve
ER -