a b s t r a c t

The purpose of this article is to summarize pharmacotherapy related emergency medicine (EM) literature indexed in 2022. Articles were selected utilizing a modified Delphi approach. The table of contents from pre-determined journals were reviewed and independently evaluated via the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system by paired authors, with disagreements adjudicated by a third author. Pharmacotherapy-related publications deemed to be GRADE 1A and 1B were reviewed by the group for inclusion in the review. In all, this article summarizes and provides commentary on the potential clinical impact of 13 articles, 4 guidelines, and 3 meta-analyses covering topics including Anticoagulant reversal, tenecteplase in acute ischemic stroke, guideline updates for heart failure and aortic aneurysm, magnesium in atrial fibrillation, sedation in Mechanically ventilated patients and pain management strategies in the Emergency Department (ED), and Tranexamic acid use in epistaxis and GI bleed.

(C) 2023

1. Introduction

Remaining current with emergency medicine (EM) literature can be a challenge given the dynamic and broad scope of Disease states that EM healthcare professionals may encounter. In response, the Emergency Medicine PHARMacotherapy Research NETwork (EMPHARM-NET) started an annual review highlighting the top EM pharmacotherapy ar- ticles [1,2]. EMPHARM-NET is a network of geographically and demo- graphically diverse EM clinical pharmacist researchers that was formed in 2019 with the goal of fostering and conducting high quality, transformative, multidisciplinary research pertaining pharmacotherapy

* Corresponding author at: Department of Pharmacy, University of New Mexico Hospital, Albuquerque, NM 87106, USA.

E-mail address: [email protected] (P. Sarangarm).

in the emergently ill population across the United States (US). The purpose of this article is to summarize the most pertinent pharmacotherapy-related EM literature indexed over the past year.

1. Methods

Articles were selected utilizing a modified Delphi approach. Pre- selected journals (Appendix A) germane to EM were divided among pairs of authors. The table of contents from the previous year were then reviewed independently by two reviewers for publications related to pharmacotherapy in adult EM patients. Each article was then assessed by two independent reviewers based on the Grading of Rec- ommendations, Assessment, Development and Evaluation (GRADE) system, a validated and objective tool used to evaluate the quality of published articles into four levels: high, moderate, low, and very low

https://doi.org/10.1016/j.ajem.2023.04.023

0735-6757/(C) 2023

[3]. Literature related to Coronavirus-19 were excluded given the tran- sitory nature of this topic. Articles deemed to be GRADE 1A or 1B were considered for inclusion. Disagreements in assigned GRADE level be- tween reviewers were reassessed, with the final determination made by the primary author (PS). Fifty-nine publications met the inclusion criteria and were further reviewed for final inclusion by the full research team. Although the scope of EM is broad, literature focusing primarily on pharmacotherapy and where most of the care was administered in the Emergency Department (ED) were given preference. In addition, GRADE scoring, clinical impact, and the novelty subject matter were taken into consideration by the research team during exclusion discus- sions. In all, 13 articles, 4 guidelines, and 3 meta-analyses were included for summary and discussion stratified into six categories: anticoagulant reversal, acute ischemic stroke (with a focus on tenecteplase), cardiol- ogy, pain management, sedation, and tranexamic acid.

1. Anticoagulant reversal
   1. Fixed versus variable dosing of prothrombin complex concentrate for Bleeding complications of vitamin K antagonists—The PROPER3 random- ized clinical trial [GRADE 1B] [4]

Guidelines recommend 4-factor prothrombin complex concentrates (4F-PCCs) for reversal of vitamin K antagonist -related bleeding, but do not provide specific guidance for dosing strategies [5,6]. Tradi- tional dosing is based on total body weight and baseline International normalized ratio [6]. However, lower fixed-doses are alternatively used because they represent a simpler, less expensive dosing method with similar efficacy [7-10]. The PROPER-3 study was the first prospec- tive, multicenter randomized controlled trial (RCT) to determine if fixed-dose 4F-PCC was non-inferior in hemostatic effectiveness com- pared to variable-dose in VKA-related extracranial bleeding emergencies [4]. Patients were randomized to receive fixed-dose (1000 Factor IX) or a variable-dose (calculated per manufacturer instructions) [11,12]. The primary outcome was the proportion of patients with good hemostatic effectiveness defined by the International Society on Thrombosis and Haemostasis [13]. Important secondary outcomes included door-to- needle (DTN) time for reversal, proportion of patients reaching an INR

<=2.0 at 60 min after reversal, and Thromboembolic events. The primary outcome was achieved in 67 (87.3%) in the fixed-dose cohort versus 71 (89.9%) in the variable-dose cohort (Risk difference 2.5%; 95% CI -13.3 to 7.9%). Door-to-needle times were significantly shorter in the fixed- dose group (109 vs 142 min; difference - 33 min; 95% CI -56 to

-4 min, p = 0.027), but there was no difference in patients with an INR <=2.0 at 60 min or thromboembolic events.

Due to a flawed study design and premature cessation leading to an underpowered study, fixed-dose failed to demonstrate non-inferiority compared to variable-dose. With the lack of difference in hemostatic ef- fectiveness, fixed-dose might be a viable alternative to variable-dose, but adequately powered studies are needed to determine the impact on patient centered outcomes.

1. Acute Ischemic Stroke - Tenecteplase

Although alteplase has been an industry standard for acute ischemic stroke for many years, recent literature supporting the use of te- necteplase (TNK) as an alternative thrombolytic has shown favorable outcomes for patients eligible for Mechanical thrombectomy [14].

• 1. Intravenous tenecteplase compared with Alteplase for Acute Ischaemic Stroke in Canada (AcT): pragmatic, multicentre, open-label, registry-linked, randomized, controlled, non-inferiority trial [GRADE 1A] [15]

The AcT trial was a multicenter, parallel-group, open-label, RCT, with blinded outcomes in Canada comparing TNK 0.25 mg/kg (n = 806) to alteplase 0.9 mg/kg (n = 771) for AIS causing disabling neurological

deficit within 4.5 h of symptom onset [15]. This trial demonstrated non-inferiority in functional outcome at 90 to 120 days (Modified Rankin scale [mRS] score 0 to 1, unadjusted risk difference 2.1%; 95% CI -2.6 to 6.9) with TNK versus alteplase. The direction of effect favored TNK, but TNK was not found to be superior to alteplase in the secondary analysis (p = 0.19). There were no differences among secondary outcomes or rates of symptomatic intracranial hemorrhage (ICH) (risk

difference - 0.2; 95% CI -1.5 to 2.0) and 90-day mortality (risk differ- ence - 0.1; 95% CI -3.7 to 3.5).

• 1. Tenecteplase versus Alteplase for the management of Acute Ischaemic Stroke in Norway (NOR-TEST 2, Part A): a phase 3, randomized, open- label, blinded endpoint, non-inferiority trial [GRADE 1A] [16]

In contrast to AcT, NOR-TEST 2, part A compared TNK 0.4 mg/kg (n = 100) to alteplase 0.9 mg/kg (n = 104) for AIS patients presenting with symptom onset within 4.5 h and a National Institutes of Health Stroke Scale >6 [16]. This was a multicenter, randomized, open-label, non-inferiority, phase 3 study of 11 hospitals with stroke units in Norway. This study failed to demonstrate non-inferiority in functional outcome at 90 days (mRS of 0 to 1, unadjusted OR 0.45; 95% CI 0.25 to 0.8) with TNK versus alteplase. Additionally, there was higher mortality in the TNK group compared to alteplase at 90 days (unadjusted OR 3.56; 95% CI 1.24 to 10.21) and a higher rate of any ICH (unadjusted OR 3.68; 95% CI 1.49 to 9.11).

The differences in outcomes between these two studies is likely attributable to the higher dose of TNK evaluated and suggests TNK dosed at 0.25 mg/kg may be considered outside of the endovascular thrombectomy population.

• 1. Safety and efficacy of tenecteplase in older patients with Large vessel occlusion: a Pooled analysis of the EXTEND-IA TNK trials [GRADE 1B] [17]

A pooled analysis of the EXTEND-IA TNK trials evaluated the safety and efficacy of TNK stratified by age (>80 years) in patients with large vessel occlusion within 4.5 h of symptom onset (n = 502) [17]. The study stratified patients by dosing scheme: TNK 0.25 mg/kg (n = 251), TNK 0.4 mg/kg (n = 150), and alteplase 0.9 mg/kg (n = 101). [4]. Data was reported as an adjusted common OR (acOR), accounting for baseline NIHSS, age, and time from symptom onset to puncture. In patients older than 80 years of age, TNK 0.25 mg/kg demonstrated im- proved functional outcome at 90 days as compared to TNK 0.4 mg/kg (mRS score reduction, acOR 2.70; 95% CI 1.23 to 5.94) and alteplase

0.9 mg/kg (mRS score reduction, acOR 2.28; 95% CI 1.03 to 5.05). No dif- ference in functional outcome was seen between alteplase and TNK

0.4 mg/kg. Also, TNK 0.25 mg/kg was associated with a reduction in mortality as compared to TNK 0.4 mg/kg (acOR 0.34; 95% CI 0.13 to 0.91), which was not seen between TNK 0.4 mg/kg versus alteplase. Re- sults from this study affirm that a lower dose of TNK at 0.25 mg/kg may be considered as an alternative to alteplase in older patients with large vessel occlusion.

• 1. Prospective observational cohort study of Tenecteplase versus Alteplase in routine clinical practice [GRADE 1B] [18]

Evaluating TNK in routine clinical practice, a prospective observa- tional cohort trial of 10 hospitals in Texas compared TNK (n = 234) to alteplase (n = 354) in regard to timing (e.g., DTN time) and clinical out- comes [18]. Functional outcome at 90 days analyzed by adjusted origi- nal regression favored TNK (mRS, OR 0.66; 95% CI 0.45 to 0.97). More

TNK patients achieved a DTN <= 45 min (aOR 1.85; 95% CI 1.27 to 2.71). Also, the percentage of patients meeting door-in-door-out (DIDO) time <= 90 min for Transferred patients favored TNK over alteplase (aOR 3.62; 95% CI 1.30 to 10.7). However, the DIDO analysis is likely

skewed due to an emergency medical system policy that prevented transportation of patients until alteplase was completely infused.

• 1. Comparison of Tenecteplase with Alteplase for the Early Treatment of Ischaemic Stroke in the Melbourne Mobile Stroke Unit (TASTE-A): a Phase 2, randomized, open-label trial [GRADE 1A] [19]

Given the ease of bolus administration without the need for an infu- sion pump, TNK has been evaluated in the prehospital setting in con- junction with a computed tomography (CT) equipped mobile stroke unit. The TASTE-A trial was a randomized, open-label, blinded endpoint, phase 2 trial targeting AIS patients eligible for thrombolysis with symp- tom onset within 4.5 h. A comparison of TNK 0.25 mg/kg (n = 55) to alteplase 0.9 mg/kg (n = 49) found that the primary outcome of CT-perfusion Lesion volume on imaging performed on arrival to the receiving hospital was significantly smaller in the TNK arm (adjusted in- cidence rate ratio 0.55; 95% CI 0.37 to 0.81). Additionally, Thrombolytic treatment was initiated faster in the TNK group compared with alteplase (adjusted difference in medians -7.0; 95% CI -11.9 to

-2.11) and those in the TNK group had a greater proportion of distal

clot migration (OR 2.9; 95% CI 1.1 to 7.5), meaning partial or complete thrombolysis at the original clot site was likely occurring.

Published literature indicates that TNK dosed at 0.25 mg/kg is non- inferior to alteplase in the management of AIS. Additionally, TNK is an easy to administer IV push and has the potential to reduce DTN time. Tenecteplase should continue to be evaluated as an alternative to alteplase for management of AIS.

1. Cardiology
   1. 2022 ACC/AHA guideline for the diagnosis and management of Aortic disease [20]

acute aortic syndrome (AAS), such as aortic dissection, intramural hematoma and penetrating atherosclerotic ulcer, are associated with life threatening complications and require prompt intervention [20]. While recent guidelines from the American Heart Association (AHA)/ American College of Cardiology (ACC) focus on the management of aor- tic disease from a holistic standpoint, they also provide recommenda- tions for pharmacologic management [20]. For patients with AAS, systolic Blood pressure should be <120 mmHg or to lowest BP that maintains adequate end-organ perfusion with a target heart rate of 60-80 bpm (Class of Recommendation [COR]-1 [strong] Level of evidence [LOE] C-limited data [LD]). Initial management should include intravenous (IV) Beta blockers (e.g., esmolol) unless there are contrain- dications such as bradycardia, heart block, or acute aortic regurgitation. Patients with a contraindication or intolerance to beta blockers should be initiated on an IV non-dihydropyridine calcium channel blocker (e.g., diltiazem; COR-2a [moderate], LOE B-nonrandomized [NR]). If the BP is not at goal after initial therapy, IV vasodilators (e.g., nicardipine, clevidipine, sodium nitroprusside) should be initiated (COR-1, LOE C-LD). Lastly, patients should be treated for pain control as needed to help with hemodynamic management (COR-1, LOE C-expert opinion [EO]). Although this guideline update does not represent a sig- nificant departure from previous recommendations, EM clinicians should be aware of the preferred use of beta-blockers, like labetalol or esmolol, as first line therapy followed by initiation of IV vasodilators if BP remains not at goal.

• 1. 2022 AHA/ACC/HFSA guideline for the management of heart failure [21]

The 2022 joint guideline from the AHA, ACC, and the Heart Failure Society of America (HFSA) for the management of heart failure replaced guidelines from 2013 and 2017 [21-23]. This update empha- sizes HF prevention, reclassification of the stages of HF, new long-term management strategies (introducing sodium glucose cotransporter-2 inhibitors [SGLT2i]), and role of implantable devices.

Patients identified in this guideline may fall into one of four catego- ries: stage A (at risk for HF), stage B (pre-HF), stage C (symptomatic HF),

and stage D (advanced HF). For individuals in stage C HF, the terminol- ogy for the classification has been updated and is based on the patients left ventricular ejection fraction (LVEF). Most notably, individuals with HF with improved ejection fraction (HFimpEF) will now include pa- tients with a previous LVEF <=40% and follow-up measurement of LVEF

>40% and HF with mildly reduced ejection fraction (HFmrEF) includes

individuals with LVEF between 41 and 49%.

While there are no new recommendations for the acute manage- ment of stage C and stage D HF patients, the 2022 joint guideline in- cludes recommendations for decongestion strategies, vasodilation therapies, and inotropic support. When individuals present with HF and significant fluid overload, they should be treated with IV loop di- uretics with the goal of improving symptoms and reducing morbidity (COR-1, LOE B-NR). Diuretics should be initiated at a minimum of two times the daily home diuretic dose (mg to mg) administered IV. How- ever, when diuresis is inadequate, the dose should be increased, or a second diuretic should be added (COR-2a, LOE B-NR). Titration of Loop diuretics may require doubling initial doses or adding a thiazide diuretic to increase the intensity of the regimen [24]. For those individuals that present with decompensated HF and are not hypotensive, IV nitroglyc- erin or nitroprusside is an option to add to the diuretic therapy for relief of any pulmonary congestion and dyspnea (COR-2b [weak], LOE B-NR). While no data exists to suggest one vasodilation agent is more effective than the other, sodium nitroprusside may cause profound hypotension that may require more Invasive blood pressure monitoring as well as an increased risk for cyanide toxicity in the setting of renal and liver dys- function during prolonged infusions. Lastly, for those individuals that present with HF progressing to cardiogenic shock, IV inotropic agents should be used to maintain perfusion and provide end organ support (COR-1, LOE B-NR). There is currently no literature to suggest a clear benefit of one inotropic agent (i.e., dobutamine or milrinone) over an- other for patients in cardiogenic shock [25]. The decision of which ino- tropic agent to start should ultimately be based on patient specific factors such as blood pressure, concurrent arrhythmias, and what is readily available for administration.

• 1. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes [26]

The American College of Emergency Physicians created a clinical pol- icy addressing adult patients who present to the ED with Acute HF syn- dromes. This author group addressed four key issues and provided “Recommendation Levels” based on the current body of literature

[26]; level A, B, and C recommendations are for principles for patient care that reflect a high, moderate, or low degree of scientific certainty, respectively.

The use of point-of care Lung ultrasound as an imaging modality combined with the adult patient’s medical history and physical exami- nation may be used to diagnose acute HF when diagnostic uncertainty exists (Level B recommendation). Early administration of diuretic ther- apy can only be recommended for adult patients presenting to the ED with suspected acute HF when physicians are confident in the diagnosis of volume overload (Level C recommendation). Accurate identification of acute HF is imperative as to avoid harm that may be caused by provid- ing diuretic therapy to a patient without volume overload. High-dose

nitroglycerin (IV infusion >=200 ug/min or IV bolus dose of 2000 ug every 3-5 min) is safe and effective for adult patients presenting to the ED with suspected acute HF and Elevated blood pressure (Level C

recommendation). While the evidence for high-dose nitroglycerin is not robust, there is a single nonrandomized open-label trial from 2007 that found a lower incidence of endotracheal (ET) intubation within 6 h, BiPAP ventilation, and intensive care unit admission in the high-dose nitroglycerin group compared to nonintervention patients [27]. Although the clinical policy authors note the lack of guidance in consensus statements and guidelines for the dosing of nitroglycerin or

nitroprusside in patients with suspected acute HF and elevated blood pressure [28,29], high-dose nitroglycerin should be considered given the available evidence.

• 1. magnesium sulfate in the”>Utility of magnesium sulfate in the treatment of rapid atrial fibrillation in the emergency department: a systematic review and meta-analysis [GRADE 1B] [30]

Rate control agents such as beta-blockers and non-dihydropyridine calcium channel blockers are Mainstays of treatment for atrial fibrilla- tion with rapid ventricular response (RVR) in the ED setting. However, when these agents are unsuccessful or contraindicated, other agents such as IV magnesium sulfate have been evaluated as an alternative or add-on treatment. A recent meta-analysis of five RCTs examined the ef- fect of IV magnesium sulfate [30] for patients with rapid atrial fibrilla- tion in the ED. The authors found that IV magnesium sulfate significantly reduced the heart rate [standardized mean difference

0.34 (95% CI 0.21 to 0.47; p-value <0.001)] but did not increase the

rate of conversion to normal sinus rhythm (OR 1.46; 95% CI 0.726 to 2.94). Magnesium sulfate was not associated with an increase incidence of hypotension or bradycardia (OR 2.2; 95% CI 0.62 to 8.09). Interest- ingly, the initial loading dose of magnesium did not lead to a larger re- duction in heart rate, though a larger maintenance dose infused up to six hours did reduce the heart rate. Notably, there was variability in doses and infusion rates used in the included studies making the ideal regimen unclear. The meta-analysis also did not elucidate the role of magnesium sulfate as either monotherapy or as adjunct therapy. In some studies, patients could receive rate control agents in addition to magnesium or placebo at the discretion of the treating physician. Based on data from this analysis, if clinicians chose to utilize IV magne- sium in patients with atrial fibrillation with RVR, a small loading dose to target 3-4 g over 4-6 h may be considered to reduce heart rate without leading to increased rates of bradycardia or hypotension.

1. Pain management

Fractures are frequently encountered in the ED and have tradition- ally been treated with nonsteroidal anti-inflammatory medications (NSAIDs) or opioid analgesics [31]. Maintaining adequate pain control using safe treatment options that minimize opioid exposure necessi- tates the exploration of alternative pain management strategies. One approach gaining in popularity in the ED is regional anesthesia, which includes the injection of local anesthetics with or without ultrasonogra- phy to guide placement.

• 1. Periosteal block versus intravenous regional anesthesia for reduction of Distal radius fractures: a randomized controlled trial [GRADE 1B] [32]

This was a randomized, unblinded controlled trial comparing two regional anesthetic strategies: periosteal block (n = 40) to intravenous regional anesthesia (IVRA) (n = 41), for ED patients with displaced distal radius fractures requiring closed reduction technique [32]. Physicians in intravenous lidocaine for the manag”>the ED received training on periosteal blocks, which involves injection of lidocaine 1% around the periosteum of the distal radius proximal to the fracture [33]. IVRA entailed using 3 mg/kg 0.5% prilocaine IV through a peripheral cannula in the hand of the injured extremity after placement of a double-cuff pneumatic tourniquet. Most patients received premedication, of which the most common were acetaminophen (APAP) and fentanyl. The primary endpoint of median reduction of pro- cedural pain scores measured on a 100-mm Visual analog scale immediately following the reduction was better in the IVRA group rela- tive to periosteal blocks (5 [interquartile range (IQR) 1 to 27.5] vs 26 (IQR 8.5 to 63), p < 0.01). Use of adjunct pain control during the reduc- tion was also lower in the IVRA group (22.5% vs 57.5%, p < 0.01). Though both treatment strategies offer opioid-sparing analgesia, IVRA provided better pain control relative to periosteal block.

• 1. Fascia Iliaca block in hip and femur fractures to reduce opioid use [GRADE 1B] [34]

This study included 166 adults with hip and proximal femur frac- tures who received fascia iliaca compartment block (FICB; consisting of bupivacaine or ropivacaine +- epinephrine) and systemic opioids (n = 81) or only systemic opioids (n = 85) [34]. The primary outcome of average Morphine equivalent per hour was reduced in the FICB group by 0.6 mg/h (0.7 mg/h vs. 1.3 mg/h, p = 0.054) with no impact on length of stay. There was no difference in opioid-related adverse effects between groups. While this study does not quantify long term outcomes in terms of discharge Opioid requirements or refill requirements, it dem- onstrates a short-term reduction in opioid requirements while in the ED with FICB.

Both trials highlight the utility of local anesthetics in acute pain management in the ED.

• 1. Comparative efficacy of sedation or analgesia methods for reduction of anterior Shoulder dislocation: a systematic review and network meta- analysis [GRADE 1B] [35]

Pain associated with an Anterior shoulder dislocation may cause Muscle spasms, making reduction of the dislocation difficult. Adequate pain and sedation can facilitate reduction, however, it is unclear whether intravenous sedation (IVS), intraarticular anesthetic injection (IAA), or Peripheral nerve block (PNB) is the optimal strategy. This net- work meta-analysis included RCTs of patients >=15 years old (16 RCTs,

n = 957) diagnosed with anterior shoulder dislocation and treated

with IVS, IAA, PNB, placebo or no sedation/analgesia [35]. Any sedative, analgesic, and local anesthetic was included. The primary outcomes were immediate success rate of the reduction, patient satisfaction, and emergency department length of stay. A total of 8 RCTs reported imme- diate success rate when comparing IAA versus IVS strategies (benzodi- azepines + opioids) which demonstrated no difference (n = 408, RR 0.93; 95% CI 0.84 to 1.02). One study compared PNB to IVS demonstrat- ing no difference in immediate success (n = 41; RR 1.13, 95% CI 0.84 to 1.52) and the evidence was rated as very uncertain. Patient satisfac- tion was similar when comparing various strategies to each other. ED length of stay was shorter in the IAA vs. IVS group (n 299, mean difference - 107.88 min; 95% CI -202.58 to -13.18). Adverse respira-

tory events such as hypoxia, apnea, and respiratory depression were

common in the IVS group. Agitation and drowsiness were reported in the IAA group while mild Local anesthetic systemic toxicity was re- ported in the PNB group. Limitations included varying outcome defini- tions among included studies, use of short-acting sedatives (propofol, etomidate, or ketamine) were underreported, and RCTs included were small, single-center studies limiting the certainty of results. Overall, immediate success rate and patient satisfaction were similar when com- paring various strategies. Adverse respiratory events were common in patients treated with IVS. The selected strategy should continue to be based on EM clinician comfort and patient-specific characteristics until larger, high quality RCTs are completed.

• 1. Intravenous lidocaine for the management of traumatic rib fractures: a double-blind randomized controlled trial (INITIATE Program of Research) [GRADE 1A] [36]

Inadequately treated pain associated with rib fractures may lead to complications such as pneumonia and respiratory failure due to the in- ability to cough and clear secretions [37]. Opioids are often necessary to control pain, however, given their Adverse effect profile and abuse potential, opioid-sparing strategies are warranted [38]. This single- center, double-blind, randomized trial was conducted in 34 adult patients presenting with at least two rib fractures associated with a traumatic injury [36]. Patients received either IV lidocaine 2 mg/kg (max 100 mg) as a bolus over 30 min, then 2 mg/kg/h infusion for

72-96 h (n = 17) or matching placebo (n = 17). The primary outcome was mean pain score at rest and with movement calculated from multi- ple VAS scores. The mean duration of lidocaine infusion was 59 h with 64% not completing the full 72-96 h infusion due to discharge or unre- lated causes. As such, the authors adjusted their VAS analysis to 54 h to capture the majority of patients (53%) who received the infusion for at least this duration. The mean VAS score at rest in each group was simi- lar, however during movement pain was reduced in the lidocaine group compared to placebo (7.05 +- 1.72 vs 8.22 +- 1.28; p = 0.04). There was no difference in patient satisfaction, length of stay, or adverse effects be- tween groups. All patients required treatment with opioids during the study period. Though there was no difference in opioid administration statistically, a Clinically meaningful reduction was observed in the lido- caine group over the entire study period (morphine equivalents: 167 mg vs. 290 mg; p = 0.194). In this study, lidocaine was safe and re- duced pain scores with movement to a small degree as compared with placebo. Larger trials are needed to determine lidocaine’s optimal dose and duration, opioid sparing effects, ability to reduce Respiratory complications and length of stay.

• 1. intravenous acetaminophen does not “>Intravenous acetaminophen does not reduce morphine use for pain relief in emergency department patients: a multicenter, randomized, double-blind, placebo-controlled trial [GRADE 1B] [39]

The utility of the IV formulation of APAP within the ED remains in question given mixed efficacy relative to other routes, adverse events including clinically Significant hypotension, and increased pharmacoEconomic burden [40]. However, IV APAP may have opioid- sparing effects. Two studies evaluated IV APAP compared to opioid an- algesics. The first evaluated a single 1 g dose of IV APAP in combination with 0.1 mg/kg of IV morphine compared to morphine alone [39]. This multicenter, randomized, double-blinded, placebo-controlled trial en- rolled ED patients >18 years of age with a VAS of >4/10. Patients could receive additional 0.05 mg/kg IV morphine every 15 min until pain scores were < 4. The primary outcome evaluated the mean mor- phine dose needed to achieve pain relief with secondary outcomes eval- uating the total amount of morphine administered, time to pain relief achievement, and any reported adverse events. A total of 202 patients (102 in the APAP + morphine group and 100 in the morphine alone group) were evaluated for the primary endpoint. There was no differ- ence in the primary endpoint with a mean morphine dose of 12.0 +-

5.8 mg (0.15 +- 0.07 mg/kg) for the combination group and 13.0 +-

6.2 mg (0.16 +- 0.07 mg/kg) for the morphine alone group (p = 0.2). With respect to the secondary outcomes there was no difference in the total morphine dose between the two groups (15.1 +- 7.5 mg vs 15.5 +- 8.6 mg; p = 0.68), time to pain relief (30 min for both groups; p = 0.18), and the proportion of patients experiencing at least one adverse event was no different between both groups.

• 1. A Randomized study of Intravenous hydromorphone versus intrave- nous acetaminophen for older adult patients with acute severe pain [GRADE 1B] [41]

A similar study evaluated the use of IV APAP in an older cohort of pa- tients [41]. Patients >=65 years of age, in the ED, with severe pain using the same self-reported ordinal pain scale were included in this

double-blind, parallel group RCT. Rather than morphine, this study uti- lized 1 g of IV APAP versus 0.5 mg hydromorphone and measured pain scores at 15-min intervals for the first hour as the primary endpoint. Secondary outcomes included the use of any additional analgesic regi- mens, percentage of patients who failed to achieve any clinically mean- ingful reduction in pain scores, and any reported adverse events. A total of 81 patients were included in both groups, the majority of patients were 70-79 years of age, and over 60% were female. The duration of pain, baseline pain scores, and location of pain (abdomen) were not dif- ferent between each group. Improvement in pain scores were

statistically better in the hydromorphone group compared to the APAP cohort (4.6 +- 3.3 vs 3.6 +- 2.9, difference of 1.0; 95% CI 0.1-2.0), however the authors note this was likely not clinically significant. The percentage of patients who required an additional analgesia was similar between the APAP and hydromorphone group (37% vs 31%, 7%; 95% CI

-8 to 23) as well as similar incidence of adverse events between each group.

Unlike the post-operative setting, the use of IV APAP does not seem to improve patient pain scores in a clinically meaningful way and there- fore should not routinely be recommended in the ED based upon these two trials.

1. Sedation
   1. the feasibility of implementing targeted SEDation in mechanically ventilated emergency department patients: The ED-SED pilot trial [GRADE 1B] [42]

deep sedation in mechanically ventilated ICU patients is associated with worse outcomes (e.g., mortality), which is especially evident dur- ing the First two days of ICU stay [43,44]. Because of wide variation in ED sedation practices, it is unknown if ED-based practice changes can be implemented to reduce deep sedation and improve clinical outcomes. The ED-SED pilot trial was a pragmatic, multi-center, pro- spective before and after study aimed at assessing feasibility of imple- menting an ED-based sedation protocol in mechanically ventilated patients in a larger, multi-center trial [42]. The goal of the pilot trial was to assess feasibility in terms of 1) recruitment, 2) protocol imple- mentation and practice change, and 3) safety. The study consisted of a 5-month pre-intervention period, 3-month protocol implementation period, and a 5-month post-intervention period. The intervention in- cluded educational initiatives aimed at improving adherence to seda- tion protocols focused on reliable sedation depth documentation and reduction of deep sedation. The intervention was associated with in- creased sedation depth documentation (64.8% vs 88.6%; p < 0.01) and light sedation at any point in the ED (49.2% vs 69.1%; p < 0.01). Deep se- dation was significantly reduced (60.2% to 38.8%; p < 0.01), and rates of ventilator-free days, ICU-free days, and hospital mortality were signifi- cantly lower in the intervention group. Safety data was consistent with published literature or similar between groups suggesting lighter sedation does not increase adverse effects. Findings confirmed the feasi- bility of implementing targeted sedation for mechanically ventilated ED patients. Improved patient outcomes must be confirmed in a large multi-center trial.

1. Tranexamic acid
   1. Tranexamic acid in gastrointestinal bleeding: a systematic review and meta-analysis [GRADE 1A] [45]

The benefits of Tranexamic acid in GI bleeding continues to be debated. A meta-analysis reviewed 12 trials evaluating mortality and bleeding outcomes [45]. Studies were split into high-dose IV TXA (>2 g in 24 h) and enteral/low-dose IV administration. The high-dose IV TXA group included five studies (n = 13,219) showing no reduction in mortality (RR 0.98; 95% CI 0.88 to 1.09), rebleeding (RR 0.92; 95% CI 0.82 to 1.04), surgical intervention (RR 0.92; 95% CI 0.76 to 1.09), or transfusion (RR 1.0; 95% CI 0.99 to 1.01) in those receiving TXA. In the high-dose IV TXA group, there were higher rates of deep vein thrombo- sis (RR 2.01; 95% CI 1.08 to 3.72) and pulmonary embolism (RR 1.78; 95% CI 1.06 to 3) but not arterial thrombosis. Only the HALT-IT trial eval- uated seizures and those receiving TXA were found to be at higher risk (RR 1.73; 95% CI 1.03-2.93) [46]. Seven studies (n = 880) looked at enteral/low-dose TXA and found no benefit in mortality (RR 0.62; 95% CI 0.36 to 1.09) or need for transfusion (RR 1.03; 95% CI 0.93 to 1.13). This group did show decreased risk of rebleeding (RR 0.5; 95% CI 0.33

to 0.75) and surgical intervention (RR 0.58; 95% CI 0.38 to 0.88). Adverse events such as Arterial and venous thrombosis or seizure were not reported.

Since the 2014 Cochrane review, we now have adequate evidence against the use of high-dose TXA in GI bleeding [47]. Enteral/low-dose TXA showed some benefits though most studies were published before evidence demonstrating improved outcomes with restrictive transfu- sions, therefore, a more liberal transfusion approach may have affected outcomes [48]. The benefits of TXA in lower GI bleed cannot be concluded due to the low number of patients included in studies.

• 1. topical application of t”>Intranasal topical application of tranexamic acid in atraumatic anterior epistaxis: a double-blind randomized clinical trial [GRADE 1B] [49]

There have been conflicting results regarding the efficacy of TXA in epistaxis [50,51]. This double-blind randomized trial aimed to identify if the addition of TXA to phenylephrine and lidocaine pledgets de- creased the need for anterior nasal packing [49]. Two-hundred and forty patients were randomized to cotton pledget soaked in 5 mL of an intravenously injectable TXA solution (100 mg/mL), 10 mL (0.05 g) of phenylephrine hydrochloride and sprayed with 5 puffs of a 10% lido- caine spray (10 mg/puff) or phenylephrine and lidocaine alone (no TXA). Anterior nasal packing was required less often for those receiving TXA compared to the control group (50.0% vs 64.2%, OR 0.56; 95% CI 0.33 to 0.94). Less patients in the TXA group had an emergency department stay >2 h (9.2% vs 20.8%, OR 0.38; 95% CI 0.18 to 0.82) and rebleeding

within 24 h (15% vs 30%, OR 0.41; 95% CI 0.22 to 0.78). There were no differences in rates of cauterization or re-bleeding within 1-7 days. Limitations of this study include it was conducted in a specialty ear, nose, and throat ED, patients on anticoagulants were excluded, and only approximately 30% of patients in each arm were on aspirin. Exclu- sion of patients on anticoagulants is particularly notable given that recent literature (i.e., the NoPac study published in 2021) had contradic- tory findings of no benefit of TXA compared to placebo in a population where approximately 60% were anticoagulated [50]. Taking that into ac- count as well as the results of the current study, it is reasonable to trial TXA in epistaxis in patients not on anticoagulation.

1. Conclusion

This review described 13 articles, 4 guidelines, and 3 meta-analyses indexed in 2022 related to EM pharmacotherapy. Included articles dis- cussed anticoagulant reversal, tenecteplase in acute ischemic stroke, guideline updates for heart failure and aortic aneurysm, magnesium in atrial fibrillation, sedation in mechanically ventilated patients and pain management strategies in the ED, and tranexamic acid use in epistaxis and GI bleed.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

CSB has funding from Alexion/Astra Zeneca. All other authors have nothing to disclose relevant to this article.

Appendix A. Academic Emergency Medicine

Annals of Emergency Medicine. Annals of Pharmacotherapy.

Canadian Journal of Emergency Medicine. CHEST.

Circulation.

Clinical Infectious Diseases.

Cochrane Library. Critical Care.

Critical Care Medicine. Emergency Medicine Australasia. Emergency Medicine Journal.

European Journal of Emergency Medicine. Journal of the American College of Cardiology. Journal of the American Medical Association.

Journal of the American Medical Association-Cardiology. Journal of the American Medical Association-Surgery.

Journal of Trauma and Acute Care Surgery. Lancet.

Lancet-Infectious Diseases. Lancet-Neurology.

Neurocritical care. Neurology.

New England Journal of Medicine. Pharmacotherapy.

prehospital emergency care. Resuscitation.

Scandinavian Journal of Trauma, Resuscitation, and Emergency Medicine.

SHOCK.

Stroke.

The American Journal of Emergency Medicine. The Journal of Emergency Medicine.

Western Journal of Emergency Medicine. World Journal of Emergency Surgery.

References

1. Brown CS, Sarangarm P, Faine B, Rech MA, Flack T, Gilbert B, et al. The emergency medicine pharmacotherapy literature of 2021. Am J Emerg Med. 2022;60:88-95. https://doi.org/10.1016/j.ajem.2022.07.039.
2. Zimmerman DE, Sarangarm P, Brown CS, Faine B, Flack T, Gilbert BW, et al. Staying InformED: top emergency medicine pharmacotherapy articles of 2020. Am J Emerg Med. 2021;49:200-5. https://doi.org/10.1016/j.ajem.2021.05.061.
3. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommenda- tions. BMJ. 2008;336:924-6. https://doi.org/10.1136/bmj.39489.470347.AD.
4. Abdoellakhan RA, Khorsand N, ter Avest E, Lameijer H, Faber LM, Ypma PF, et al. Fixed versus variable dosing of prothrombin complex concentrate for bleeding com- plications of vitamin K antagonists-the PROPER3 randomized clinical trial. Ann Emerg Med. 2022;79:20-30. https://doi.org/10.1016/j.annemergmed.2021.06.016.
5. Witt DM, Nieuwlaat R, Clark NP, Ansell J, Holbrook A, Skov J, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: opti- mal management of anticoagulation therapy. Blood Adv. 2018;2:3257-91. https:// doi.org/10.1182/bloodadvances.2018024893.
6. Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, Eikelboom JW, et al. 2020 ACC expert consensus decision pathway on Management of Bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Solution set Oversight Committee. J Am Coll Cardiol. 2020;76:594-622. https://doi. org/10.1016/J.JACC.2020.04.053.
7. Cicci CD, Weiss A, Dang C, Stanton M, Feldman R. Impact of timing and dosing of Four-factor prothrombin complex concentrate administration on outcomes in warfarin-associated intracranial hemorrhage. Pharmacotherapy. 2022;42:366-74. https://doi.org/10.1002/phar.2680.
8. Dietrich SK, Mixon MA, Rech MA. Fixed-dose prothrombin complex concentrate for Emergent warfarin reversal among patients with intracranial hemorrhage. Am J Emerg Med. 2021;49:326-30. https://doi.org/10.1016/J.AJEM.2021.06.032.
9. Dietrich SK, Mixon M, Holowatyj M, Werth JC, Delgado SA, Mascolo NE, et al. Multi- centered evaluation of a novel fixed-dose four-factor prothrombin complex concen- trate protocol for warfarin reversal. Am J Emerg Med. 2020;38:2096-100. https:// doi.org/10.1016/J.AJEM.2020.06.017.
10. Jansma B, Montgomery J, Dietrich S, Mixon MA, Peksa GD, Faine B. Emergent warfarin reversal with fixed-dose 4-factor prothrombin complex concentrate. Ann Pharmacother. 2020;54:1090-5. https://doi.org/10.1177/1060028020920855/ FORMAT/EPUB.
11. Medicines Evaluation Board CBG-MEB. Cofact (human prothrombin complex) Prod- uct Monograph n.d. https://www.geneesmiddeleninformatiebank.nl/smpc/h17060_ smpc.pdf (accessed January 20, 2023).
12. Medicines Evaluation Board CBG-MEB. Beriplex P/N (human prothrombin complex) Product Monograph n.d. https://www.geneesmiddeleninformatiebank.nl/smpc/ h101080_smpc.pdf (accessed January 20, 2023).
13. Khorsand N, Majeed A, Sarode R, Beyer-Westendorf J, Schulman S, Meijer K. Assess- ment of effectiveness of major bleeding management: proposed definitions for

effective hemostasis: communication from the SSC of the ISTH. J Thromb Haemost. 2016;14:211-4. https://doi.org/10.1111/jth.13148.

1. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the early management of patients with Acute Ischemic Stroke: 2019 update to the 2018 guidelines for the early management of Acute Ischemic Stroke: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2019;50:e344-418. https://doi.org/10.1161/ STR.0000000000000211.
2. Menon BK, Buck BH, Singh N, Deschaintre Y, Almekhlafi MA, Coutts SB, et al. Intra- venous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022;400:161-9. https://doi.org/10.1016/S0140-6736 (22)01054-6.
3. Kvistad CE, Naess H, Helleberg BH, Idicula T, Hagberg G, Nordby LM, et al. Tenecte- plase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non- inferiority trial. Lancet Neurol. 2022;21:511-9. https://doi.org/10.1016/S1474-4422 (22)00124-7.
4. Yogendrakumar V, Churilov L, Mitchell PJ, Kleinig TJ, Yassi N, Thijs V, et al. Safety and efficacy of Tenecteplase in older patients with large vessel occlusion: a pooled anal- ysis of the EXTEND-IA TNK trials. Neurology. 2022;98:E1292-301. https://doi.org/ 10.1212/WNL.0000000000013302.
5. Warach SJ, Dula AN, Milling TJ, Miller S, Allen L, Zuck ND, et al. Prospective observa- tional cohort study of Tenecteplase versus Alteplase in routine clinical practice. Stroke. 2022. https://doi.org/10.1161/strokeaha.122.038950.
6. Bivard A, Zhao H, Churilov L, Campbell BCV, Coote S, Yassi N, et al. Comparison of te- necteplase with alteplase for the early treatment of ischaemic stroke in the Mel- bourne Mobile stroke unit (TASTE-A): a phase 2, randomised, open-label trial. Lancet Neurol. 2022;21:520-7. https://doi.org/10.1016/S1474-4422(22)00171-5.
7. Isselbacher EM, Preventza O, Hamilton Black Iii J, Augoustides JG, Beck AW, Bolen MA, et al. ACC/AHA guideline for the diagnosis and management of Aortic Disease: a report of the American Heart Association/American College of Cardiology Joint Committee on clinical practice guidelines. J Am Coll Cardiol. 2022;2022(80): e223-393. https://doi.org/10.1016/j.jacc.2022.08.004.
8. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ ACC/HFSA guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association joint committee on clinical prac- tice guidelines. Circulation. 2022;145:E895-1032. https://doi.org/10.1161/CIR. 0000000000001063.
9. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM, et al. 2017 ACC/AHA/ HFSA focused update of the 2013 ACCF/AHA guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the Heart Failure Society of America. Circulation. 2017;136:e137-61. https://doi.org/10.1161/CIR.0000000000000509.
10. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/ AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guide- lines. Circulation. 2013;128:e240-327. https://doi.org/10.1161/CIR.0b013e318 29e8776.
11. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011; 364:797-805. https://doi.org/10.1056/NEJMoa1005419.
12. Mathew R, Di Santo P, Jung RG, Marbach JA, Hutson J, Simard T, et al. Milrinone as compared with Dobutamine in the treatment of cardiogenic shock. N Engl J Med. 2021;385:516-25. https://doi.org/10.1056/NEJMoa2026845.
13. Silvers SM, Gemme SR, Hickey S, Mattu A, Haukoos JS, Diercks DB, et al. Clinical pol- icy: critical issues in the Evaluation and Management of Adult Patients Presenting to the emergency department with acute heart failure syndromes: approved by ACEP Board of directors, June 23, 2022. Ann Emerg Med. 2022;80:e31-59. https://doi. org/10.1016/j.annemergmed.2022.05.027.
14. Levy P, Compton S, Welch R, Delgado G, Jennett A, Penugonda N, et al. Treatment of severe decompensated heart failure with high-dose Intravenous nitroglycerin: a fea- sibility and outcome analysis. Ann Emerg Med. 2007;50:144-52. https://doi.org/10. 1016/j.annemergmed.2007.02.022.
15. Collins SP, Levy PD, Martindale JL, Dunlap ME, Storrow AB, Pang PS, et al. Clinical and research considerations for patients with hypertensive acute heart failure: a consen- sus statement from the Society for Academic Emergency Medicine and the Heart Failure Society of America acute heart failure working group. Acad Emerg Med. 2016;23:922-31. https://doi.org/10.1111/acem.13025.
16. Mebazaa A, Yilmaz MB, Levy P, Ponikowski P, Peacock WF, Laribi S, et al. Recommen- dations on pre-hospital & early hospital management of acute heart failure: a con- sensus paper from the heart failure Association of the European Society of cardiology, the European Society of Emergency Medicine and the Society of Aca- demic Emergency Medicine. Eur J Heart Fail. 2015;17:544-58. https://doi.org/10. 1002/ejhf.289.
17. Hoffer M, Tran QK, Hodgson R, Atwater M, Pourmand A. Utility of magnesium sulfate in the treatment of rapid atrial fibrillation in the emergency department: a

systematic review and meta-analysis. Eur J Emerg Med. 2022;29:253-61. https:// doi.org/10.1097/MEJ.0000000000000941.

1. Rech MA, Griggs C, Lovett S, Motov S. Acute pain management in the emergency de- partment: use of multimodal and non-opioid analgesic treatment strategies. Am J Emerg Med. 2022;58:57-65. https://doi.org/10.1016/j.ajem.2022.05.022.
2. Beck S, Brunner-Parker A, Stamm R, Douglas M, Conboy A. Periosteal block versus in- travenous regional anesthesia for reduction of distal radius fractures: a randomized controlled trial. Acad Emerg Med. 2022;29:1213-20. https://doi.org/10.1111/acem. 14555.
3. Tageldin ME, Alrashid M, Khoriati A-A, Gadikoppula S, Atkinson HD. Periosteal nerve blocks for distal radius and ulna fracture manipulation-the technique and early re- sults. J Orthop Surg Res. 2015;10:134. https://doi.org/10.1186/s13018-015-0277-6.
4. Jain N, Kotulski C, Al-Hilli A, Yeung-Lai-Wah P, Pluta J, Heegeman D. Fascia Iliaca block in hip and femur fractures to reduce opioid use. J Emerg Med. 2022;63:1-9. https://doi.org/10.1016/j.jemermed.2022.04.018.
5. Hayashi M, Kano K, Kuroda N, Yamamoto N, Shiroshita A, Kataoka Y. Comparative efficacy of sedation or analgesia methods for reduction of anterior shoulder disloca- tion: a systematic review and Network meta-analysis. Acad Emerg Med. 2022;29: 1160-71. https://doi.org/10.1111/acem.14568.
6. Patton P, Vogt K, Priestap F, Parry N, Ball IM. Intravenous lidocaine for the manage- ment of traumatic rib fractures: A double-blind randomized controlled trial (INITIATE program of research). J Trauma Acute Care Surg. 2022;vol. 93:496-502. https://doi.org/10.1097/TA.0000000000003562. Lippincott Williams and Wilkins.
7. Mayberry JC, Trunkey DD. The fractured rib in chest wall trauma. Chest Surg Clin N Am. 1997;7:239-61.
8. Karmakar MK, Ho AM-H. Acute pain management of patients with multiple frac- tured ribs. J Trauma. 2003;54:615-25. https://doi.org/10.1097/01.TA.0000053197. 40145.62.
9. Minotti B, Mansella G, Sieber R, Ott A, Nickel CH, Bingisser R. Intravenous acetamin- ophen does not reduce morphine use for pain relief in emergency department pa- tients: a multicenter, randomized, double-blind, placebo-controlled trial. Acad Emerg Med. 2022;29:954-62. https://doi.org/10.1111/acem.14517.
10. Sin B, Koop K, Liu M, Yeh J-Y, Thandi P. Intravenous acetaminophen for renal colic in the emergency department: where do we stand? Am J Ther. 2017;24:e12-9. https:// doi.org/10.1097/MJT.0000000000000526.
11. Kolli S, Friedman BW, Latev A, Chang AK, Naeem F, Feliciano C, et al. A randomized study of intravenous hydromorphone versus intravenous acetaminophen for older adult patients with acute severe pain. Ann Emerg Med. 2022;80:432-9. https:// doi.org/10.1016/j.annemergmed.2022.06.016.
12. Fuller BM, Roberts BW, Mohr NM, Faine B, Drewry AM, Wessman BT, et al. The fea- sibility of implementing targeted SEDation in mechanically ventilated emergency department patients: the ED-SED pilot trial*. Crit Care Med. 2022;50:1224-35. https://doi.org/10.1097/CCM.0000000000005558.
13. Stephens RJ, Dettmer MR, Roberts BW, Ablordeppey E, Fowler SA, Kollef MH, et al. Practice patterns and outcomes associated with early sedation depth in mechani- cally ventilated patients: a systematic review and meta-analysis. Crit Care Med. 2018;46:471-9. https://doi.org/10.1097/CCM.0000000000002885.
14. Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186:724-31. https://doi.org/10.1164/rccm.201203-0522OC.
15. Dionne JC, Oczkowski SJW, Hunt BJ, Antonelli M, Wijnberge M, Raasveld SJ, et al. Tranexamic acid in gastrointestinal bleeding: a systematic review and Meta-analysis. Crit Care Med. 2022;50:E313-9. https://doi.org/10.1097/CCM. 0000000000005362.
16. HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleed- ing (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395:1927-36. https://doi.org/10.1016/S0140-6736(20)30848-5.
17. Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastro- intestinal bleeding. Cochrane Database Syst Rev. 2014;2014:CD006640. https://doi. org/10.1002/14651858.CD006640.pub3.
18. Villanueva C, Colomo A, Bosch A, Concepcion M, Hernandez-Gea V, Aracil C, et al. Transfusion strategies for Acute upper gastrointestinal bleeding. N Engl J Med. 2013;368:11-21. https://doi.org/10.1056/NEJMoa1211801.
19. Hosseinialhashemi M, Jahangiri R, Faramarzi A, Asmarian N, Sajedianfard S, Kherad M, et al. Intranasal topical application of tranexamic acid in atraumatic anterior ep- istaxis: a double-blind randomized clinical trial. Ann Emerg Med. 2022;80:182-8. https://doi.org/10.1016/j.annemergmed.2022.04.010.
20. Reuben A, Appelboam A, Barton A, Vickery PJ, Body R, Hilton M, et al. Novel use of tranexamic acid to reduce the need for nasal packing in epistaxis (NoPac) randomised controlled trial: research protocol. BMJ Open. 2019;9:e026882. https://doi.org/10.1136/bmjopen-2018-026882.
21. Musgrave KM, Powell J. A systematic review of anti-thrombotic therapy in epistaxis. Rhinology. 2016;54:292-391. https://doi.org/10.4193/Rhino16.040.