Pilot Study on the Impact of Early Subcutaneous Basal Insulin Administration in Diabetic Ketoacidosis.

Purpose/Background: Recent studies have shown improved outcomes with the initiation of earlier subcutaneous (SQ) basal insulin. The purpose of this study was to examine the effects of early SQ basal insulin administration on hospital length of stay in patients with mild to moderate diabetic ketoacidosis (DKA). Methods: This was a retrospective, single-center study from a large community teaching hospital that included patients 18 years or older with mild to moderate DKA, identified using ICD-10 codes, who received intravenous (IV) insulin. Patients who received SQ basal insulin prior to a documented anion gap ≤12 mmol/L were considered to have received early SQ basal insulin and were compared to patients who received SQ basal insulin after closure of their anion gap (AG). The primary outcome was hospital length of stay. Secondary outcomes included intensive care unit length of stay, duration of IV insulin, time to anion gap closure, and incidences of rebound hyperglycemia. Safety outcomes included incidences of hypoglycemia, and hypokalemia. Results: Of 301 patients screened, 108 patients were included in the final analysis. Forty patients received early SQ basal insulin and 68 did not. Median hospital length of stay in the nonearly group was 71 h, compared to 62 h in the early group (P = .57). Secondary and safety outcomes were similar between groups. Conclusions: In this study, there was no statistically significant difference in length of stay in patients that received early SQ basal insulin. Larger trials are needed to determine the significance of earlier SQ basal insulin in DKA.

Prothrombin complex concentrate administration timing in warfarin-associated intracranial hemorrhage.

INTRODUCTION: Guidelines recommend "rapid" and "urgent" reversal of anticoagulation for warfarin-associated intracranial hemorrhage (ICH) treatment; however, they do not specify goals for time-to-administration. There are limited studies evaluating time to reversal, or international normalized ratio (INR) correction, on hematoma expansion and outcomes in intervals of <4 h. The purpose of this study was to evaluate the association of 4-factor prothrombin concentrate (4F-PCC) time-to-administration on rates of achieving effective hemostasis, determined by hematoma expansion, for treatment of warfarin-associated ICH. METHODS: This was a retrospective, observational, single center study performed at a large community teaching hospital. Patients were stratified into three groups based on time of CT diagnosis of ICH to administration of 4F-PCC: <45 min, 45-90 min, and >90 min. The primary outcome was rates of achieving effective hemostasis in each group defined as a ≤20% increase in hematoma volume as estimated by a radiologist. RESULTS: A total of 227 patients were screened for inclusion with ultimately 39 being included. Baseline characteristics were similar between groups. The primary outcome was not significantly different among groups stratified by time to 4F-PCC administration of <45 min, 45-90 min, and >90 min (85.7% vs 73.3% vs 90%, p value 0.514). There was no difference among secondary outcomes between groups including in-hospital mortality, hospital length of stay (LOS), and intensive care unit LOS. CONCLUSION: There was no association with time-to-administration of 4F-PCC on rates of hemostasis achievement, defined as hematoma expansion of ≤20%, identified in this study.

EDucated: The emergency medicine pharmacotherapy literature of 2023.

The purpose of this article is to summarize pharmacotherapy related emergency medicine (EM) literature indexed in 2023. 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. Pharmacotherapy-related publications deemed to be GRADE 1A and 1B were reviewed by the collective group for inclusion in the review. In all, this article summarizes and provides commentary on the potential clinical impact of 13 articles, 6 guidelines, and 5 meta-analyses covering topics including guideline releases and updates on rapid sequence intubation in the critically ill, managing cardiac arrest or life-threatening toxicity due to poisoning, and management of major bleeding following trauma. Also discussed are ongoing controversies surrounding fluid resuscitation, time and treatment modalities for ischemic stroke, steroid use in community-acquired pneumonia, targeted blood product administration, and much more.

Pseudomonas aeruginosa survives in epithelia by ExoS-mediated inhibition of autophagy and mTOR.

One major factor that contributes to the virulence of Pseudomonas aeruginosa is its ability to reside and replicate unchallenged inside airway epithelial cells. The mechanism by which P. aeruginosa escapes destruction by intracellular host defense mechanisms, such as autophagy, is not known. Here, we show that the type III secretion system effector protein ExoS facilitates P. aeruginosa survival in airway epithelial cells by inhibiting autophagy in host cells. Autophagy inhibition is independent of mTOR activity, as the latter is also inhibited by ExoS, albeit by a different mechanism. Deficiency of the critical autophagy gene Atg7 in airway epithelial cells, both in vitro and in mouse models, greatly enhances the survival of ExoS-deficient P. aeruginosa but does not affect the survival of ExoS-containing bacteria. The inhibitory effect of ExoS on autophagy and mTOR depends on the activity of its ADP-ribosyltransferase domain. Inhibition of mTOR is caused by ExoS-mediated ADP ribosylation of RAS, whereas autophagy inhibition is due to the suppression of autophagic Vps34 kinase activity.

What are we waiting for? A review of early basal insulin therapy in diabetic ketoacidosis management.

Diabetic ketoacidosis (DKA) remains a significant challenge for healthcare systems due to prolonged lengths of stay and rising costs. The current American Diabetes Association (ADA) guidelines recommend starting basal insulin after resolution of DKA. However, these guidelines have not been updated since 2009, which can potentially limit optimal care. Meanwhile, the Joint British Society guidelines on DKA management, which were more recently updated in March 2023, do advocate for early administration of basal insulin in their treatment algorithm. This article assesses the rationale and literature associated with the recommendation for early basal insulin administration in the management of DKA. Benefits of early basal insulin in this cohort appears to be associated with less rebound hyperglycemia, reduction in time to DKA resolution, reduced intravenous insulin requirements, and reduced length of stay without associated increases in hypoglycemic or hypokalemic events.

UpdatED: The emergency medicine pharmacotherapy literature of 2022.

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.

Indirect antiplatelet effects of rivaroxaban in a patient with intracranial hemorrhage: An underappreciated coagulopathy of factor Xa inhibitors?

Rivaroxaban is a direct oral anticoagulant (DOAC) used for prophylaxis and treatment of many prothrombotic states. The anticoagulation effects of rivaroxaban are produced by selectively binding and inhibiting factor Xa, causing delayed thrombin generation. Additionally, the delay in thrombin generation produces an indirect, dose dependent antiplatelet effect via reduction in tissue factor platelet aggregation. As with any anticoagulant, rivaroxaban use increases a patient's risk for major and minor hemorrhagic events. With mortality rates reported as high as 25% for those who experience an intracranial hemorrhage (ICH), immediate mitigation of hematoma and hemorrhage volume expansion is imperative. Management strategies include utilizing prothrombin complex concentrates (PCC) and factor Xa inhibitor specific antidotes, such as coagulation factor Xa recombinant, inactivated-zhzo. Routine monitoring or management of DOAC induced antiplatelet effects is ill-defined and not a part of routine standard of care. We report the first case, to our knowledge, of rivaroxaban's indirect antiplatelet effects identified by platelet function assays and managed with four-factor PCC and desmopressin in a patient experiencing an ICH. Further exploration is needed to determine the true clinical impact attributed to rivaroxaban's antiplatelet effects.

The Emergency Medicine Pharmacotherapy Literature of 2021.

This article highlights the most relevant emergency medicine (EM) pharmacotherapy publications indexed in 2021. A modified Delphi approach was utilized for selected journals to identify the most impactful EM pharmacotherapy studies via the GRADE system. After review of journal table of contents GRADE 1A and 1B articles were reviewed by authors. Twenty articles, 2 guidelines, 2 position papers, and 2 meta-analysis were selected for full summary. Articles included in this review highlight acute agitation management, acute appendicitis treatment, sexually transmitted infection updates, optimizing sepsis management and treatment, updates for the ideal thrombolytic agent in acute ischemic stroke and endovascular therapy candidates, indications for tranexamic acid, calicium for out of hospital cardiac arrest, optimial inotrope for cardiogenic shock, awareness during rapid sequence intubation paralysis, comparison of propofol or dexmedetomidine for sedation, treatment of cannabis hyperemsis syndrome, and prophylactic use of diphenhydramine to reduce neuroleptic side effects. Selected articles are summarized to include design, results, limitations, conclusions and impact.

Anticoagulation Monitoring in the Intensive Care Unit.

Patients with critical illness often display variable hypo- and hypercoagulable sequalae requiring intense monitoring and anticoagulation pharmacotherapy to prevent or treat inappropriate clot formation. It is imperative to understand the various stages of the clotting cascade and where each pharmacotherapy agent exerts its therapeutic effect. Common coagulation tests are utilized to monitor the areas of the clotting cascade and the effects that anticoagulant pharmacotherapy exhibits. Many novel coagulation tests are also in development. The purpose of this narrative review is to evaluate commonly utilized coagulation tests that monitor anticoagulation while in the intensive care unit.

Successful Use of Aspirin, Apixaban, and Viscoelastography in a Patient with Severe COVID Disease and Allergy to Porcine Products.

Coagulation abnormalities are frequently described in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Common thromboprophylaxis and anticoagulation treatment strategies include the use of heparinoid therapy. We describe a 57-year-old woman with an allergy to porcine products that was started on apixaban for anticoagulation therapy given her allergy profile and need for venous thromboembolism prophylaxis. Apixaban and aspirin therapy were optimized with the support of serial viscoelastography and platelet function assays. Our patient experienced respiratory failure requiring intubation for 7 days but was successfully weaned to room air, tolerated a regular diet, and ultimately discharged to home after a 17-day hospital course. Here we report the safe and successful use of aspirin, apixaban, and viscoelastography for COVID-19-associated coagulopathy.

A teaspoon of sugar and a pinch of salt: Reviewing hyperosmolar therapy.

ABSTRACT: The traditional hyperosmolar agents used to treat patients with elevated intracranial pressure are mannitol and hypertonic sodium chloride solution. This article focuses on some of the pros and cons of these treatments for managing cerebral edema.

Staying InformED: Top emergency Medicine pharmacotherapy articles of 2020.

The year 2020 was not easy for Emergency Medicine (EM) clinicians with the burden of tackling a pandemic. A large focus, rightfully so, was placed on the evolving diagnosis and management of patients with COVID-19 and, as such, the ability of clinicians to remain up to date on key EM pharmacotherapy literature may have been compromised. This article reviews the most important EM pharmacotherapy publications indexed in 2020. A modified Delphi approach was utilized for selected journals to identify the most impactful EM pharmacotherapy studies. A total of fifteen articles, eleven trials and four meta-analyses, were identified. This review provides a summary of each study, along with a commentary on the impact to the EM literature and EM clinician.

Components of Brachypodium distachyon resistance to nonadapted wheat stripe rust pathogens are simply inherited.

Phytopathogens have a limited range of host plant species that they can successfully parasitise ie. that they are adapted for. Infection of plants by nonadapted pathogens often results in an active resistance response that is relatively poorly characterised because phenotypic variation in this response often does not exist within a plant species, or is too subtle for genetic dissection. In addition, complex polygenic inheritance often underlies these resistance phenotypes and mutagenesis often does not impact upon this resistance, presumably due to genetic or mechanistic redundancy. Here it is demonstrated that phenotypic differences in the resistance response of Brachypodium distachyon to the nonadapted wheat stripe rust pathogen Puccinia striiformis f. sp. tritici (Pst) are genetically tractable and simply inherited. Two dominant loci were identified on B. distachyon chromosome 4 that each reduce attempted Pst colonisation compared with sib and parent lines without these loci. One locus (Yrr1) is effective against diverse Australian Pst isolates and present in two B. distachyon mapping families as a conserved region that was reduced to 5 candidate genes by fine mapping. A second locus, Yrr2, shows Pst race-specificity and encodes a disease resistance gene family typically associated with host plant resistance. These data indicate that some components of resistance to nonadapted pathogens are genetically tractable in some instances and may mechanistically overlap with host plant resistance to avirulent adapted pathogens.

Modified version of the American College of Cardiology's recommendation for low-dose prothrombin complex concentrate is effective for warfarin reversal.

BACKGROUND: Dosing of four factor prothrombin complex concentrate (4PCC) for warfarin reversal remains controversial. Recently, the American College of Cardiology (ACC) recommended a low-dose PCC regimen as an option for warfarin reversal in acute major bleeding. We performed a retrospective study evaluating if a modified version of the ACC guideline recommendations was effective for warfarin reversal in acute major bleeds when compared to traditional variable dosing. METHODS: This was a retrospective cohort study of patients who received 4PCC for warfarin reversal in a 12 month period. We included patients that were ≥18 years of age, received 4PCC for warfarin reversal, and had an initial International Normalized Ratio (INR) of >2. Our primary outcome was the number of patients who had a post-4PCC infusion INR of <1.6. RESULTS: A total of 60 patients were included in the final analysis with 30 patients stratified to the traditional dosing and low-dose groups, respectively. Patient demographics were similar between both groups. We found no difference in the number of patients who had a post-4PCC infusion INR <1.6 between the traditional dosing and low dosing group (90.0% vs. 86.7%; p = 0.68). Additionally, we found no difference between post-infusion median INRs in each group (1.35 vs. 1.30; p = 0.16). Approximately 1000 units per patient were spared when utilizing the low-dose regimen. CONCLUSION: A modified version of the ACC's low-dose 4PCC option for warfarin reversal achieves similar outcomes for lowering INR values compared to traditional variable dosing regimens.

Tracing the Lines: A Review of Viscoelastography for Emergency Medicine Clinicians.

BACKGROUND: Viscoelastography (VE) is an established method to identify coagulopathies in various disease processes. Clinical decisions can be made with real-time tracings and quantitative values at the bedside. Thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) have been utilized in several disease states with clinical varying success. OBJECTIVES: This review will summarize the literature and provide recommendations pertaining to major disease processes where VE may be beneficial, including trauma, anticoagulation reversal, liver disease, acute ischemic stroke, and acquired brain injuries. DISCUSSION: VE has a role in many emergency medicine patients encountered by clinicians. Reduced mortality, decreased blood product utilization, and prognostication ability makes VE an intriguing tool that can be utilized by providers to improve patient care. CONCLUSION: This review serves as a way for emergency medicine clinicians to utilize VE in their practice and provides an insightful literature overview.

A Case of Antibiotic-Induced Posterior Reversible Encephalopathy Syndrome.

Purpose: To report a case of posterior reversible encephalopathy syndrome (PRES) in a 75 year-old patient who was taking concomitant ciprofloxacin and metronidazole. Method: Case report Results: A patient had been prescribed ciprofloxacin and metronidazole during a recent hospitalization and continued this regimen outpatient. Two weeks after discharge and 3 weeks after initiation of her regimen, she was brought to the emergency department after developing acute weakness and lightheadedness. After admission, the patient declined more rapidly and began seizing with subsequent intubation. Initial computed tomographic (CT) imaging showed no acute neurological abnormalities, and a sepsis workup was initiated. After negative CT, a magnetic resonance imaging scan was performed that showed a T2 flair and hyperdensity consistent with PRES. The final diagnosis was considered to be PRES secondary to ciprofloxacin/metronidazole utilization. Conclusion: Antibiotic induced PRES is a condition that needs to be explored more thoroughly.

Small molecule targeting of the STAT5/6 Src homology 2 (SH2) domains to inhibit allergic airway disease.

Asthma is a chronic inflammatory disease of the lungs and airways and one of the most burdensome of all chronic maladies. Previous studies have established that expression of experimental and human asthma requires the IL-4/IL-13/IL-4 receptor α (IL-4Rα) signaling pathway, which activates the transcription factor STAT6. However, no small molecules targeting this important pathway are currently in clinical development. To this end, using a preclinical asthma model, we sought to develop and test a small-molecule inhibitor of the Src homology 2 domains in mouse and human STAT6. We previously developed multiple peptidomimetic compounds on the basis of blocking the docking site of STAT6 to IL-4Rα and phosphorylation of Tyr641 in STAT6. Here, we expanded the scope of our initial in vitro structure-activity relationship studies to include central and C-terminal analogs of these peptides to develop a lead compound, PM-43I. Conducting initial dose range, toxicity, and pharmacokinetic experiments with PM-43I, we found that it potently inhibits both STAT5- and STAT6-dependent allergic airway disease in mice. Moreover, PM-43I reversed preexisting allergic airway disease in mice with a minimum ED50 of 0.25 µg/kg. Of note, PM-43I was efficiently cleared through the kidneys with no long-term toxicity. We conclude that PM-43I represents the first of a class of small molecules that may be suitable for further clinical development against asthma.

Utilization of thromboelastography and a low molecular weight heparin anti-Xa assay for guidance in apixaban reversal: A case report.

Reversal of oral factor Xa (FXa) inhibitors, such as apixaban, remains a controversial topic. However, the controversy goes beyond what reversal agent to utilize. Often times these patients present with an acute major bleed and are difficult to assess whether reversal is warranted or not. Furthermore, it is difficult to assess whether reversal was successful in a timely manner. A paucity of literature exists regarding the utilization of low molecular weight heparin (LMWH) anti-Xa assays and thromboelastography for identifying coagulopathies associated with oral FXa inhibitors. We report a case of apixaban induced coagulopathy utilizing thromboelastography and a LMWH anti-Xa assay as a guide for reversal.

Pharmacoeconomic impact of an alternative workflow process for stroke.

OBJECTIVE: The objective of this study was to evaluate a new multidisciplinary process in which intravenous alteplase (tPA) waste, used for acute ischemic stroke (AIS), was salvaged in an attempt to maximize cost effectiveness without impacting door-to-needle (DTN) administration times. DESIGN: This was a retrospective cohort between May 2017 and February 2018. The primary endpoint evaluated for this study was the total tPA salvaged and total cost savings in U.S. dollars. Secondary endpoints evaluated included overall DTN time in minutes. SETTING: Emergency department of a primary stroke center. PATIENTS: A convenience sample of sequential adult (>18 years) patients who received tPA in the ED for AIS were included for analysis. INTERVENTIONS: New stroke process which involved bedside mixing of tPA and salvaging of excess waste in the main central pharmacy. MEASUREMENTS AND MAIN RESULTS: A total of 50 patients were included in the final analysis. There were 25 patients included in the new process and old process groups respectively. A total of 605 mg of alteplase was salvaged from 25 patients in the new process group which was associated with an estimated cost savings of over $120,000 annually. Patients in the new process group had statistically faster average (52 min vs. 60 min; p = 0.01) and median (50 min vs. 58 min; p = 0.03) DTN administration times. CONCLUSION: Preliminary data, in this pilot study, utilizing a multidisciplinary model for tPA administration led to significant cost savings of tPA and decreases in overall DTN administration times.