The Skeptics Guide to Emergency Medicine

Date: April 30th, 2021 Guest Skeptic: Dr. Justin Morgenstern is an emergency physician and the creator of the excellent #FOAMed project called First10EM.com. He is also one of the SGEM Hot Off the Press Faculty. Reference: Donaldson et al. Review article: Why is there still a debate regarding the safety and efficacy of intravenous thrombolysis in the management of presumed acute ischaemic stroke? A systematic review and meta-analysis. Emerg Med Australas 2016. This SGEM Xtra is based on the new recommendation on TheNNT website for tPA in acute ischemic stroke. This is the third time there has been a recommendation on this topic. The first review gave thrombolytics a "red color recommendation: no benefit." The second review gave alteplase, a single agent, a "green color recommendation: benefit>harm." Since no relevant trials were published between the two and both author groups examined essentially the same data and arrived at opposing conclusions, we wanted to understand and try to explain the conflicting interpretations. Our interpretation of the available literature was to give it a “yellow colour recommendation: net benefits and harms unclear due to uncertainty in data”. This resulted in the summary statistic of the benefit NNT (not reported: Uncertain) and Harms in NNT (not reported: Uncertain). More details on the NNT Rating System are available. It would be hubris to presume that our summary would arrive at the one true answer. But our goal wasn’t to provide an answer. Our goal was simply to explain the science as well as we could, so people could understand why there is a debate – and the uncertainty that underlies that debate. The Donaldson et al SRMA included 10,431 patients in 26 randomized trials comparing intravenous thrombolysis with placebo or standard care in acute ischemic stroke [1]. Their efficacy endpoint was good functional outcome, defined as a modified Rankin Score (mRS) of 3 or less. This is defined as some residual disability requiring assistance but able to walk and care for personal needs independently. The harm endpoints were symptomatic intracranial hemorrhage (as defined by individual trials) and overall mortality The authors report a 3.2% improvement in good neurologic outcome, a 5.4% increase in symptomatic intracranial hemorrhage, and a 2.5% increase in mortality. However, we question the certainty implied by these summary numbers. Emberson and colleagues reported only on alteplase (a problem we will discuss further) and found a 5% improvement in neurologic outcomes, a 5.5% increase in intracranial hemorrhage, and a 1.4% increase in 90-day mortality that was not statistically significant [2]. A 2014 Cochrane review by Wardlaw et al and arrived at similar conclusions with significant improvement in neurologic outcomes, increased intracranial hemorrhage, and increased mortality [3]. Thus, our conclusions and discussion are unchanged by choice of review and reflect our belief that pooling data on this topic is overly simplistic and masks profound uncertainty. We both really like TheNNT website, and the NNT as a concept. But there are problems with the NNT if used in isolation. One of the great conceptual difficulties of summary statistics like the number-needed-to-treat (NNT) is the implication of certainty. A major strength of the NNT is its simplicity, making complex research easier to understand. A weakness, however, is also its simplicity, because it can hide the complexity of research, ignore confidence intervals, and obscure biases. For most topics, these details are far more important than any individual number. There is an SGEM Xtra on some of the limitations of the NNT/NNH summary statistics called the NNT - WET or DRI? It was based on an article published Dec 2019 in AEM by Reeves and Reynolds. There are multiple sources or uncertainty around thrombolytics and stroke which we discussed in TheNNT recommendation. Conflicting Individual Trial Results The first source of uncertainty we highlighted was conflicting individual trial results. Among 26 trials in this systematic review by Donaldson et al, 24 research groups found no benefit in their selected primary outcome [1]. And the two that claim a benefit (NINDS part 2 and ECASS III) both had baseline imbalances that may explain the difference [4,5]. In fact, there are re-analyses that adjust for those imbalances in both trials, and the benefits disappear [6,7]. However, in some re-analyses of NINDS-2 the benefit is maintained, which adds to the uncertainty here [8,9]. We reviewed the NINDS trial with Dr. Swaminathan back on SGEM#70. More recently Prof Fatovich and I reviewed the reanalysis of ECASS-3 by Dr. Brian Alper on SGEM#297. Clinical Heterogeneity of Individual Trials Another source of uncertainty is the clinical heterogeneity of individual trials. The 26 trials are clinically heterogeneous, enrolling stroke patients of differing demographics, treatment times, stroke severities, anatomic territories, and thrombolytic agents. The author of the first NNT summary felt this was too much heterogeneity for appropriate pooling, a position supported by the major differences in conclusions drawn depending on which studies an author group chooses to include. Selective Emphasis on Trials Claiming Benefit There was also the selective emphasis on trials claiming benefit. It is circular and erroneous logic to claim efficacy for thrombolytics based on the trial characteristics of the two positive trials. First, there is legitimate debate about whether they were truly positive. Second, selectively highlighting positive results is a form of the "Texas sharpshooter fallacy". The Texas sharpshooter fallacy is committed when you cherry-picked a data cluster to suit your argument or found a pattern to fit a presumption. It comes from concept of a marksman shooting at the side of a barn. After firing multiple shots, they go up to the barn and draw the target around the spot where there are the most bullet holes. For example, because both NINDS II and ECASS III used alteplase, some have suggested alteplase is a superior agent [4,5]. However, on close inspection, that logic falters: few trials have compared thrombolytic agents head to head, so there is no strong evidence to support that claim. There are nine additional trials of alteplase are negative. And systematic reviews consistently find no heterogeneity of effect between agents – in other worse, statistically speaking the different thrombolytics all look the same for efficacy[3,5,10]. Moreover, in evaluating drug efficacy, establishing a class effect is generally a prerequisite for debating or comparing individual agents [11]. Therefore, while it may increase complexity, we believe it is a mistake to exclusively examine data from the agent used in the two trials that claimed benefit. You can’t just retrospectively decide to throw out the trials you don’t agree with. Likewise, while there are theoretical reasons to think early treatment is better, this has not been directly tested and is not strongly supported by data. Neither Donaldson et al. nor the Cochrane review find an interaction between time to treatment and effect.  IST-3, the largest placebo controlled randomized trial of thrombolytics for stroke, found better outcomes among those treated after 4.5 hours than in patients treated at 3-4.5 hours from onset of stroke symptoms [12]. Again, we feel it is best to consider this literature as a whole rather than using time windows selected based on outlying (i.e. positive) results. Individual Trial Bias Another source of uncertainty was individual trial bias. Bias is a major source of uncertainty in all scientific research. Importantly, using the GRADE tool [13], Donaldson et al. rate the risk of bias as “serious” for all outcomes.  One notable source is the outcome scales used, for instance the modified Rankin Scale (mRS) score. This score is known to have some subjectivity with poor inter-rater reliability and questionable validity. When trained neurologists examine the same patients there is substantial variability in mRS score assignments [14,15]. Compounding the problem, some trials assessed patients by phone or mail, a choice certain to increase variability and imprecision. For example in IST-3, which contributes nearly 40% of subjects in the Donaldson meta-analysis, results were obtained using telephone and mail follow-up, and non-blinded. This subjectivity is important, because removing IST-3 from the pooled analysis removes the statistical finding of benefit. Stopping Early Bias can be compounded in a SRMA when trials are stopped early. That is because larger trials are weighted more heavily in a meta-analysis. So early termination (which reduces trial size) can significantly affect results. Five thrombolytic trials were stopped early for harm or futility [16-20].  Together these would have enrolled more than 2,000 additional subjects who, had they been included, may have neutralized or even reversed findings from the two small trials claiming benefit, NINDS2 and ECASS III (combined n=1,445). Furthermore, while over 10,000 subjects were enrolled in stroke trials, some individual trials for acute myocardial infarction enrolled far more, and in aggregate those trials included more than 60,000 [20,21].  The comparatively small number of participants in stroke trials means chance findings like baseline imbalances are both more likely and more influential, furthering uncertainty. Harms In contrast to the heterogeneous data on the potential benefits, the data on the potential harms are more certain. Exact numbers vary based on definitions and whether one focuses on fatal, symptomatic, or any hemorrhage, but an increase in intracranial hemorrhage is certain. More importantly,

Date: April 19th, 2021 Guest Skeptic: Dr. Kirsty Challen (@KirstyChallen) is a Consultant in Emergency Medicine and Emergency Medicine Research Lead at Lancashire Teaching Hospitals Trust (North West England). She is Chair of the Royal College of Emergency Medicine Women in Emergency Medicine group and involved with the RCEM Public Health and Informatics groups. Kirsty is also the creator of the wonderful infographics called #PaperinaPic. Reference: Martel et al. Randomized Double-blind Trial Intramuscular Droperidol, Ziprasidone and Lorazepam for Acute Undifferentiated Agitation in the Emergency Department. AEM April 2021 Case: You are sitting minding your own business charting on shift when you become aware of shouting and banging from your ambulance bay.  On investigating you find a collection of nursing, EMS and hospital security personnel surrounding an obviously agitated patient with blood on his head who is attempting to punch them. The nurse wants to know what medications he can get to chemically restrain the patient. Background: We have covered the issue of excited delirium back in SGEM#218 with a systematic review which found that the evidence base for most pharmacological treatments at that point was poor. Way back in 2013 we looked at haloperidol for agitation due to psychosis (SGEM#45) and concluded that it was an effective treatment but had common side effects. Droperidol has been used widely, particularly in Australasia, for acute severe agitation. Unfortunately, an FDA Black Box warning and supply issues meant that droperidol effectively vanished from the US armamentarium from 2013-2019 and other agents were used and investigated. Clinical Question: In patients needing parenteral sedation for acute agitation, is droperidol, ziprasidone or lorazepam intramuscularly  most effective and safe? Reference: Martel et al. Randomized Double-blind Trial Intramuscular Droperidol, Ziprasidone and Lorazepam for Acute Undifferentiated Agitation in the Emergency Department. AEM April 2021 Population: Emergency department (ED) patients 18 years or old where the treating physician determined the need for parenteral sedation for acute agitation (it needed a patient or staff safety concern, not purely a high agitation score). Exclusions: Prisoners or those in police custody, pregnant or breast-feeding, or with documented allergy to any study medications. Intervention: Droperidol 5mg IM, Ziprasidone 10mg IM or Ziprasidone 20mg IM Comparison: Lorazepam 2mg IM Outcome: Primary Outcome: Adequate sedation at 15 minutes was defined as an Altered Mental Status Scale (AMSS) of zero Secondary Outcomes: Need for additional sedation, ED length of stay, respiratory depression (SpO2<90% requiring supplemental O2, EtCO2 falling by 10mmHg or rising by 15mmHg). Dr. Marc Martel This is an SGEMHOP episode, which means we have the lead author on the show. Dr. Martel is a practicing emergency physician at Hennepin County medical center in Minneapolis, Minnesota since 2000.  He has been a nocturnist for essentially his entire career.  Dr. Martel’s research focuses on finding the safest way to care for patients with acute agitation while respecting patient's dignity, limiting restraint use, and efficiently getting them care they need. Authors’ Conclusions: “Droperidol was more effective for sedation and was associated with fewer episodes of respiratory depression than lorazepam or either dose of ziprasidone.”  Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Unsure The study patients were recruited consecutively (i.e. no selection bias). No The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes All groups were treated equally except for the intervention. Unsure Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. No The treatment effect was large enough and precise enough to be clinically significant. Yes Results: They recruited 115 participants into the trial, 87 of whom were men. The mean age was around 40 years, and the underlying diagnosis was primarily alcohol intoxication, with other diagnoses being drug intoxication, head injury, and psychiatric conditions. Key Result: Droperidol was more effective than ziprasidone or lorazepam in treating E.D. patients with acute agitation. Primary Outcome: Adequate sedation at 15 minutes 64% of the droperidol group vs 35% and 25% of the ziprasidone groups and 29% of the lorazepam group. Droperidol: 16/25: 64% (95% CI; 45%-80%) Ziprasidone 10mg: 7/28: 25% (95% CI; 13%-43%) Ziprasidone 20mg: 11/31: 35%  (95% CI; 21%-53%) Lorazepam 9/31: 29% (95% CI; 16%-47%) Secondary Outcomes:  More patients in the lorazepam group received additional sedative medication and were reported to have respiratory depression. We have five nerdy questions for Marc to help us better understand his study better. Listen to the podcast to hear his responses to each of our questions. 1. Old Data: As you say in the discussion this data is from 2004-05 and explain the delay?   How do you think it will apply in the landscape of bath salts, crystal meth and spice? 2. Convenience Sample: You recruited when the research team was available (limitation of EM research). This could have introduced some selection bias because patients presenting on nights/holidays/weekends may be different than those who present at other times. Did you manage to cover the whole working week adequately (24/7/365)? 3. Subjectivity: Both your inclusion criteria and your primary outcome were subjective (whether a patient needed parenteral sedation and whether sedation was adequate). Do you think your team was consistent or have data on inter-rater reliability (IRR) and did you have training to improve this aspect of the study? 4. Altered Mental Status Scale (AMSS): You used the AMSS for the assessment of agitation and stated in the manuscript that it was a “validated” ordinal agitation scale. Three references were provided to support the statement. I was not familiar with AMSS and pulled the references. Two were not validation studies of the AMSS [ref 14 & 28]. The third reference said “the AMSS has not been formally evaluated except as a tool in assessing alcohol intoxication in which Miner et al. only used the responsiveness descriptor” Calver et al 2011 [ref 27]. Is there a formal validation of the AMSS in this patient population and, like Nerdy point #3, is there data on IRR? 5. Comparison Group: Did you consider comparing droperidol to ketamine which has been very popular these days or to a combination of drugs like the B52? Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors' conclusions. SGEM Bottom Line: Consider droperidol as a therapeutic option for agitated patients requiring parenteral sedation. Case Resolution: You ask the nurse to prepare for parenteral sedation with droperidol while you initially apply your techniques of verbal de-escalation. Dr. Kirsty Challen Clinical Application: In my UK practice droperidol still isn't widely available, so I will reach for haloperidol, but if droperidol becomes available I am likely to use it. What Do I Tell My Patient?  When you were first brought in, you were very distressed and a threat to yourself and others. We gave you an injection of sedative so we could treat you safely with a low risk of causing side-effects. Keener Kontest: Last weeks’ winner was Dr. Dennis Ren a PEM fellow in Washington DC. He knew the "P" in PRAM initially was for “preschool”. Listen to the podcast this week to hear the trivia question. Email your answer to TheSGEM@gmail.com with "keener" in the subject line. The first correct answer will receive a cool skeptical prize. SGEMHOP: Now it is your turn SGEMers. What do you think of this episode on droperidol for acute agitation? Tweet your comments using #SGEMHOP.  What questions do you have for Marc and his team? Ask them on the SGEM blog. The best social media feedback will be published in AEM. Also, don’t forget those of you who are subscribers to Academic Emergency Medicine can head over to the AEM home page to get CME credit for this podcast and article. We will put the process on the SGEM blog: Go to the Wiley Health Learning website Register and create a log in Search for Academic Emergency Medicine – “April” Complete the five questions and submit your answers Those who are not AEM members can also claim CME credits for this SGEM episode. The content is always free but there is a small fee for the CME. This will help support this Free Open Access Project and your support is greatly appreciated. Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

Date: April 16th, 2021 Guest Skeptic: Dr. Anthony Crocco is the Deputy Chief - McMaster Department of Pediatrics, Acting Head of Pediatric Cardiology, and creator of Sketchy EBM. Reference: Schuh et al. Effect of Nebulized Magnesium vs Placebo Added to Albuterol on Hospitalization Among Children With Refractory Acute Asthma Treated in the Emergency Department: A Randomized Clinical Trial. JAMA Nov 2020 Case: A four-year-old girl with a known history of asthma presents to your emergency department (ED) after a one-day history of runny nose and cough.  Her usual triggers are upper respiratory infections and cats.  You don the appropriate personal protective equipment (PPE) wondering if this is COVID.  On initial exam she has minimal air entry, has biphasic wheeze, is saturating 92% on room air and has suprasternal retractions.  You give her an initial Pediatric Respiratory Assessment Measure (PRAM) score of 8 - and consider her to be having a “severe” exacerbation.  You give her a dose of oral dexamethasone and start three back-to-back treatments of albuterol and ipatroprium bromide.  After one hour she is still working hard to breath and her PRAM has improved somewhat but is still 6 denoting “moderate” asthma.  You wonder whether magnesium is indicated now and rather than starting an IV to give it that way, you could just nebulize a dose instead. Background: Asthma is a common presenting complaint for children in the ED. We have covered asthma a few times on the SGEM: You mentioned the PRAM tool in the case scenario. Can you explain this further for those not familiar with the PRAM score? SGEM#52: Breakfast at Glenfield – Asthma, Social Media and Knowledge Translation SGEM#103: Just Breathe – Inhaled Corticosteroids for Asthma Exacerbations SGEM#142: We Need Asthma Education SGEM#194: Highway to the Dexamethasone – For Pediatric Asthma Exacerbations The PRAM score is a tool used to assess the severity of airway obstruction in pediatric patients. The PRAM was published in 2000 (Chalut et al) and validated in 2008 (Ducharme et al). The PRAM consists of five clinical elements: O2 saturation, suprasternal retractions, scalene muscle contraction, air entry and wheezing. A score of 0-3 is considered mild asthma, 4-7 is moderate and 8-12 is severe. The Canadian Pediatric Society (CPS) Guidelines  recommends the initial management of pediatric patients with severe asthma exacerbations consists of: keeping oxygen saturations >93%, inhaled beta agonists, inhaled ipatroprium bromide, oral steroids, consider IV steroids, consider continuous aerosolized beta-2 agonists, consider IV magnesium sulphate and keep NPO. For children with severe asthma, IV magnesium has been shown to significantly decrease hospitalization rates though practically these children are rarely sent home after this IV treatment (Cheuk et al 2005, Griffith et al 2016, Su et al 2018 and Liu et al 2016).  As IV magnesium requires an intravenous, a painful and often distressing procedure in of itself, and the magnesium itself given IV can cause hypotension, an alternate delivery system would be of benefit. Clinical Question: Does nebulized magnesium prevent hospitalization in children with moderate to severe asthma? Reference:  Schuh et al. Effect of Nebulized Magnesium vs Placebo Added to Albuterol on Hospitalization Among Children With Refractory Acute Asthma Treated in the Emergency Department: A Randomized Clinical Trial. JAMA Nov 2020 Population: Children 2 to 17 years of age with a previous diagnosis of asthma presenting to a pediatric ED with moderate to severe asthma after receiving one hour of treatments including 3 x inhaled albuterol treatments, 3 x inhaled ipatropium bromide treatments and oral corticosteroid. Moderate to severe asthma was defined by a PRAM score of greater than 4. Exclusions: Children less than 2 years of age, those requiring immediate airway management, patients who received IV magnesium prior to enrollment, had comorbidities (chronic lung, cardiovascular, kidney, neurologic, or other systemic disease), and those with a known hypersensitivity to magnesium. Intervention: Three consecutive doses of nebulized magnesium sulfate 600mg with albuterol 5mg delivered through AeroNebGo nebulizer with Idehaler holding chamber. Comparison: Three consecutive doses of nebulized placebo with albuterol 5mg delivered through AeroNebGo nebulizer with Idehaler holding chamber Outcome: Primary Outcome: Hospitalization for either persistent respiratory distress or the need for supplemental oxygen Secondary Outcomes: Changes in the PRAM score; respiratory rate and O2 saturation change from baseline at 60/120/180/240 minutes; Changes in blood pressure 20/40/60/120/180/240 minutes; number of albuterol treatments within 240 minutes; Adverse effects. Exploratory: Hospitalizations; unscheduled visits within 72h of discharge; administration of IV magnesium in the ED after experimental intervention. Authors’ Conclusions: “Among children with refractory acute asthma in the ED, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the hospitalization rate for asthma within 24 hours.  The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Yes The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. No Results: There were 816 patients eligible for analysis. The median age was 4.5 years, 63% were male, median PRAM score was 6 and 44% were hospitalized Key Results: No statistically significant difference between the nebulized magnesium group and the placebo group. Primary Outcome: Hospitalization 43.5% in the magnesium group vs 47.7% in the placebo group Absolute difference -4.2% (95% CI; −11% to 2.8%) P=0.26 No statistically significant superiority of magnesium over placebo in any of the subgroups Secondary Outcomes:  No statistically significant difference in any of the secondary outcomes Adverse events were infrequent and not attributed to treatment Admission to the ICU was the only serious adverse events and due to asthma not the experimental therapy 1. “Negative” Study – This very well done RCT found no statistical superiority of nebulized magnesium in this patient population compared to placebo. It could be labeled a “negative” study, but it is very important to publish, review and discuss these studies. Publication bias is well recognized in the medical literature. We need to value “negative” studies as much as “positive” studies in our quest for the “truth”.  The authors should be commended on asking an important question, conducting the trial, analyzing the data, writing it up and getting it published. Another really important point is that they did not try to spin the data. 2. Optimized Delivery of Magnesium – They used equipment in the MAGNUM PA trial that might not be standard everywhere. Specifically, they used the AeroNebGo nebulizer with Idehaler holding chamber which apparently delivers 20% medication to the lungs vs. 4% with conventional nebulizers. Had they shown a difference, we would be asking whether this can be applied to centres that do not have this optimal setup. The fact that they did not find a statistical difference makes me believe the results even more. Rural and small community hospitals are unlikely to have such equipment. If it does not “work” in an optimized system with the best technology, it is very unlikely to work in the community setting. 3. Sample Size - Early on, they had planned for a small number of patients required for this study (n=284). The calculation was based on a hospitalization rate of 30% and powered to find a 15% absolute reduction with nebulized magnesium. However, during the early part of the study they observed a hospitalization rate of around 50%.  No in-group analysis was performed at this point, so blinding was maintained.  They redid their power calculation and powered the study to find a 10% reduction on hospitalizations. This resulted in them needing to recruit 816 patients which took eight years to accomplish. 4. Severe Asthmatics - Another point to make about sample size would be about the small number of patients in the severe cohort (16%) as per the PRAM score. The vast majority (84%) of children included in the study had a PRAM score of <8 (moderate severity). One reason they did not recruit as many severe asthmatics is they often received IV magnesium before being considered for the trial early in their presentation to the ED based on physician judgment. 5. Intravenous Magnesium – This data applies to nebulized magnesium for the treatment of moderate to severe asthma in children. We should try not to over interpret the data and conclude that IV magnesium does not work in these patients. Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusion and appreciate their work conducting and publishing a well-run study with negative results.

Date: April 6th, 2021 Guest Skeptic: Dr. Casey Parker is a Rural Generalist from the NW of Australia. He is a GP by training but works in Emergency Department, Anaesthesia, Internal Medicine and Paediatrics. Dr. Parker is currently studying to become a Sonologist. He has a wonderful #FOAMed blog and podcast called Broomedocs and also work with me on the Primary Care RAP team. Reference: Risk of Overcorrection in Rapid Intermittent Bolus vs Slow Continuous Infusion Therapies of Hypertonic Saline for Patients With Symptomatic Hyponatremia: The SALSA Randomized Clinical Trial. JAMA Intern Med 2021 Case: A 60-year-old man presents to the emergency department (ED) after his wife found him to be drowsy and confused at home. He had been vomiting that morning. He had a background of hypertension treated with a thiazide diuretic. His wife reports that he had experienced diarrhoea in the week prior to this presentation.  On arrival to the ED his vitals are normal aside from a decreased level of consciousness and he is found to have a serum sodium concentration of 118 mmol/L.  You are unsure as to the best way to correct his sodium and are aware that rapid overcorrection may lead to an osmotic demyelination syndrome.  However, he is also at risk of a seizure and further harm at this level. Background: The most common electrolyte abnormality in clinical practice is a low sodium level (hyponatremia). This imbalance occurs in 14% to 42% of admitted patients. There is a high mortality associated with hyponatremia [1-3].  Symptomatic hyponatremia has traditionally been treated with a careful slow continuous infusion of hypertonic saline. This has been to prevent the horrible adverse event called osmotic demyelination syndrome (ODS). ODS includes both central pontine myelinolysis and extrapontine myelinolysis. In recent times several expert consensus guidelines have recommended the use of rapid, intermittent boluses of hypertonic saline  instead of a slow continuous infusion [3,4].   There is very little randomized data to prove the superiority of either strategy prior to the SALSA trial.  Most of the trials were done in marathon and ultra-marathon runners whom we do not see very often in the ED [5-7]. Using a fixed bolus has a number of potential benefits [8-9]:  Efficacy: Ability to reach rapid partial correction hyponatremia Safety: It can limit the risk of overcorrection that can commonly occur with continuous infusion of hypertonic saline No Math: It omits need for calculations Clinical Question: When treating symptomatic hyponatremia what are the risks of overcorrection in patients using either a slow continuous infusion vs. a rapid intermittent bolus of hypertonic saline strategy? Reference: Risk of Overcorrection in Rapid Intermittent Bolus vs Slow Continuous Infusion Therapies of Hypertonic Saline for Patients With Symptomatic Hyponatremia: The SALSA Randomized Clinical Trial. JAMA Intern Med 2021 Population: Patients 18 years of age and older with moderate or severe symptomatic hyponatremia (corrected serum sodium [sNa] of 125 mmol/l or less). Moderate symptoms include nausea, headache, drowsiness, general weakness and malaise. Severe symptoms include vomiting, stupor, seizure, and coma (Glasgow Coma Scale [GCS] score ≤8).  Exclusions: Primary polydipsia; pregnant or breastfeeding; anuria, arterial hypotension, liver disease, uncontrolled diabetes mellitus; or had a history of cardiac surgery, acute myocardial infarction, sustained ventricular tachycardia, ventricular fibrillation, acute coronary syndrome, cerebral trauma, and increased intracranial pressure within 3 months prior to randomization.  Intervention: Rapid intermittent bolus (RIB) groups received 2ml/kg of 3% saline over 20 minutes. Patients were dichotomized into moderate or severe hyponatremia. The severely symptomatic patients had 2 separate boluses delivered initially. The 2ml/kg bolus was repeated every 6 hours until the target sNa was achieved and symptoms were relieved. Comparison: Slow continuous infusion (SCI) group received 0.5 ml/ kg/hr in the moderate group and 1ml/kg/hr in the severe group.  There was a complicated titration of the infusion rate determined by the monitored sNa changes at each sample point. Outcome:  Primary Outcome: Incidence of overcorrection of serum sodium at any given period up to 48 hours.  Over correction was defined as an increase in sNa by >12 mmol/L within 24 hours or an increase in sNa by >18 mmol/L within 48 hours  Secondary Outcomes: There were nine secondary outcomes measured including: Rapid improvement in symptoms by 24 hours; change in GCS at various time points; a number of laboratory targets; and osmotic demyelination syndrome (ODS) Authors’ Conclusions: “This randomized clinical trial found that both RIB and SIC therapies of hypertonic saline for treating hyponatremia were effective and safe, with no difference in the overcorrection risk. However, RIB had a lower incidence of therapeutic relowering treatment and tended to have a better efficacy in achieving sNa within 1 hour than SCI. RIB could be suggested as the preferred treatment of symptomatic hyponatremia, which is consistent with the current consensus guidelines.”  Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. Unsure Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. No Results: There were 178 patients randomized in this trial. The mean age was 73 years, 45% were male and the mean sNA was 118 mmol/L. Hyponatremia was determined to be cause by thiazide diuretics (30%), SIADH (29%), adrenal insufficiency (16%), decreased extracellular cellular fluid volume due to non renal sodium loss (14.0%), and increased extracellular fluid volume (11%).  Key Result: No statistical difference in overcorrection between the rapid intermittent bolus group and slow continuous infusion group. Primary Outcome: Overcorrection 17.2% in the RIB group and 24.2% in the SCI group 6.9% absolute difference (95% CI; −18.8% to 4.9%) p=0.26 Secondary Outcomes: There was generally no difference between groups with the exception that the RIB group achieved target serum concentrations more often at the 1-hour mark which is not really surprising as they received a lot more 3% saline as an initial bolus.   The SCI group did receive significantly more “relowering therapies” 41% vs 57%.  As such more subsequent interventions were needed in the SCI group. That is to say about 15% more patients in the SCI group needed to have a subsequent intervention to prevent too rapid sodium correction. There were very few adverse events reported with no statistical difference between groups: incidence of ODS (0), pulmonary edema (1), phlebitis (2) oliguria (1) and mortality (7 RIB vs 2 SCI) 1. Population: We answered “yes” that the study population included or focused on those in the ED. The patients were recruited from three South Korean General Hospitals, for the first two years of recruitment they were all ED patients. However, this was expanded to include inpatients after that time to accomplish a sufficient study population. Approximately three-quarters of the final cohort of patients were enrolled in the ED. 2. Blinding: This is an unblinded trial of an intervention that requires a lot of clinician judgement and subjective assessment.  As such there is a large potential for bias.  If you were a strong believer in either strategy and the patient in front of you was not doing so well - there is a big incentive to either change strategy or add additional therapy.   The fact that there was a difference in “relowering therapy” between the groups could in fact be capturing this bias in the act. So how do we overcome this limitation of blinding? One possible solution would be to have a computer algorithm monitor the sNa level and adjust things accordingly on some kind of pump. The machine could be giving a sham placebo, 3% saline or relowering therapy all without the treating clinician knowing. There could be safety protocols to override the system on parameters determined a priori. 3. Comparison Group: This RCT was designed with an active comparison group rather than a placebo group. It would have been unlikely to get ethics approval for a placebo controlled trial. A basic premise for ethics approval is that equipoise must exist. Hyponatremia can be a life threatening condition and it would not be appropriate to withhold treatment in a moderate to severely symptomatic population.  It is widely agreed upon that comparison to placebo is acceptable only when no proven intervention exists (Millum and Grady 2013). In contrast, placebo comparison is not considered acceptable in life-threatening conditions if there is an available treatment. The argument against the use of placebos in these circumstances is guided by the Declaration of Helsinki. This documents state: “In any medical study, every patient — including those of a control group, if any — should be assured of the best proven diagnostic and therapeutic methods.” Thus, if an effective treatment exists,

Date: March 31st, 2021 Guest Skeptic: Prof Daniel Fatovich is an emergency physician and clinical researcher based at Royal Perth Hospital, Western Australia. He is Head of the Centre for Clinical Research in Emergency Medicine, Harry Perkins Institute of Medical Research; Professor of Emergency Medicine, University of Western Australia; and Director of Research for Royal Perth Hospital. Reference: Toyoda et al. MRI-guided thrombolysis (0.6 mg/kg) was beneficial for unknown onset stroke above a certain core size. THAWS RCT Substudy. Stroke 2021 Case: A 74-year-old man presents to the emergency department after waking up with left sided weakness. He was last seen well when going to bed at 10pm the night before. He has a history of hypertension and dyslipidemia. His medications include an angiotensin-converting enzyme inhibitor and a statin. The NIHSS score is 7. The MRI shows an occlusion of the right MCA-M2, the DWI-ASPECT is 9, and lesion volume is 3.5ml. Background: We have talked about stroke management a number of times recently including SGEM#297 on the reanalysis of ECASS-3 by Alper et al 2020.  The SGEM bottom line was that the "reanalysis of the original ECASS-3 data does not support the potential benefit of tPA given between 3-4.5 hours after onset of stroke symptoms and confirms the known potential harm". There have been 13 foundational trials looking at thrombolysis for acute ischemic stroke. Of the 13, eleven failed to show benefit for their primary outcome and four were stopped early due to harm or futility. Only two RCTs claimed benefit for their primary outcome. Those were ECASS-3 in 2008 and the NINDS trial from 1995. Both of those “positive” studies have been reanalyzed and question the potential efficacy while confirming the potential harm. Dr. Jackson We wrote an article together for the Lown Institute summarizing some of the stroke literature. The question asked was: will it take 50 or 100 years to get the right answer about tPA for acute ischemic stroke? One aspect that we did not address was the newer trials that are using advanced imaging techniques like MRI to extend the window beyond 4.5 hours after the onset of stroke symptoms (Extend NEJM 2019 and ECASS-4: Extend 2016). Both of these trials were stopped early which can introduce additional bias towards efficacy. The majority of patients included in the two trials extending the time window past 4.5 hours would now qualify for endovascular therapy (EVT) clot retrieval. EVT does have more robust evidence for efficacy and safety than systemic thrombolysis. A SRMA was published by Mistry et al Stroke 2017. This included 13 studies, three randomized control trials (25% of all patients) and ten observational studies (75% of all patients). Good neurologic outcome was defined as a modified Rankin Scale (mRS) score of 0-2. The number needed to treat (NNT) was 17. However, there was no statistical difference if you only look at the higher quality RCT data and excluded the lower quality observational data. Yang P et al. published a non-inferiority RCT in NJEM 2020 looking at this issue. The primary outcome was mRS at 90 days and found EVT alone was not non-inferior to EVT plus tPA. Two recent RCTs were published in JAMA investigating this issue. Suzuki et al failed to demonstrate non-inferiority while in contrast Zi et al found EVT alone was non-inferior to EVT plus tPA. These two EVT trials are going to be covered on a future episode of the SGEM in the near future. The trial we are reviewing today is a sub analysis of the THAWS (Thrombolysis for Acute Wake-Up and Unclear-Onset Stroke) randomized control trial of using low dose tPA in patients with symptoms on awaking or unknown time of onset. Clinical Question: Is MRI guided thrombolysis (0.6 mg/kg) beneficial for patients with an unknown stroke onset time? Reference: Toyoda et al. MRI-guided thrombolysis (0.6 mg/kg) was beneficial for unknown onset stroke above a certain core size. THAWS RCT Substudy. Stroke 2021. Population: Patients with stroke symptoms on awaking or with unknown time of onset (greater than 4.5 hours since last known well and less than 4.5 hours of symptom recognition). Substudy of THAWS published 2020 (n = 131). Intervention: IV alteplase 0.6 mg/kg (10% bolus followed by 90% infusion over 60 minutes) Comparison: Standard care, not placebo controlled. Standard care was the use of one to three antithrombotic drugs, including oral aspirin (160–300 mg/day), oral clopidogrel (75 mg/day), intravenous argatroban, or intravenous unfractionated heparin, but excluding the combination of argatroban and heparin, according to decisions of the attending physician. (Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor). In this SUBSTUDY (n= 126), patients were dichotomized by ischemic core size or NIHSS. Outcome: Primary Outcome: Good neurologic function using modified Rankin Scale (mRS) score of 0-1 at 90 days Secondary Outcomes: Category (ordinal) shift in mRS at 90 days; mRS 0-2 at 90 days; category shift NIHSS score at 24 hours and 7 days; imaging outcomes: recanalization on MRA at 22-36 hours; infarct volume on FLAIR at 7 days minus infarct volume on DWI at baseline. Safety: sICH at 22-36 hours and major extracranial bleeding and death. Authors’ Conclusions: SUBSTUDY: “Patients developing unknown onset stroke with DWI-ASPECTS 5 to 8 showed favorable outcomes more commonly after low-dose thrombolysis than after standard treatment.” Note: “ASPECTS” stands for the Alberta Stroke Program Early CT Score. It is used to determine MCA stroke severity using available CT data. To compute ASPECTS, 1 point is subtracted from 10 for any evidence of early ischaemic change for each of the defined regions. Normal CT = 10 points. Using the traditional cutoff (less than 8 vs equal to or greater than 8) as a rough estimate for predicting independence may help inform decisions. ASPECTS suggests that early CT changes in stroke may be a harbinger of poor outcomes.  As a reminder, the authors’ conclusions from the original THAWS RCT were: “No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. No The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. No All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. No Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. No Results: The original THAWS trial enrolled 131 patients. It was to have 300 patients but was stopped early due to results from the WAKE-UP trial. The mean age was 74 years, 69% had hypertension, 35% dyslipidemia, 37% atrial fibrillation, 20% diabetic and 17% had a history of ischemic stroke/TIA. THAWS Subgroup Analysis: Some subgroups had better neurologic outcomes with tPA compared to control while others did not. Primary Outcome: Good neurologic outcome (mRS 0-1) at 90 days DWI-ASPECTS 5 to 8 (RR 4.75 [95% CI, 1.33–30.2]) * (statistically significant) DWI-ASPECTS 9 to 10 (RR 68 [95% CI, 0.45–1.02]) Core volume >4 ml (RR 6.15 [95% CI, 0.87–43.64]) Core volume ≤6.4 ml (RR 81 [95% CI, 0.57–1.17]) THAWS: No statistical difference in good neurologic outcome at 90 days. Primary Outcome: Good neurologic outcome (mRS 0-1) at 90 days 47.1% tPA vs 48.3% control RR 97 [95% CI; 0.68–1.41] P=0.892 Secondary Outcomes:  All p > 0.05 except recanalization of culprit artery on MRA 73.7% tPA vs 40.9% control. Intracranial hemorrhage (ICH) was 26% tPA vs 14% control. ASPECT Data: The baseline DWI-ASPECTS was 10 in 38 patients, 9 in 41, 8 in 18, 7 in 11, 6 in 11, and 5 in 7, with a median of 9. So, only a small subgroup of 47 patients had an ASPECT of 5-8. Remember that the THAWS trail was planned to have 300 patients and was stopped early at 131 patients. This subgroup represents 37% of the cohort and only 16% of the population determined a priori. They also dichotomized patients by core volume with a cutoff level based on the receiver operating characteristic (ROC) curve ROC of 6.4 ml. They observed some baseline differences between these two groups. Core Volume Data: Patients with core volume >6.4 ml more commonly had atrial fibrillation (P=0.014), less commonly recognized symptoms at waking up (P=0.007), had higher NIHSS score (P<0.001), and had lower DWI-ASPECTS (P<0.001) than those with volume ≤6.4 ml. These baseline differences are summarized in Table 1. With this dichotomization based on CORE volume the percentage of favourable outcome was not different between the tPA and control groups (P=0.376). In patients with volume >6.4 mL, although not statistically significant, favourable outcome was more common in the tPA group than in the control group (RR, 6.15 [95% CI, 0.87–43.64] P=0.069). Change in the NIHSS score was larger in the control group for patients with volume ≤6.4 ml and category shift in the mRS score was larger in the tPA group for those with volume >6.4 ml. 1) WAKE Up “Positive”?

Date: March 17th, 2021 Guest Skeptic: Dr. Emil Ejersbo Iversen is an emergency medicine resident at the University Hospital of Zealand, Denmark. He currently serves as Vice-Chair of the Danish Society for Emergency Medicine and Chair of the Young Doctors in Emergency Medicine in Denmark. He has a passion for FOAMed and is the creator of the Danish EM platform www.akutmedicineren.dk. Reference: Schuster et al. Spirometry not pain level predicts outcomes in geriatric patients with isolated rib fractures. J Trauma Acute Care Surg. 2020 Case: A 74-year-old woman who suffered a fall earlier today presents to the emergency department (ED) and is found to have five rib fractures to her right thorax, but no other injury. She is otherwise well, and her vitals are stable, but she is in some pain. Recent guidelines recommend admitting the patient to the intensive care unit (ICU), but the patient is eager to return home to her husband who is also well, and whom she claims will be able to help her. Background: Rib fractures are a common injury among the older population and can potentially lead to life-threatening complications such as pneumonia, pneumothorax or decreased inspiratory capacity. Some recent guidelines recommend admitting patients older than 65 years of age with two or more with rib fractures to an intensive care unit (ICU) or other step-down monitored setting [1]. Currently, patients with three or more rib fractures are often admitted for analgesia and monitoring and subsequently discharged without complications. Recent retrospective studies have suggested that early spirometry may be a useful indicator of prognosis in patients with multiple rib fractures [2]. Identifying patients with a good prognosis that could be safely discharged home with analgesia could potentially avoid unnecessary hospitalization. This would likely lower healthcare costs and decrease the risk of hospital-acquired infections. Spirometry includes metrics such as forced vital capacity (FVC), peak expiratory flow (PEF), forced expiratory volume 1 second (FEV1), and negative inspiratory force (NIF). The PEF has not been demonstrated to be closely correlated with patient outcomes [3]. However, FVC has been shown to correlate with patient outcomes and length of stay (LOS) in patients who have multiple rib fractures [4-5] These studies were limited by their retrospective observational nature. Hand grip strength has also been used to measure overall frailty. GeriEM guru Chris Carpenter has done some work in this area over ten years ago. His team found grip strength was weakly correlated with frailty in older ED patients [6]. Future research should confirm this association and assess the correlation of grip strength with other measures of frailty. Multiple other authors have investigated this simple and inexpensive tool for predicting frailty [7-8]. Clinical Question: Can spirometry testing identify patients 60 years and older with at least three rib fractures who can safely be discharged home from the ED? Reference: Schuster et al. Spirometry not pain level predicts outcomes in geriatric patients with isolated rib fractures. J Trauma Acute Care Surg. 2020 Population: Patients 60 years of age and older admitted to hospital with at least three rib fractures within 24 hours of injury Exclusions: Injury occurred >24hrs before presentation, significant additional musculoskeletal injury or cognitive impairment and able to cooperate with testing Exposure: Spirometry measuring (FVC, FEV1 and NIF) Comparison: Hand grip strength and pain assessment (VAS) Outcome: Primary Outcomes: Discharge disposition and length of stay (LOS) Secondary Outcomes:Mortality, pneumonia, intubation, unplanned transfer to higher level of care and readmission (within 30 days) Authors’ Conclusions: “Spirometry measurements early in the hospital stay predict ultimate discharge home, and this may allow immediate or early discharge. The impact of pain control on pulmonary function requires further study.” Quality Checklist for A Prognostic Study: The study population included or focused on those in the ED? Yes The patients were representative of those with the problem? Yes The patients were sufficiently homogenous with respect to prognostic risk? Yes Objective and unbiased outcome criteria were used? Yes/No The follow-up was sufficiently long and complete? Yes/No The effect was large enough and precise enough to be clinically significant? Unsure Result: There were 346 patients over the age of 60 admitted to hospital with isolated rib fractures. Exclusion criteria was met in 260 patients. This resulted in a cohort of 86 patients with a mean age of 77 years and 50% female. Just over half (45/86) were admitted to the step-down unit, 19/86 (22%) were admitted to the ICU and 22/86 (26%) to the surgical floor. The mechanism of injury was a fall (54%), motor vehicle collision (45%) or motorcycle collision (1%). The median number of fractured ribs was five. Pneumothorax was present in 5% and hemothorax in 4%. One patient out of 86 died (1.2%). Key Results: Higher spirometry values and grip-strength were associated with early discharge from hospital Primary Outcomes: Discharge disposition and length of stay FEV1 Adjusted Odds Ratio (aOR) 1.03 (95% CI; 1.01 to 1.06) p = 0.001 Grip strength was also significantly associated with being discharged home FVC and NIF were not statistically significant Pain score was poorly predicative of length of stay Secondary Outcomes: There were a few patients that had some of the secondary outcomes of interest (n). This included mortality (1), pneumonia (2), intubation (1), unplanned transfer to higher level of care (3) and readmission (3) within 30 days 1. Selection Bias: All patients were screened except when an investigator was unavailable. We suspect that this was nights, weekends and holidays. No details were provided in the manuscript of how many of the 260/346 (75%) of the exclusions were due to this reason. This could have introduced some selection bias into the data. 2. Power: There was no formal power calculation done a priori. The authors say a “rough” estimate to find a difference between the two groups would have been about 400 patients. It is unclear exactly how they arrived at this number. They did estimate a complication rate of about 20% based on the Geriatric Trauma Outcome Score (GTOS) [9]. The GTOS is calculated by taking the patients age + (injury severity score x 2.5) + 22 (if given packed red blood cells by 24 hours). Post hoc power (PHP) calculations really shouldn’t be done. It is good practice to do a power calculation a priori to plan your research project. In contrast, doing a PHP calculation can be misleading. It is better just to look at the confidence interval around the point estimate. The results are the results and looking backwards with a PHP calculation does not help interpret the results. Thank you to Andrew Althouse from EpiTwitter for providing me with a number of citations discussing this issue. Hoenig and Heisey. The Abuse of Power: The Pervasive Fallacy of Power Calculations for Data Analysis [10] Althouse AD. Post Hoc Power: Not Empowering, Just Misleading [11] Dziak et al. The Interpretation of Statistical Power after the Data have been Gathered [12] 3. Blinding: The investigators in this study were not blinded and although spirometry is a seemingly objective measurement it does require significant instructing of the patient and the fact that the same investigator performed both the pain assessment and the spirometry could have introduced “coaching/spectrum bias” Spectrum Bias When we use the term “bias” it is referring to something that systematically moves us away from the “truth”. And by truth we mean the best point estimate of an observed effect size with a confidence interval around estimate. Can you tell us more about Coaching/spectrum bias?  Coaching bias could be conscious or unconscious. It could occur when patients who were thought to have higher levels of pain were not pushed as hard to go through with the spirometry. This coaching bias is a form of spectrum bias. Sensitivity depends on the spectrum of disease, while specificity depends on the spectrum of non-disease. So, you can falsely raise sensitivity if the cohort has lots of very sick people and specificity can look great if you have no sick patients in the cohort. The best resource on understanding the direction of bias in diagnostic test accuracy is by Kohn et al published in AEM [13]. 4. Rib Fractures: All but four patients had their injuries identified by CT scan. Rib fractures are often missed on initial CXR in up to 50% of cases and one rib fracture on CXR is associated with a high risk of multiple rib fractures [14]. Are we discharging patients with undiagnosed multiple rib fractures? This could introduce denominator neglect. How many people were seen and not suspected of having a fractured rib, had CXR and was read as normal, or had a CXR and only one rib fracture was seen? There is evidence of this issue in the manuscript. The authors did not screen 322 acutely injured patients who were discharged directly from the ED. Three were believed to have subacute rib fractures by imaging characteristics. 5. Follow-up: The final nerdy point is about the follow-up in this study. They had their secondary outcomes of pneumonia, readmission and mortality at 30 days. Very few patients were observed to have any of these outcomes. Perhaps this is because patients can deteriorate more gradually, and these outcomes may not be realized until after 30 days. It would have been nice to see a longer follow-up period to be more confident there were not delayed adverse events.

Date: March 16th, 2021 Guest Skeptic: Dr. Corey Heitz is an emergency physician in Roanoke, Virginia. He is also the CME editor for Academic Emergency Medicine. Reference: Westafer et al. Outpatient Management of Patients Following Diagnosis of Acute Pulmonary Embolism. AEM March 2021 Case: You are evaluating a 48-year-old female for pleuritic chest pain. She is low risk by Wells Criteria but PERC Rule positive because of an appendectomy last month. Her d-dimer comes back elevated, so you order a CT-PA to evaluate for pulmonary embolism (PE). The radiologist notes a distal sub-segmental PE on the right. The patient has normal vital signs and no comorbidities. Background: Historically most patients with PEs have been admitted to the hospital in the USA. This is in contrast to Canada where papers in the early 2000 demonstrated the safety of out-patient management of PEs (Kovacs). A study from 2010 showed that half of PE patient from one centre in Ontario were safely being treated as outpatients (Kovacs). Dr. Jeff Kline PE guru, creator of the PERC Rule and Editor-in-Chief of Academic Emergency Medicine, Dr. Jeff Kline, was senior author on a paper that looked at treating VTE with outpatient management using a DOAC (Bean et al AEM 2015). This relatively small study (n=106) reported successfully treating 51% of DVT patients and 27% of PE patients with rivaroxaban (SGEM#126). Literature from the USA reports that 90% of patients diagnosed with PE are admitted (Singer et al 2016). Another study showed less than 10% of PE patients are discharged home from the ED for out-patient therapy (Vinson et al 2017). A couple of international guidelines support the outpatient treatment of ED patients with low-risk PE. This includes the European Cardiology Society (ECS 2019) and the British Thoracic Society (Howard et al 2018). The American College of Emergency Physicians (ACEP) has a clinical policy that addresses this issue (Wolf et al 2018). The ACEP policy give outpatient management of PE patients a Level C recommendation: “Selected patients with acute PE who are at low risk for adverse outcomes as determined by PESI, simplified PESI (sPESI), or the Hestia criteria may be safely discharged from the ED on anticoagulation, with close outpatient follow-up.” PESI (Pulmonary Embolism Severity Index) is a risk stratification tool based upon studies by Donzé et al 2008 and Choi et al 2009.  The PESI consists of eleven criteria with a different number of points awarded for each variable. This can be complicated and there is an online calculator to help (MDCalc PESI Score). The PESI score has been made even easier to use with the creation of the Simplified PESI. It only has six criteria, each has only one point and can also be computed online using MDCalc sPESI. The Hestia Criteria is another scoring system to identify low risk PE patients that could be considered for outpatient PE treatment. Like the PESI score it has eleven criteria and an online calculator (MDCalc Hestia Criteria). If all eleven criteria are negative the patient is low risk with a predicted mortality of 0% and VTE recurrence of 2%. However, if any one of the criteria is positive the patient is not low risk. These patients are not considered eligible for outpatient management based on this score and it is recommended they be admitted for inpatient therapy. Clinical Question: What are the current disposition practices, and outcomes, for patients with PE in US hospitals? Reference: Westafer et al. Outpatient Management of Patients Following Diagnosis of Acute Pulmonary Embolism. AEM March 2021 Population: Patients 18 years of age or older between July 2016 and June 2018 presenting to one of 740 acute care hospitals and receiving a diagnosis of PE based upon ICD-10 codes Exclusion: Patients diagnosed with PE in the previous 90 days, and those patients who expired during the ED visit Intervention: Outpatient management Comparison: Inpatient management Outcome: Primary Outcome: Initial disposition from the ED Secondary Outcomes: Costs, return visits to the ED (chest pain, shortness of breath, bleeding) and rehospitalization withing 30 days Dr. Lauren Westafer This is an SGEMHOP episode which means we have the lead author on the show. Dr. Lauren Westafer is an Assistant Professor in the Department of Emergency Medicine at the University of Massachusetts Medical School – Baystate. She is the cofounder of FOAMcast and is a pulmonary embolism and implementation science researcher. Dr. Westafer serves as the Social Media Editor and a research methodology editor for Annals of Emergency Medicine and is an Associate Editor for the NEJM Journal Watch Emergency Medicine. She is also the newest member of the SGEMHOP faculty. Authors’ Conclusions: “Despite guidelines promoting outpatient management, few patients are currently discharged home in the US; however, practice varies widely across hospitals. Return visit rates were high but most did not result in hospitalization.” Quality Checklist for Observational Study: Did the study address a clearly focused issue? Yes Did the authors use an appropriate method to answer their question? Yes Was the cohort recruited in an acceptable way? Yes Was the exposure accurately measured to minimize bias? Yes Was the outcome accurately measured to minimize bias? Yes Have the authors identified all-important confounding factors? Unsure Was the follow up of subjects complete enough? Yes How precise are the results? Fairly precise Do you believe the results? Yes Can the results be applied to the local population? Unsure Do the results of this study fit with other available evidence? Yes Results: The cohort of patients identified in the database was 61,070. The mean age was 62 years with slightly more females (53%). About two-thirds of patients had Medicare (51%) or Medicaid (12%) while 29% had private insurance. The top three comorbidities were hypertension (60%), chronic pulmonary disease (25%) and obesity (25%). Key Result: The vast majority of patients diagnosed with PE were admitted to hospital. Primary Outcome: Initial disposition from the ED 4% discharged from the ED at the index visit and 96% admitted Secondary Outcomes: Outpatient charge was $1,214 while the total cohort was $9,225 28% of those discharged had a return visit 11% of those discharged were subsequently admitted on a return visit Factors associated with admission: Respiratory failure/hypoxia (OR 0.06, 95% CI 0.04-0.07), Shock (OR 0.17, 95% CI 0.00-0.48), Hypotension (OR 0.07; 95% CI 0.00-0.14), Heart failure (OR 0.24; 95% CI 0.18-0.34) and malignancy (OR 0.45; 95% CI 0.36, 0.53) 1.9% of admitted patient died 1.3% of patients returning within 30 days were for a bleeding associated diagnosis Here are the five nerdy questions we asked Lauren to help us better understand her study. Listen to her respond to each question on the SGEM podcast. 1. Database: You used the Premier Healthcare Database (PHD) for this retrospective cohort study. This is a publicly traded company. Can you tell us a bit more about this resource and why you are confident in the fidelity of the data? 2. Risk Stratification: Did you consider calculating a risk score (PESI, sPESI or Hestia) for the patients and would it have been useful in interpreting the results? 3. Size and Location: We did not see any discussion about the size or location of the PEs. The ACEP clinical policy gives a level C recommendation whether or not to withhold anticoagulation in adult patients with subsegmental PE. “Given the lack of evidence, anticoagulation treatment decisions for patients with subsegmental PE without associated DVT should be guided by individual patient risk profiles and preferences.” [Consensus recommendation] 4. Subgroup Analysis: You did some subgroup analyses based on the hospital location, size, teaching and rural or urban. Did you find anything interesting and what is your interpretation for any differences? 5. Concordance: Why do you think clinicians are still admitting the vast majority of patients (96%) when data exists that this number could safely be cut in half? In fact, the number is even higher because you excluded 212 hospitals that admitted 100% of PE patients. What is driving this clinical practice in the USA when in Canada we discharge 50% of PE patients for outpatient management. Comment on the Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusion. SGEM Bottom Line: Patients with PE, given the right criteria, can be discharged home from the ED. US healthcare systems should consider decreasing the number of patients who are admitted, with the understanding that the risk of return visits is high. Case Resolution: You discuss anticoagulation outpatient management with your patient. She prefers to be discharged and has close follow up with her primary care clinician in two days. Using shared decision making, you and the patient agree to discharge her home on oral anticoagulants. Clinical Application: Consider using risk score systems and having shared decision-making discussions with your patients to determine who can be safely managed as an outpatient. What Do I Tell My Patient? You have a small blood clot in your right lung. Your vital signs are normal, and all other risk factors are minimal. There is some weak evidence that you do not need to be treated with blood thinners. However, most people still decide to be treated for their blood clot. This treatment can be either in the hospital or as an outpatient. There is a 1 in 4 chance that if you decide to be treated at home you will return to the hospital and 1 in 10 patients need to be admitted when they return. What would you like to do?

Date: March 11th, 2021 Guest Skeptic: Dr. Robert Edmonds is an emergency physician in the US Air Force in Ohio. DISCLAIMER: THE VIEWS AND OPINIONS OF THIS PODCAST DO NOT REPRESENT THE UNITED STATES GOVERNMENT OR THE US AIR FORCE. Reference: Post et al. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. Lancet 2021 Case: You’re working a busy evening shift in your community emergency department (ED) when a 58 year old female presents with a rapid onset terrible intensity headache.  She has no significant headache history and you are concerned for subarachnoid hemorrhage so you order a head CT which confirms your suspicions.  You page neurosurgery at the bigger ED in town, and while you wait for the page back, you wonder if giving tranexamic acid (TXA) could help improve the patient’s chances for a good outcome given its effects in other bleeding processes. Background: In the case presented, the woman would qualify using the Ottawa SAH Rule because of the rapid onset of an intense headache and her age. We have discussed the incredible work done by Dr. Jeff Perry and his group in the development of the Ottawa SAH Rule. Jeff was actually on the SGEM as the guest skeptic discussing this clinical decision instrument way back in 2013 (SGEM#48). The Ottawa SAH Rule is to be applied to alert patients older than 15 years of age with new severe non-traumatic headache reaching maximum intensity within one hour. It is not meant for patients with new neurologic deficits, previous aneurysms, SAH, brain tumor, or who have a history of recurrent headaches. This is defined as at least three or more episodes over the course of at least six months. Our SGEM Bottom Line eight years ago was that the Ottawa SAH “Tool” was not ready for prime time to rule out low risk patients from investigations. Fast forward to 2018 and the validation of the Ottawa SAH Rule by Dr. Perry and his group. The results of this prospective observational study were that the clinical decision instrument was 100% sensitive (missed no SAH patients) and 13.6% specific. Dr. Chris Carpenter The guest skeptic for SGEM#201 was Dr. Chris Carpenter, who literally wrote the book on diagnostic accuracy of clinical decision instruments in the ED with Dr. Jesse Pines. The SGEM bottom line from the episode was that the Ottawa SAH Rule needs external validation, a meaningful impact analysis performed, and patient acceptability of incorporating this rule into a shared decision-making instrument before being widely adopted. Dr. Perry did publish a prospective implementation of the Ottawa SAH Rule (Stroke 2019). This article was covered on the SGEM with EM Nerd Dr. Rory Spiegel. The results demonstrated that the Ottawa SAH Rule is highly sensitive (100%) but has very poor specificity (13%). It is unclear how it performs against unstructured clinical judgement or in non-urban tertiary care teaching hospitals (SGEM#283). Another issue the case brings up is whether a CT scan is good enough to rule out a SAH. The debate has historically been about whether or not you need to also get a lumbar puncture on these patients after a non-contrast CT head. Dr. Jeff Perry This brings us back to more work done by Jeff Perry. His team published a prospective cohort study that suggested if you got the CT scan done within six hours of headache onset, it was a third generation CT scanner, and it was read by a neuroradiologist, then you did not need to get an LP to rule out a SAH (BMJ 2011). There were some limitations to this observational study. Another study was done in the UK that tried to address this issue of LP post normal CT. This was covered on SGEM#134. It found that the NNTap (number needed to Tap) to diagnose one aneurysm not identified by CT scan was 250. The final issue the case identified was the use of TXA in treating patients with a SAH. We are skeptical given the previous review we did on the topic (SGEM#236). This was a structured critical review of the 2018 TICH trial published in the Lancet. The primary outcome showed no superiority of TXA compared to placebo for the mRS at 90 days. The SGEM bottom line was that TXA does not currently have evidence of improving outcomes in hemorrhagic stroke and routine administration cannot be recommended at this time. However, as good healthy skeptics our positions are tentative and will change when presented with convincing evidence. Just because TXA was not demonstrated to “work” in one RCT does not mean we can claim TXA does not work. The burden of proof is on those making the claim of efficacy. Patients deserve the best care, based on the best evidence. TXA has been discussed on the SGEM numerous times for treating a variety of conditions including: Trauma, isolated traumatic brain injury, gastrointestinal bleeding, post-partum hemorrhage and epistaxis.  Although some EM docs would like to believe TXA is one of the universal duct tapes of the ED, it has mixed results. Patients suffering an aneurysmal SAH are at risk of rebleeding, which could worsens their long term clinical outcome and chance of death.  A hypothesis raised in the previous Sprigg et al RCT was that perhaps by treating these people earlier with TXA they would have a patient-oriented benefit. Clinical Question: Does rapid administration of tranexamic acid in patients with CT confirmed SAH improve clinical outcome? Reference:  Post et al. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. Lancet 2021 Population: Adults 18 years and older with signs and symptoms for less than 24 hours indicating subarachnoid hemorrhage (SAH) AND who have a non-contrast CT confirming SAH. Exclusions: Perimesencephalic bleed in combination with a GSC score of 13–15, and without loss of consciousness directly after ictus or focal neurological deficit on admission; traumatic SAH; ongoing treatment for VTE (DVT/PE); a history of a hypercoagulability disorder; pregnancy; severe renal failure, or imminent death within 24 h. Intervention: TXA 1g IV bolus as soon as possible after a non-contrast CT proven diagnosis of SAH. This was followed by 1g infusion every 8 hours up to 24 hours (4g total) or until endovascular or surgical treatment, whichever came first. Comparison: Usual care Outcome: Primary Outcome: Neurologic outcome dichotomized to good (mRS of 0-3) or poor (mRS 4-6) at six months Secondary Outcomes: Excellent clinical outcome (mRS 0-2), ordinal shift of the mRS score, all-cause mortality (30 days and 6 months) and serious adverse events. Authors’ Conclusions: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale. Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Unsure The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. No Results: The cohort consisted of 955 patients with a mean age of 58 years and two-thirds were female. The median time from ictus to CT scan was 93 minutes and the median time from signs and symptoms suggestive of SAH and TXA was 185 minutes.  Key Result: No superiority of TXA compared to usual care for patients with a subarachnoid hemorrhage. Primary Outcome: Good clinical outcome (mRS 0-3) 60% TXA vs 64% control Adjusted Odds Ratio (aOR) 0.86 ( 95% CI; 0.66 to 1.12) Secondary Outcomes:  Excellent clinical outcome (mRS 0-2): 48% TXA vs 56% control, aOR 73 (95% CI; 0.57 to 0.95) Ordinal shift of the mRS: No statistical difference All-cause mortality at 30 days (22%) and 6 months (26%): No statistical difference Adverse events: No statistical difference 1. Open label: The patient, investigators, and clinicians treating the patient were ALL aware of the patient’s inclusion in the treatment arm of the trial. This opens the study to significant biases. It’s unknown why the authors elected to pursue an open label study instead of providing the control group with a placebo, as this would have reduced the chances for bias significantly. 2. Patient Selection: It was not stated in the methods section that these were ED patients but it is likely that they were from the ED. They also did not explicitly say the patients were recruited consecutively 24/7/365. Twenty patients allocated to the TXA group did not receive treatment with nine of the twenty for “unknown” reasons. Patients were also excluded on the subjective assessment that death was imminent within 24 hours. These factors could have introduced some selection bias into the cohort of included patients. 3. Subgroup Analysis: The authors state that their findings show that routine use of TXA in spontaneous SAH cannot be recommended. However, the fact that their secondary outcome of excellent clinical outcome (mRS 0-2) was worse in the TXA group by a statistically significant amount is concerning. We need to be careful not to over-interpret subgroup analyses.

Date: March 4th, 2021 Guest Skeptic: Dr. Anand Swaminathan is an Assistant Professor of Emergency Medicine at St. Joseph’s Regional Medical Center in Paterson, NJ. Managing editor of EM:RAP and Associate Editor at REBEL EM. Reference:  Reuben A et al. The Use of Tranexamic Acid to Reduce the Need for Nasal Packing in Epistaxis (NoPAC): Randomized Controlled Trial. Ann Emerg Med 2021 Case: A 70-year-old man presents with epistaxis. He’s got a history of atrial fibrillation and hypertension. His medications include apixaban, metoprolol and perindopril. He states that the nosebleed started that morning all of a sudden. Vitals are; a blood pressure 145/73 mmHg, heart rate 64 beats/minute, and oxygen saturation 99% on room air. You apply direct pressure for 10 minutes, but the bleeding continues. You administer phenylephrine topically, reapply pressure and, consider the use of tranexamic acid (TXA). Background: Epistaxis is a common Emergency Department (ED) complaint with over 450,000 visits per year and a lifetime incidence of 60% (Gifford 2008, Pallin 2005). The majority of refractory hemorrhages are seen in the elderly and in more than two-thirds of the time no cause for the epistaxis is identified. Standard anterior epistaxis treatment consists of holding pressure, use of local vasoconstrictors, topical application of silver nitrate and placement of an anterior nasal pack. The most common vasoconstrictor used in the US is oxymetazoline.  Emergency physicians have multiple tools in the toolbox to address this condition. We covered the topic of epistaxis on SGEM#53: Sunday Bloody Sunday. That episode we discussed 11 questions concerning epistaxis. It is a great review on the management of nosebleeds. The episode included the Dundee protocol for adult epistaxis management from 2012. I searched and could not find an updated version. ED patients with epistaxis often fail conservative management and end up with anterior nasal packs which are uncomfortable. This is even more common in the group of patients who are taking antiplatelet agents or anticoagulants. In recent years, TXA has been added to many physicians’ armamentarium based on a few relatively small studies. We reviewed two  of these randomized control trials (RCTs) on the SGEM including the 2018 publication looking at using TXA in patients taking antiplatelet drugs. (SGEM#210). Some of these RCTs looking at TXA for epistaxis have also been reviewed on REBEL EM and other FOAMed sites. The results were encouraging. Topical TXA has minimal safety concerns and is relatively inexpensive. However, the studies did have a number of limitations including, being single centered, relatively small sample sizes and a lack of blinding. The SGEM structured critical review was skeptical of TXA for treating nosebleeds and had a conservative bottom line: Despite some limitations in this un-blinded trial, topical tranexamic acid appears to improve some patient important outcomes in patients who are taking antiplatelet medications who present with epistaxis. Clinical Question: Does the use of topical, intranasal TXA reduce the need for application of anterior nasal packing in ED patients with epistaxis who fail conservative management? Reference:  Reuben A et al. The Use of Tranexamic Acid to Reduce the Need for Nasal Packing in Epistaxis (NoPAC): Randomized Controlled Trial. Ann Emerg Med 2021 Population: Patients older than 18 years of age presenting with persistent epistaxis after local pressure and/or ice was applied to the bridge of the nose for at least 10 minutes. If bleeding persisted (continued presence of blood on the upper lip after wiping emanating from the nares) patients were treated with cotton wool dental roll soaked with a topical vasoconstrictor and inserted into the affected nostril for 10 minutes. If the bleeding persisted after the removal of the vasoconstrictor dental roll, they were enrolled in the trial. Exclusions: Hemodynamic unstable patients, epistaxis due to trauma, out-of-hospital packing, allergy to TXA, ENT thought should be excluded, nasopharyngeal malignancy, pregnancy, hemophilia, and inability or unwillingness to provide consent. Intervention: Tranexamic acid (TXA) 200 mg in 2 ml applied to a cotton wool dental roll (could packing be repeated once). Dental roll held in place for 10 minutes with pressure. The treatments were done by EM consultants, junior house officers, or emergency nurse practitioners. Control: Cotton wool dental roll soaked in sterile water. Dental roll held in place for 10 minutes with pressure Outcome: Primary Outcome: Use of anterior nasal packing (of any type) during the index ED visit regardless of any other additional treatments (intention to treat analysis) Secondary Outcomes: Hospital admission, need for blood transfusion, recurrent epistaxis, thrombotic events, hospital reattendance within 1 week. Authors’ Conclusions: “In patients presenting to an ED with atraumatic epistaxis that is uncontrolled with simple first aid measures, topical tranexamic acid applied in the bleeding nostril on a cotton wool dental roll is no more effective than placebo at controlling bleeding and reducing the need for anterior nasal packing.” Quality Checklist for Randomized Clinical Trials: 1. The study population included or focused on those in the emergency department. Yes 2. The patients were adequately randomized. Yes 3. The randomization process was concealed. Yes 4. The patients were analyzed in the groups to which they were randomized. Yes 5. The study patients were recruited consecutively (i.e. no selection bias). No 6. The patients in both groups were similar with respect to prognostic factors. Yes 7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes 8. All groups were treated equally except for the intervention. Yes 9. Follow-up was complete (i.e. at least 80% for both groups). Yes 10. All patient-important outcomes were considered. No 11. The treatment effect was large enough and precise enough to be clinically significant. No Results: The cohort consisted of 496 patients. The mean age was 71 years, slightly more male patients, 65% were taking anticoagulant medication, and 61% had hypertension. Key Result: No statistical difference in patients getting anterior packing between TXA and placebo Primary Outcome: Use of anterior packing Placebo 41.3% vs TXA 43.7% required packing (2.4% difference) Odds Ratio (OR) 1.107 (95% CI; 0.769 to 1.594; p=0.59) Secondary Outcomes:  No statistical difference in any of the secondary outcomes including recurrent epistaxis, hospital admission or blood transfusion Also, no statistical difference with a per-protocol analysis This is the largest trial and only double-blind study looking at topical TXA for epistaxis. The authors should be congratulated for successfully completing this multicentered study and getting it published. There are always limitations that need to be considered, even in very well-done studies. We will discuss five issues. 1. Patient Population: This is one of the major limitations to this study. It was a very select/narrow group of patients. There were 2,622 initially eligible but 2,126 (81%) were excluded. Almost 1/3 were excluded because a research nurse was unavailable. We understand that this is often a reality of doing research in an ED that is open 24/7/365. However, 29% of eligible patients were excluded for the reasons listed as “other”. What does that mean? Could it have introduced some subjectivity into excluding some patients but not others resulting in some selection bias? Also, when you drill down these are patients that have “failed” standard therapy of at least 10 minutes of pressure and/or ice on the bridge of their nose followed by another 10 minutes of anterior packing soaked in a vasoconstricting drug. In the US, the most common vasoconstrictor is oxymetazoline. It is unclear if one agent is superior to the other and thus, it’s unclear how this affects application of this evidence. The authors also excluded another 6% of patients if the emergency department was considered too busy. Was this objectively determined and if so how; wait times, length of stay, volume of patients, acuity of patients, or another metric? In addition, who made the decision that the department was too busy, EM consultant, junior house officer, nurse practitioner or the research assistant? Patients “expected” to be seen by the ENT in-patient team for specialist treatment were also excluded. They also did not include pregnant patients which is an example of women being under-represented in clinical trials. All these issues lead to a very narrow cohort of patients with epistaxis and some of these could have introduced an element of selection bias. 2. Anticoagulation: A super majority of patients included in the study (65%) were taking anticoagulant medication. There were no additional details given in the manuscript as to what type of anticoagulants the patients were using: DOACs (factor Xa inhibitors or direct thrombin inhibitors), vitamin K antagonists (warfarin), or low molecular weight heparin (enoxaparin). Also, we are unsure if the term anticoagulation includes antiplatelet drugs (ASA, clopidogrel, and ticagrelor)? The high proportion of select patients on anticoagulation with epistaxis who failed conservative treatment and packing with a topical vasoconstrictor could explain why no statistical difference was found between the intervention group (TXA) and the placebo group. 3. Dosing: The initial dose of TXA used was 200mg. The clinician could repeat the dose once if the bleeding persisted. This is different from the 500mg dose used in the previous TXA trials.

Date: February 18th, 2021 Guest Skeptic: Dr. Chris Bond is an emergency medicine physician and assistant Professor at the University of Calgary. He is also an avid FOAM supporter/producer through various online outlets including TheSGEM. Reference: Brichko et al. Rapid Administration of Methoxyflurane to Patients in the Emergency Department (RAMPED): A Randomised controlled trial of Methoxyflurane vs Standard care. AEM Feb 2021. Case: A 46-year-old female presents to the emergency department (ED) with sudden onset, severe right flank pain. She is pacing around at triage in tears and says she has a history of kidney stones. She is asking for something to help with her pain, but the department is very busy, and it will be some time before she can get into a treatment space. Background: Pain is the primary reason patients present to the emergency in many cases (1-6).  Oligoanalgesia is the term used to describe poor pain management through the under use of analgesia (7-11).  Effective pain management is an important indicator of the quality of patient care (12). Multiple factors have been thought to contribute to oligoanalgesia (overcrowding, language barriers, age, gender, ethnicity, insurance status) (13-16).  Delays in providing adequate analgesia leads to poorer patient outcomes, prolonged ED length of stay and reduced patient satisfaction (17, 18). It can take a long time for someone in severe pain to receive an analgesic in the ED. Previous research in Australia has shown that the median time can be between 40-70 minutes for analgesia administration (19, 20). Delays are not unique to Australia and a study done in the USA reported a mean of 116 minutes for patients presenting to the ED with pain to receive analgesia (21). To minimize delays, different strategies have been implemented to address the problem (advanced protocols, provision of oral analgesics at triage, and the use of novel analgesic agents that do not require intravenous access) (22). Recently, there has been increased interest in using methoxyflurane (Penthrox), an inhaled non-opioid analgesic, to provide rapid short-term analgesia (23, 24).  In Australia, Methoxyflurane has been widely used at sub-anesthetic doses for analgesia in the pre-hospital setting since 1975. Its use has become more global in recent years and at low doses, it has a very reassuring safety profile. Furthermore, there have been no reports of addiction or abuse related to these inhaler devices (25-28). The majority of studies of methoxyflurane for pain focus on traumatic pain, this study aimed to assess its effectiveness in treatment of both traumatic and non-traumatic pain. Clinical Question: What is the effectiveness of methoxyflurane versus standard care for the initial management of severe pain among adult ED patients? Reference:  Brichko et al. Rapid Administration of Methoxyflurane to Patients in the Emergency Department (RAMPED): A Randomised controlled trial of Methoxyflurane vs Standard care. AEM Feb 2021. Population: Adult patients aged 18-75 years with severe pain defined as an initial Numerical Rating Scale (NRS) pain score greater than or equal to 8. Exclusion criteria: Transferred patients, HR <40 or >140 bpm, SBP <90 or >180 mmHg, RR <6 or >36/min, GCS <15, possible ACS, headache, pregnancy, breastfeeding, known renal or hepatic failure, previous malignant hyperthermia, known sensitivity to fluorinated anesthetics, or agitated/aggressive per nursing staff. Intervention: Inhaled Methoxyflurane 3 mL Comparison: Standard analgesic care which could include paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and oral oxycodone or IV morphine Outcome: Primary Outcome: Proportion of patients that had at least a 50% reduction in their pain score at 30 minutes Secondary Outcomes: Median pain score at 15, 30, 60 and 90 minutes, and the proportion of patients that achieved a >2 point drop in their pain score on the NRS. Additional secondary outcomes included data pertaining to adverse effects, both minor and major. Dr. Lisa Brichko This is an SGEMHOP episode which means we have the lead author on the show. Dr Lisa Brichko is an emergency physician working in a combination of private and public tertiary hospital Emergency Departments in Melbourne Australia. She has authored 24 peer-reviewed emergency medicine research publications primarily focusing on projects promoting safe and efficient patient care. This interest in improving the quality of care we can provide our emergency department patients has previously been developed through undertaking a Masters Degree in Health Management, attaining Associate Fellowship with the Royal Australasian College of Medical Administrators and her current role as Quality Improvement Manager on the emergency department leadership team for Cabrini Hospital. Authors’ Conclusions: “Initial management with inhaled methoxyflurane in the ED did not achieve the pre-specified substantial reduction in pain, but was associated with clinically significant lower pain scores compared to standard therapy.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Yes The patients were adequately randomized. Yes The randomization process was concealed. Unsure The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). No The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). Yes All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. Unsure Key Results: They randomized 121 patients into the RAMPED study and data was available for analysis in 120 patients. The mean patient age was 42 years and 51% were female. 84% of patients were enrolled during daytime hours (0700-1800). The vast majority of patients arrived by private transport with only 4% arriving by ambulance. There was no statistical difference in the primary outcome between methoxyflurane and standard care. Primary Outcome: Reduction of pain score by >50% at 30 minutes 6 (10%) of patients in the methoxyflurane arm and 3 (5%) in the standard care arm (p=0.49) Hazard ratio (HR) for the favourable outcome was 1.07 (95% CI: 0.75-1.53, p=0.70) Secondary Outcomes:  The administration of methoxyflurane was associated with a significant reduction in pain score at all time points. See the show notes for table. The median time to rescue analgesia was longer in the methoxyflurane arm at 66 minutes compared to 46 minutes in the standard therapy arm (p=0.024) There were no serious adverse effects that could be attributed to the intervention and median ED LOS was similar between the two groups. We have ten nerdy questions for Lisa to help us better understand her study. Listen to her respond to each question on the SGEM podcast. 1. Convenience Sample: This was a convenience sample when research assistants were available. Do you think this could have impacted the results and if so, in what way? 2. Arrival: The vast majority (96%) of included patients in the cohort arrived by private vehicle. Only 4% of patients were brought in by ambulance. This number seems low to us. What this surprising to your team? Do you think this low number limits the generalizability of your results? 3. This One Goes to Eleven: Different outcome measures in pain trials have been used (29). Why did you choose an 11-point numerical ratings scale (NRS) for pain rating over other options (eg. Visual analogue scale)? 4. Age: One of your exclusion criteria was age. Why did you decide to exclude patients younger than 18 years of age and also those >75 years of age? There is evidence that children and older adults are at more risk for oligoanalgesia. 5. Hemodynamics: Another exclusion for your study was hemodynamic instability. This was defined as a heart rate < 40 or > 140 beats/min or a systolic blood pressure < 90 or> 180 mm Hg, I did not think methoxyflurane had a clinically significant impact on HR and BP (30). 6. Outcome: You measured the NRS up to 90 minutes. Would measuring time points beyond 90 minutes be useful in order to see if patients did not have adequate analgesia after 90 minutes? 7. Blinding: You did not have an active or placebo control (sham) in an attempt to blind this trial. All clinicians and participants were aware of group allocation. This could have biased the study. We understand the ethical concerns about using a placebo control (inhaled 0.9% saline) for patients with painful conditions. Did you consider having inhaled nitrous oxide as an active comparator? 8. Cost: Cost can be an important factor when considering a treatment modality in the ED. We say that with IV acetaminophen it was priced too high for broad adaptation in the USA. Do you know what the cost of methoxyflurane is compared to standard care? 9. Malignant Hyperthermia: Methoxyflurane is a volatile anaesthetic agent. It has the potential to trigger malignant hyperthermia. There has apparently only been only one incident of MH after administration in Australia (31).  Regardless, methoxyflurane is still contraindicated in those individuals thought to at risk for malignant hyperthermia (32). How concerned should we be about using this medication, and do you need to stock dantrolene because of the risk? 10. Aerosolizing: We are still in a global pandemic. Is there any concern to using this inhaler during COVID19?