The Skeptics Guide to Emergency Medicine

Date: May 21st, 2021 Guest Skeptic: Dr. Lauren Westafer an Assistant Professor in the Department of Emergency Medicine at the University of Massachusetts Medical School – Baystate. She is the cofounder of FOAMcast and 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 an Associate Editor for the NEJM Journal Watch Emergency Medicine. Reference: Varner et al. A randomized trial comparing prescribed light exercise to standard management for emergency department patients with acute mild traumatic brain injury. AEM May 2021 Case: A 32-year-old female presents with headache after a low-speed motor vehicle collision as a restrained driver. She was ambulatory on scene. The patient is not anticoagulated, has no midline neck pain, and no evidence of other injuries. She is generally well appearing without any deficients on neurological examination, given her minor mechanism, and normal examination no imaging or further testing is required. You tell her you believe she has a concussion. Background: Concussions or mild traumatic brain injury (mTBI) are commonly diagnosed in the Emergency Department (ED). Most patients recover within the first week; however, 15-30% of patients develop persistent post-concussive symptoms. Historically, cognitive and physical rest have been recommended following the diagnosis of mTBI and patients have been advised to resume exercise only once symptoms have abated. Recent studies have challenged this dogma of "rest is best" with one multicenter study finding that early return to physical activity within a week of injury was associated with an improvement in time to symptom reduction. One of the issues that comes up with minor head injuries is do we need to get advanced imaging. We looked at the Canadian CT Head Rule (CCHR) published by Dr. Ian Stiell in the Lancet 2001 on SGEM#106. You can find this clinical decision instrument on MDCalc. The SGEM has also covered the issue of getting CT scans in pediatric patients with minor head injuries. That used the PECARN data which has a protocol for children less than two years of age and those older than two years of age. That SGEM#112 episode on pediatric concussions was covering a study that asked if there is a benefit to recommending strict rest after a child has a concussion. The bottom line from that episode was that in children with concussion, two days of rest followed by a gradual return to activity is preferred over five days of rest followed by a gradual return to activity. The longer strict rest period appears to cause more post-concussive symptoms. We have also looked at the diagnostic accuracy if the CCHR in patients 65 years of age or older in predicting clinically important brain injuries (SGEM#266). The published study opened the door for reducing the number of unnecessary head CTs in this cohort of patients, but further high-quality prospective studies are required prior to clinical application. There is limited information on the best strategy for preventing post-concussion syndrome (PCS). Clinical Question: Are patients presenting to the ED with mild concussion who are prescribed light exercise less likely to develop post-concussive syndrome at 30 days compared with those given standard discharge instructions? Reference: Varner et al. A randomized trial comparing prescribed light exercise to standard management for emergency department patients with acute mild traumatic brain injury. AEM May 2021 Population: Adults 18-64 years old presenting to the ED with a mild TBI. This was defined as a direct blow to body with force transmitted to the head resulting in somatic, cognitive, emotional, or behavioral or sleep symptoms within the prior 48 hours. Exclusions: Patients with acute intracranial injury, multisystem injuries preventing light exercise, GCS <15 at time of discharge, intoxication at time of discharge, or inability for telephone follow up Intervention: Standardized discharge instructions that included 48 hours of rest and then gradual return to usual activity with a prescription for 30 minutes of light exercise daily (ex walking) Comparison: 48 hours of rest and then gradual return to usual activity but instructed not to exercise until symptoms had resolved or advised to do so by a medical provider Outcomes: Primary Outcome: Proportion of patients with post-concussive syndrome at 30 days, defined as the presence of three or more symptoms on the Rivermead Post-concussion Symptoms Questionnaire (RPQ) at 30 days Secondary Outcomes: Change in RPQ from baseline to 7, 14, and 30 days after the initial ED visit; number of missed days of school or work; and repeat visits to a health care provider. Dr. Catherine Varner This is an SGEMHOP episode which means we have the lead author on the show. Dr. Catherine Varner is an emergency physician and clinician scientist at the Schwartz / Reisman Emergency Medicine Institute at Mount Sinai Hospital in Toronto and Assistant Professor in the Faculty of Medicine at the University of Toronto. Her research areas are in both concussion and obstetrical emergencies. This trial used the Rivermead Post-concussion Symptom Questionnaire (RPQ). It is a self-report scale to measure the severity of post-concussive symptoms following a mild traumatic brain injury. It asks participants to compare their symptoms at the time of assessment to before the injury on a scale of 0 to 4, where 0 means the symptom is not experienced at all, 1 is no more of a problem and 4 is a severe problem. The questionnaire asks about 16 defined symptoms and 2 undefined symptoms, and has been used in the emergency department setting and over the telephone. Authors’ Conclusions: “In this trial of prescribed early light exercise for acute mTBI, there were no differences in recovery or health care utilization outcomes. Results suggest that early light exercise may be encouraged as tolerated at ED discharge following mTBI, but this guidance is not sufficient to prevent PCS.” 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). 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. Unsure Follow-up was complete (i.e. at least 80% for both groups). No All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. No Results: They enrolled 367 patients with a median age of 32 years 57% were female. The most common mechanism of injury was a fall (32%) followed by bike/motor vehicle (28%). One-third of included patients had a history of anxiety and more than one-quarter had a history of depression. A third of patients had a history of a previous concussion. Key Result: No statistical difference between the light exercise group and the comparison group.  Primary Outcome: Proportion of patients with PCS at 30 days 13.4% in the control group vs 14.6% in the intervention group Absolute difference of 1.2% (95% CI; −6.2 to 8.5). Secondary Outcomes:  The median change of RPQ scores, number of return visits to a healthcare provider, number of missed days of work or school were not different between groups. There were more unplanned return ED visits within 30 days in the control group (9.9%) compared with the intervention group (5.6%); however, this difference was not statistical significance. We asked Dr. Varner five questions to better understand her research publication. Listen to the SGEM podcast to hear her responses. 1. Lack of Blinding – Both the physician and the patient knew the group allocation. Did they know the hypothesis of the study? It would have been good to get some baseline data on what the physicians and patients thought was best (rest or early light exercise) to try and control for any pre-conceived notions that could have influenced the results. 2. Adherence to the Assigned Groups – Participants in the control group reported 30 minutes of light exercise at 7 days and those in the light exercise group reported 35 minutes – a similar relationship was found at all measured time points. This suggests that adherence in the intervention group (where 30 minutes of exercise 5x/week was advised after the first 48 hours) was quite low. It’s doubtful that a difference of 5 minutes of exercise over the course of a week (or 30 days) would have a measurable impact. Thus, we wouldn’t expect a difference between groups if there was no difference in light exercise between groups. 3. Potential Biases – Participants self-reported how frequently and for how many minutes they exercised on surveys at 7, 14, and 30 days. This could have introduced some reporting bias. Without  diary entries or other near real-time entries, it’s difficult to tell whether participants were reporting accurately or over-or-under reported. Speaking of bias, nearly 20% of potentially eligible patients were missed. This could have introduced some selection bias. Without having information on those who were ‘missed’ for inclusion in this trial, it’s impossible to know if these patients were somehow different than those who were ultimately enrolled in the trial. 4.

Date: May 6th, 2021 Guest Skeptic: Dr. Daniel Schwerin is employed with Prisma Health-Upstate as a clinical assistant professor, emergency medicine GME director for emergency medical services and medical director for several local EMS agencies and has lectured on prehospital stroke management. Reference: Fatima et al. Mobile stroke unit versus standard medical care in the management of patients with acute stroke: A systematic review and meta-analysis. International Journal of Stroke 2020 Case: A 70-year-old man develops sudden right-sided weakness beginning shortly after breakfast and his partner appropriately calls emergency medical services (EMS). Their local EMS service arrives quickly with a conventional ambulance. He has heard about these special ambulances with CT Scanners and wonders if that will make an important difference for his partner. Background: We have discussed stroke so many times on the SGEM. It is one of the five most popular topics like TXA, PE, POCUS and ketamine. Justin Morgenstern from First10EM and I recently downgraded the NNT website recommendation for tPA in acute ischemic stroke to “yellow”. A yellow recommendation means the benefits and harms are unclear due to the uncertainty in data. But something that often comes up when discussing stroke treatment is we need to go fast because time is brain. The term “time is brain” was coined by Dr. Camilo Gomez back in 1993. He modified his position in 2018 and said: “It is no longer reasonable to believe that the effect of time on the ischaemic process represents an absolute paradigm. It is increasingly evident that the volume of injured tissue within a given interval after the estimated time of onset shows considerable variability in large part due to the beneficial effect of a robust collateral circulation.” We never did have high-quality evidence to support the position that treating stroke patients earlier was better. All we had was an association because there were no RCTs that randomized stroke patients into getting thrombolytics early or late. This means there could have been unmeasured confounders responsible for the observed effect. The largest placebo controlled RCT looking at tPA for acute ischemic stroke was IST-3 which was covered on SGEM#29. There were several serious problems with that trial including: Largely unblinded trial (91%) Stopped early Self-reported outcome by telephone or mailed questionnaire No superiority for primary outcome 4% absolute increase in early mortality Another interesting point about IST-3 is the subgroup analysis did not support the claim that time was brain. There was no statistical difference between the <3hrs, 3-4.5hrs and >4.5hrs. However, the point estimate favored tPA in <3hrs, then placebo between 3-4.5hrs and then back to tPA in >4.5hrs? You also need to look very carefully at the figure to see they used the 99% confidence interval instead of the standard 95% confidence intervals. If calculating the Odds Ratio for the 3-4.5hr group you find it is statistically significant favouring the placebo group. Clinical Question: Does a mobile stroke unit (MSU) with earlier imaging and delivery of tPA improve outcomes, or is the downstream effect of improved resources at a comprehensive stroke center that improves outcomes for patients with strokes? Reference: Fatima et al. Mobile stroke unit versus standard medical care in the management of patients with acute stroke: A systematic review and meta-analysis. International Journal of Stroke 2020 Population: This was a systematic search that found 11 articles that were either randomized controlled trials (RCTs), retrospective or prospective studies that compared the clinical outcomes among patients treated in either a mobile stroke unit or through conventional care/standard medical care for the acute stroke. Exclusions: Case–control studies, case series, and case reports Intervention: MSU that is a specialized ambulance equipped with a CT-scanner, point-of-care laboratory, and thrombolysis is started immediately within the MSU vehicle. Comparison: Conventional care that consists of transferring to the patient the emergency department or specialized stroke centres and given thrombolysis in-hospital according to the imaging report. Outcome: Primary Outcomes: Neurologic outcome as defined by modified Rankin scale (mRS) score at day 7 and day 1 post treatment. Good neurologic outcome was an mRS of 0-2 while a poor neurologic outcome was an mRS of 3-6 Secondary Outcomes: All-cause mortality, stroke related-neurological death, other adverse events, and mean time gains Authors’ Conclusions: “Our results corroborate that patients treated in mobile stroke unit lead to short-term recovery following acute stroke without influencing the mortality rate. Further prospective studies are needed to validate our results.” Quality Checklist for Therapeutic Systematic Reviews: The clinical question is sensible and answerable. Unsure The search for studies was detailed and exhaustive. Yes The primary studies were of high methodological quality. No The assessment of studies were reproducible. Yes The outcomes were clinically relevant. No There was low statistical heterogeneity for the primary outcomes. No The treatment effect was large enough and precise enough to be clinically significant. Unsure Results: Eleven publications (seven RCTs and four observational studies) were included in this SRMA with a total of 21,297. Most patients (97%) were from Germany. There were 28% (n=6,065) in the MSU group and 72% (n=15,232) in the conventional care (CC) group. The mean age was 70 years and the mean NIHSS score was 9.8 MSU and 8.4 CC. Key Result: Better neurologic outcome was not observed at one day post treatment but was at seven days in patients treated by the MSU compared to conventional care. Primary Outcomes: Good neurologic outcome day 7: OR 1.46 (95% CI; 1.306–2.03, p=0.02) 1 RCT (23%) and 2 Obs (77%) n=885 Good neurologic outcome day 1: OR 1.18 (95% CI; 0.88-1.57, p=0.26) 1 RCT (16%) and 1 Obs (84%) n=758 Secondary Outcomes: There was no statistical difference in mortality, stroke related death or other serious adverse events. Patients were treated 13 min faster with MSU compared to CC which was statistically significant. Mortality: OR 0.98 (95% CI; 0.81–1.18, p=0.80) Stroke-related or neurological death (OR: 1.37, 95% CI: 0.81–2.32, p=0.24) Stroke related neurological deficits: OR 1.37 (95% CI; 0.81–2.32, p=0.24) Other serious adverse events: OR 0.69 (95% CI; 0.39–1.20, p=0.19) Mean time-to-treatment MSU 62 min vs 75 min CC; mobile stroke unit compared to conventional care (62.0 min vs. 75.0 min; p=0.03  1. External Validity: The majority (97%) of the patients included in the SRMA were from Germany. Europe has a different pre-hospital system than North America. It is unclear if these results could be applied to our practice. Only 618 patients out of the 21,297 patients were from studies done in the USA. 2. GIGO: This is the concept of garbage-in, garbage-out. It means if you combine observational studies which are of lower methodological quality with higher-quality RCTs, mashing them all up into a meat grinder does not get you closer to the “truth”. A case could be made for whether it was even appropriate to meta-analyze some of the data. The secondary outcomes of time to scan and treatment all had an I2 test of heterogeneity of 99%. While they did appropriately use a random effects model for the analysis that level of heterogeneity it would be reasonable to suggest that the data should not have been combined. Looking at the primary outcomes there were only three studies meta-analyzed for the seven-day result and more than ¾ of the data came from two observational studies. The heterogeneity was also moderate at 44% using the I2 metric. It was even worse for the one-day outcome where there were only two studies included with more than 80% of the data coming from the one observational study. I grew up on an apple farm. To make great apple pies you need great ingredients. A cow pie is something that comes out of the back of a cow and when it lands on the ground it is about the size of a pie. Adding a cow pie to an apple pie does not make the apple pie taste any better. Combining observational studies to RCTs does not increase my confidence in the results.  3. Primary Outcome: They had two primary outcomes and SGEM listeners know…there can be only one, primary outcome. However, the outcomes were at one- and seven-days post treatment. This is a very short time frame for stroke studies. Usually, the primary outcome for thrombolytic use in acute ischemic stroke studies is at 3 or 6 months. We know from the NINDS-Part 1 trial published in 1995 that there was not statistical difference in their primary outcome (an improvement of 4 points over base-line values in NIHSS score or the resolution of the neurologic deficit within 24 hours of the onset of stroke symptoms). 4. Misleading: While the study did include over 20,000 patients, less than 1,000 were meta-analyzed for the two primary outcomes. Just reading the abstract could give the impression that this was a much bigger study for the summary statistic odds ratio (OR) of good neurologic outcome. 5. Cost: This is an important aspect to consider. MSU ambulances are much more expensive to buy (initial startup price tag around 1 million dollars) and operate (cost of a critical care paramedic/nurse/CT tech along with having a neurologist on standby to review the head CT) than regular ambulances. If we do not have high-quality evidence that giving thrombolytics 13 minutes earlier makes a patient-oriented outcome difference then the expense cannot be justified.

Date: May 7th, 2021 Guest Skeptic: Dr. Ryan Stanton is a community emergency physician with Central Emergency Physicians in Lexington, KY. He is on the Board of Directors for the American College of Emergency Physicians and host of the ACEP Frontline Podcast. He is an EMS medical director with Lexington Fire/EMS as well as the AMR/NASCAR Safety Team. Reference: Shah and Mitra. Use of Corticosteroids in Cardiac Arrest - A Systematic Review and Meta-Analysis. Crit Care Med Feb 2021 Case: A 58-year-old male has a witnessed cardiac arrest while admitted to the observation unit for a chest pain evaluation. CPR is initiated and a hospital rapid response team is called. The resuscitation team arrives and ACLS protocols are continued. The issue of whether corticosteroids should be administered is brought up during the code. Background: Cardiac arrests have  high morbidity and mortality rates both in-hospital cardiac arrests (IHCAs) and out of hospital cardiac arrests (OHCAs). It is estimated that the survival to discharge for an IHCA is approximately 18% with only 10% for OHCAs. This contrasts with what the public sees watching CPR being done on TV. Survival on screen is four to five times higher than reality, according to one study (see graphic). Improving outcomes for patients with cardiac arrests has been an ongoing challenge in pre-hospital and in hospital medicine. We have discussed many aspects of such care on the SGEM including: Therapeutic hypothermia (SGEM#54, SGEM#82, SGEM#183 and SGEM#275) Epinephrine (SGEM#64 and SGEM#238) IV vs IO Access (SGEM#231) Supraglottic Airways (SGEM#247) Crowd Sourcing CPR (SGEM#143 and SGEM#306) Mechanical CPR (SGEM#136) We understand more physiologic changes that take place following cardiac arrest and there have been several studies looking at the potential role of corticosteroids in the intra-arrest timeframe. SGEM#50 looked at a RCT published in JAMA 2013 looking to see if a vasopressin, steroids, and epinephrine (VSE) protocol for IHCAs could improve survival with favorable neurologic outcome compared to epinephrine alone. That RCT had 268 patients and demonstrated a better odds ratio for ROSC and survival to discharge with good neurologic outcome. The SGEM bottom line at the time was that the results were very interesting, but a validation study should be done to try and replicate the results. I have not seen a validation study published. We know that epinephrine can increase ROSC, survival to hospital, and even survival to hospital discharge based on the Paramedic 2 Trial. Unfortunately, epinephrine was not superior to placebo for the patient-oriented outcome of survival with good neurologic outcome. Corticosteroids have been suggested as a possible therapy in these clinical situations. However, there is an old RCT that looked at dexamethasone in OHCA and it failed to demonstrate an improvement in survival to hospital discharge (Paris et al AEM 1984). A SRMA published in 2020 on the use of steroids after cardiac arrest reported an increase in ROSC and survival to discharge but was limited by the availability of adequately powered high-quality RCTs (Liu et al JIMR 2020). Clinical Question: Does the use of corticosteroids impact neurologic outcomes and mortality in patients with a cardiac arrest? Reference: Shah and Mitra. Use of Corticosteroids in Cardiac Arrest - A Systematic Review and Meta-Analysis. Crit Care Med Feb 2021 Population: Randomized controlled trials and comparative observational studies of patients with in or out of hospital cardiac arrests Exclusions: Any single arm studies, case reports/ series, narrative reviews, and studies irrelevant to the focus of this article. Intervention: Corticosteroids as adjunct therapy in cardiac arrest Comparison: Patients that did not receive corticosteroids in cardiac arrest Outcome: Primary Outcomes: Good neurologic outcome (measured using the Glasgow-Pittsburgh Cerebral Performance Category score), survival to hospital discharge, and survival at greater than or equal to 1 year Secondary Outcomes: Return of spontaneous circulation (ROSC), Intensive Care Unit (ICU) and hospital length of stay (LOS), duration of vasopressor and inotropic treatment, and blood pressure (systolic blood pressure, diastolic blood pressure, and mean arterial pressure [MAP]) during CPR and after ROSC. Authors’ Conclusions: “The study found that there are limited high-quality data to analyze the association between corticosteroids and reducing mortality in cardiac arrest, but the available data do support future randomized controlled trials. They did find that corticosteroids given as part of a vasopressin, steroids, and epinephrine regimen in in-hospital cardiac arrest patients and for post resuscitation shock did improve neurologic outcomes, survival to hospital discharge, and surrogate outcomes that include return of spontaneous circulation and hemodynamics. They found no benefit in in-hospital cardiac arrest or out-of-hospital cardiac arrest patients receiving corticosteroids only; however, a difference cannot be ruled out due to imprecision and lack of available data.” Quality Checklist for Therapeutic Systematic Reviews: The clinical question is sensible and answerable. Yes The search for studies was detailed and exhaustive. Yes The primary studies were of high methodological quality. No The assessment of studies were reproducible. Yes The outcomes were clinically relevant. Yes There was low statistical heterogeneity for the primary outcomes. No The treatment effect was large enough and precise enough to be clinically significant. No Results: Seven studies were included in this SRMA (5 RCTs and 2 observational studies). Total cohort was 6,199 with 90% coming from one retrospective study from Taiwan. Key Result: Statistical difference in good neurologic outcome and survival to hospital discharge with steroids but not survival at 1 year or longer. Primary Outcomes:  Good neurologic outcome: 4 RCTs RR 2.85 (95% CI; 1.39-5.84) Survival to hospital discharge: 4 RCTs RR 2.58 (95% CI; 1.36-4.91) Survival at greater than or equal to 1 year: 1 RCT RR 2.34 (95% CI; 0.83–6.54) Secondary Outcomes: ROSC: 4 RCTs RR 1.32 (95% CI; 1.16–1.50) ICU and Hospital LOS: 1 RCT No statistical difference Duration of vasopressor and inotropic treatment: No studies Hemodynamic: 2 studies in supplemental material Safety: 3 studies with no statistical differences 1. Few Studies – Despite cardiac arrest being a common event with high morbidity and mortality only five RCTs with a total of 530 patients could be found searching the world’s literature on this topic that met the inclusion and exclusion criteria. You would think that there would be much more data to help inform our care. 2. High Risk of Bias – Of the five trials that they could find to include only four could be assessed for bias using the Cochrane Risk of Bias Assessment 2 Tool. Three out of the four were at high-risk of bias. This further threatens the validity of the findings and the strength of the conclusions that can be drawn. 3. Single Research Group – When you drill down into this SRMA you find that 92% of the RCT data for IHCA comes from two trials by the same author group in Greece. One trial was published in 2008 and the other in 2013. This can raise the issue of external validity to other healthcare systems in 2021. 4. VSE Protocol – We can drill down even farther into the data and say that the largest RCT (n=268) was the multi-centered trial from Greece. This is the trial we reviewed on SGEM#50 that used vasopressin, steroids, and epinephrine not steroids alone. In addition, it was only for IHCA not for OHCA. So, we don’t have any RCTs to answer the question of whether steroid alone used during cardiac arrest (IHCA or OHCA) result in an improved patient-oriented outcome (POO). 5. Reproducibility Crisis – Nature published a survey by Baker in 2016 asking more than 1,500 scientists if there was a reproducibility crisis in science and 90% said yes and only 3% said no. The Greek study from 2013 has not been replicated in over eight years as far as we know. There are too many examples of one and done in medicine. Think of tPA for stroke. There is only one placebo-controlled trial in <3hours (NINDS-I 1995) that claims efficacy for its primary outcome and only one in 3-4.5hrs (ECASS-III 2008). Neither of these trials has been replicated and look at the debates were are still having due to a lack of high-quality evidence. Comment on Authors’ Conclusion Compared to SGEM Conclusion:  Overall, we agree with the findings of the authors and feel they made a realistic evaluation and conclusions, based on the available data. SGEM Bottom Line: We have no evidence to support the use of corticosteroid in OHCA and only very weak evidence for corticosteroids in IHCA as part of a VSE protocol. Case Resolution: ROSC is achieved, and the patient is transferred to the ICU. The patient eventually went to the cath lab where an LAD stent was placed. Resuscitation care included targeted temperature management and a newly established VSE protocol. The patient full-recovered and was discharged home a few days later to continue cardiac rehab. Clinical Application: Physicians will have different levels of evidence to adopt a new treatment into their clinical practice. It would be reasonable to consider using corticosteroids as part of a VSE protocol in patients with IHCA but certainly should not be mandated or made into a quality metric.  This is because we only have one relatively small RCT from Greece that was of low risk of bias but has never been replicated. What Do I Tell the  Patient? Your loved one experienced cardiac arrest. We got his heart going again and he is doing better.

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?