The Skeptics Guide to Emergency Medicine

Date: July 1st, 2021 Guest Skeptic #1: Dr. Chris Carpenter is Professor of Emergency Medicine at Washington University in St. Louis and a member of their Emergency Medicine Research Core. He is a member of the SAEM Board of Directors and the former Chair of the SAEM EBM Interest Group and ACEP Geriatric Section. He is Deputy Editor-in-Chief of Academic Emergency Medicine. He is also Associate Editor of Annals of Internal Medicine’s ACP Journal Club and the Journal of the American Geriatrics Society, and he serves on the American College of Emergency Physician’s (ACEP) Clinical Policy Committee. Dr. Carpenter also wrote the book on diagnostic testing and clinical decision rules. Reference: Musey et al. Guidelines for reasonable and appropriate care in the emergency department (GRACE): Recurrent, low-risk chest pain in the emergency department. AEM July 2021 This is an extra special SGEM. It is a combo of an SGEM Xtra and an SGEMHOP. The Society of Academic Emergency Medicine (SAEM) has decided to publish its own clinical practice guidelines (CPGs). They are called Guidelines for Reasonable and Appropriate Care in the Emergency Department (GRACE). This episode will review the GRACE-1 guideline looking at low-risk recurrent chest pain. Because this is a new initiative by SAEM, I interviewed Dr. Chris Carpenter about these new GRACE guidelines. Dr. Chris Carpenter Listen to the SGEM podcast to hear him answer five background questions about these new CPGs. Who came up with the idea of doing CPGs? Why do we need more guidelines? Walk us through the GRACE process? Why pick recurrent, low-risk chest pain to be the first CPG? What do you hope to achieve with these CPGs Guest Skeptic #2: Dr. Suneel Upadhye is an Associate Professor of Emergency Medicine & Clinical Epidemiology at McMaster University. He is a founding member of the Best Evidence in Emergency Medicine (BEEM) program. Suneel is also the inaugural Research Lead for the EM Researchers of Niagara, which is a novel community-based EM research group within Niagara region, Canada. He is also a Guidelines Methodologist within CAEP and the SAEM GRACE groups. Case: You are seeing a patient who has returned to the emergency department (ED) with recurrent chest pain. It is their fourth visit in the last twelve months.  He has had his chest pain for approximately three to four hours now and is not classic for ischemic symptomatology.  His initial high-sensitivity (hs) troponin is negative, and his ECG is unremarkable.  In reviewing his records, you note that he has undergone significant cardiac testing in the recent past, which was unremarkable. This included a normal exercise stress test and CCTA 18 months ago.  You also note that he has an underlying anxiety disorder, which is being treated and followed by his family physician.   Background: This new SAEM GRACE initiative is committed to using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system, GRADE was pioneered at McMaster University, in creating rigorous, transparent, and trustworthy guidelines on common clinical problems for emergency medicine (EM) physicians that are not always directly studied in EM research activities. The steering group/panelists explored many different potential questions, and voted on the top eight, that were then reviewed in systematic fashion; evidence was rated using GRADE methods, and then final recommendations were made using the GRADE Evidence-to-Decision framework (Upadhye et al CJEM 2021 and Courtney and Lang AEM 2021).  The Methods team sought initial GRADE training, then shared that learned expertise with the question groups, many of whom were relative novices in guideline methodology. After two years, a comprehensive document is being published that answers the key diagnostic dilemmas in recurrent chest pain patients who have had recent normal cardiac investigations, to streamline testing and ED length of stay without risk of major adverse coronary events (MACE) at 30 days. Clinical Question: What are the recommendations for managing patients with recurrent, low-risk chest pain in the ED? Recurrent Chest Pain: Patients who have had a previous visit to an ED with chest pain that led to a diagnostic protocol for its evaluation that did not demonstrate evidence of acute coronary syndrome (ACS) or flow-limiting coronary stenosis.  This included two or more ED visits for chest pain in a 12-month period. Low-Risk: This was defined by HEART score <4 points (and other scores validated in the ED setting such as the HEART pathway or TIMI score) for disease-related poor outcomes within 30 days all of which require an electrocardiogram (ECG) for risk stratification. Expedited: This was considered a period of three to five days. There is no 100% guaranteed safety outcome for patients with low-risk chest pain with respect to 30-day MACE, but the “warranty” on negative high-sensitivity troponin test results (assay- and institution-dependent), either single or double tests “x” hours apart, should be reassuring to ED physicians to discharge such patients with reasonably expedited follow-up. This 30-day MACE risk is even lower when there is a negative CCTA result (ie. no coronary stenosis) in the preceding two years, or less than 50% obstructing stenosis on prior angiography in preceding five years.  Finally, in patients in whom depression/anxiety might be a driver of recurrent ED visits for low-risk chest pain, use of screening tools in the ED for mood disorder detection and subsequent referral for mental health supports may be warranted. Reference: Musey et al. Guidelines for reasonable and appropriate care in the emergency department (GRACE): Recurrent, low-risk chest pain in the emergency department. AEM July 2021 Authors’ Conclusions: “These guidelines outline and summarize the evidence and strength of GRACE recommendations regarding eight priority questions of interest to emergency clinicians, other healthcare professionals, patients, and policymakers with regard to the evaluation and management of patients with recurrent, low-risk chest pain seen in the ED. Direct evidence for the selected priority questions in this population is lacking, which highlights areas which will benefit from further robust prospective investigation in this specific population.” Quality Checklist for a Diagnostic Study: The study population included or focused on those in the emergency department? Yes An explicit and sensible process was used to identify, select and combine evidence? Yes The quality of the evidence was explicitly assessed using a validated instrument? Unsure An explicit and sensible process was used to the relative value of different outcomes? Unsure The guideline thoughtfully balances desirable and undesirable effects? Yes The guideline accounts for important recent developments? Yes The guidelines has been peer-reviewed and tested? Yes/No Practical, actionable and clinically important recommendations are made? Yes The guideline authors’ conflicts of interest are fully reported, transparent and unlikely to sway the recommendations of the guidelines? Yes GRACE-1 Recommendations: Here are the five nerdy questions I asked Suneel to help us better understand the GRACE-1 guidelines. Listen to his respond to each question on the SGEM podcast. The Panel: The panel was described as including geographically, ethnically, and gender diverse ED clinician. You also included a cardiologist. What I really liked is you had a patient representative and three methodologists. Can you discuss why you think having non-clinicians are important to have on the panel? Conflicts of Interest (COIs): These can introduce bias into CPGs. The Institute of Medicine published a document on improving CPGs and specifically addressed how to deal with COIs (Graham et al 2011). What COI were declared and how did your group manage these issues? Strength of Recommendations: Six out of the eight recommendations were based on low or very low levels of evidence. One recommendation had no evidence and only one had moderate evidence to support the recommendations. What are clinicians to do when there is a lack of good evidence to inform our management? Cost: You considered potential benefits and potential harms, but did you consider the cost of these recommendations. Actionable: It can take over ten years for high-quality, clinically relevant information to reach the patient bedside (Morris et al 2011). This is referred to as the knowledge translation (KT) gap. It is illustrated in the leaky pipe model that has seven leaks (Diner et al 2007). Will these recommendations be “actionable” in the ED setting? Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions. SGEM Bottom Line: It all depends. The strongest evidence from GRACE-1 is recommendation #6. There is moderate level of evidence that ACS can be excluded in adult patients with recurrent, low-risk chest pain using a single hs-troponin below a validated threshold without further diagnostic testing in patients who have a CCTA within the past two years showing no coronary stenosis. Case Resolution:  After discussing the likelihood of low-risk ACS in this patient’s recurrent chest pain, acknowledgement of some anxiety drivers for recurrent ED visits, and even lower risk of 30-day MACE given a normal exercise stress test and CCTA within the past two years, you both agree to discharge without further hs-troponin/other testing, and he will follow-up with his cardiologist within a few days. Dr. Suneel Upadhye Clinical Application: The application of this GRACE-1 clinical practice guideline depends on many factors. This includes: where you work, personal risk tolerance,

Date: July 1st, 2021 Guest Skeptic: Dr. Justin Morgenstern is an emergency physician and the creator of the #FOAMed project called First10EM.com. Reference: Dankiewicz et al: TTM2 Trial Investigators. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. NEJM 2021 Case: A 58-year-old man collapsed in front of his family. When paramedics arrived, they found him to be in cardiac arrest, with ventricular fibrillation on the monitor. Paramedics managed to get return of spontaneous circulation after a single defibrillation, but the patient is still comatose on arrival. The charge nurse turns to you and asks: should I grab the ice packs? Background: Hypothermia has been a mainstay of post-arrest care after the publication of two trials in 2002 that both suggested a benefit. This trial by Bernard and colleagues randomized 77 patients with an initial cardiac rhythm of ventricular fibrillation who had achieved return of spontaneous circulation (ROSC) but were persistently comatose. The trial was not truly randomized, as the groups were based on the day of the month, and they also weren’t blinded. The results of this Australian trial seemed too good to be true. Hypothermia resulted in a large improvement in neurologic outcomes, defined as well enough to be sent home or to a rehab facility. It was 49% of the hypothermia group versus only 26% of the normothermia group. This gives a NNT of 4. The reported p value was borderline at 0.046, and when I re-calculate, it comes out as 0.06 (not statistically significant). The other trial was the Hypothermia After Cardiac Arrest (HACA), also published in NEJM 2002. They randomized 273 comatose adult patients out of 3,551 screened patients. These were witnessed OHCA who had a shockable rhythm, achieved ROSC, and had a short downtime. This trial used an air mattress to cool patients and was also not blinded. This second trial done in Europe also showed impressive results for favorable neurologic outcome. It was 55% in the hypothermia group vs 39% in the normothermia group (NNT 6). They also reported a 14% absolute decrease in mortality with therapeutic hypothermia post-OHCA. As a result of these two-small trials, hypothermia was widely adopted. However, there were many voices in the evidence-based medicine world that reminded us of the significant uncertainty that remained, and the weaknesses of these two trials. The SGEM covered a few  trials looking at therapeutic hypothermia for OCHA in the pre-hospital setting. The bottom line is there is not good evidence that therapeutic hypothermia is superior to usual care and cannot be recommended. SGEM#21: Ice, Ice, Baby (Hypothermia post Cardiac Arrest) SGEM#54: Baby It’s Cold Outside (Pre-Hospital Therapeutic Hypothermia in Out of Hospital Cardiac Arrest) SGEM#183: Don’t RINSE, Don’t Repeat Because of that uncertainty, a much larger, multi-center trial was run. This is the original Target Temperature Management (TTM) trial by Nielson et al NEJM 2013. As almost everyone knows, they compared two difference hypothermia targets, 33C and 36C. The result was no benefit for their primary outcome of mortality at the end of the trial and no benefit Cerebral Performance Category (CPC), modified Rankin Score (mRS) or mortality at 180 days. We did a structured critical appraisal of the TTM trial on SGEM#82. The bottom line was that the trial did not demonstrate a benefit of a targeted temperature of 33C vs. 36C for survival of OHCAs. But both groups in the TTM trial were hypothermic, so although it was the highest quality evidence available, it didn’t tell us whether hypothermia was any better than normothermia. Which is why the TTM2 trial was performed. Clinical Question: Does hypothermia result in improved survival after cardiac arrest as compared to controlled normothermia? Reference: Dankiewicz et al: TTM2 Trial Investigators. Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest. NEJM 2021 Population: Comatose adult patients admitted to hospital after an OHCA, irrespective of initial rhythm. Intervention: Hypothermia with a target temperature of 33 degrees Celsius, maintained for 28 hours, and then slowly rewarmed by one degree every three hours. Comparison: Normothermia with an aim to maintain a temperature of 37.5C or less. Outcome: Primary Outcome: Death from any cause at six months Secondary Outcome: The main secondary outcome was a poor functional outcome at six months, defined as a score of four to six on the modified Rankin scale (mRS) Authors’ Conclusions: “In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia.” 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 (ITT analysis). 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. 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: They assessed 4,355 patients for eligibility in the trial and randomized 1,900. The mean age was 64 years and 80% were male. Most (91%) were bystander witnessed arrest, bystander CPR was performed in 80% of the arrests and three-quarters had shockable rhythms. Key Result: No statistical difference between hypothermia vs normothermia Primary Outcome: At six months, 50% of the hypothermia group and 48% of the normothermia group had died. This gives a relative risk (RR) of 1.04 (95% CI; 0.94 to 1.14); P=0.37 Secondary Outcomes: At six months, 55% of both groups had a poor functional outcome (mRS 4-6). RR 1.00 (95% CI; 0.92 to 1.09) Harms: Arrythmias resulting in hemodynamic compromise were more common in the hypothermia group (24% versus 16%, p<0.001) 1. Blinding: Keeping everyone perfectly blinded would have been very difficult to do in a hypothermia trial, so it makes sense that this is an open label study. However, the lack of blinding certainly increases the risk of bias, especially for more subjective outcomes like neurologic function. We are unsure which direction the bias would have been. Did the clinicians and researchers think that hypothermia was going to have a benefit or not? It would have been interesting to survey them before the trial to see what their thought of this treatment a priori.  2. Death: This outcome is not as objective as we sometimes think. When a study is unblinded, you generally want to see an objective outcome being used. Death is about as objective as it gets – you are either alive or dead. There generally isn’t much debate. However, in a modern ICU, we have a lot of control of when someone dies. If the doctors truly believed in hypothermia, they might have decided to keep people alive longer, to give them a better chance, biasing the results. These authors tried to account for that by ensuring that an independent, blinded physician performed a standard assessment for neuroprognostication on all patients. Although it is worth discussing, I don’t think bias is playing a hug role in the results we are seeing here. 3. Harms: Although I anticipate that many people will focus on the harm from arrythmias, I don’t think it was ultimately all that important. Arrythmias resulting in hemodynamic compromise certainly sound important, but ultimately that is a monitor-oriented outcome (MOO). The reason we care about arrythmias is that patients might die or have poor neurologic outcomes, and those patient-oriented outcomes (POOs) that are more important. In this trial the POOs were not different. So ultimately, I don’t think this is truly a harmful practice, but rather a neutral practice. 4. Control Group: Did they choose the best control group? Both groups in this trial had their temperature controlled to some extent, but was that necessary? Although it is a common hypothesis that avoiding fever is important in this patient population, there are no RCTs that demonstrate a benefit from fever control. This study still leaves us with the question of whether any temperature control is necessary. Adding a third group without any temperature control could have settled this issue once and for all. 5. Importance of Skepticism: This story arc around therapeutic hypothermia for OHCA is a great reminder of why we should be skeptical of any claim. The time to accept a claim is when there is sufficient evidence. There are many examples in medicine that show we can fall prey to intervention bias (Foy 2013). We can be overly optimistic about small studies that are nowhere close to scientifically definitive, and quickly crown borderline practices as “silver bullets” or “standard of care”. Think thrombolytics for acute ischemic stroke, TXA for just about anything, or cardiac stress testing. Science is a process that requires replication. Single studies rarely, if ever, define the “truth”. The overzealous adoption of medical practices can hurt our patients. Time and time again, we adopt medical interventions that are unproven. In many cases, the harms end up outweighing the benefits, but we only acknowledge this decades later, when replication studies are finally done.

Date: June 25th, 2021 Guest Skeptic: Dr. Chris Bond is an emergency medicine physician and assistant Professor at the University of Calgary. He is also an avid FOAM supporter/producer through various online outlets including TheSGEM. Reference: Chinnock et al. Self-obtained vaginal swabs are not inferior to provider-performed endocervical sampling for emergency department diagnosis of Neisseria gonorrhoeae and Chlamydia trachomatis. AEM June 2021 Case: A 31-year-old female presents to the emergency department with pelvic pain and vaginal discharge for the past 24 hours. She is afebrile, vital signs are normal and she is having a significant amount of pain. She says the pain is so severe that she cannot even imagine having a pelvic exam done right now for STI testing. Background: Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) are the two most common sexually transmitted infections (STI) reported in the United States. Emergency departments (EDs) now diagnose an increasing percentage of NG/CT cases compared to STI clinics. (1,2) The standard of care for NG/CT diagnosis is nucleic acid amplification testing (NAAT), with the collection method being provider-performed endocervical sampling (PPES). PPES is uncomfortable for patients and has numerous other limitations, including the need for exam rooms, an available provider and often a female chaperone. These limitations can delay sample collection and can also add significant delay in a busy ED. The need for universal pelvic examination in the ED to perform STI testing has also come under increasing scrutiny. (3) Vaginal sample collection with self-obtained vaginal swabs (SOVS) was first developed and researched in non-ED settings based on these reasons and others. These studies demonstrated comparable sensitivity for NG/CT diagnosis when comparing SOVS to PPES, and high patient acceptability. (4-8) However, those studies were performed in a wide range of non-ED settings and were mostly asymptomatic screening rather than STI testing in an acute care environment. This study compares PPES with SOVS in an ED setting and explores patient’s acceptability or preference of SOVS versus PPES. Clinical Question: Do self-obtained swabs have noninferior sensitivity for the diagnosis of NG/CT compared to provider performed swabs in an ED setting using a rapid NAAT. Reference: Chinnock et al. Self-obtained vaginal swabs are not inferior to provider-performed endocervical sampling for emergency department diagnosis of Neisseria gonorrhoeae and Chlamydia trachomatis. AEM June 2021 Population: Female patients 18 years of age or older who were judged by the treating practitioner to need NG/CT testing Exclusions: Incarcerated any acute psychiatric condition precluded understanding instructions or giving informed consent, not English or Spanish proficient, or treated for NG/CT within the previous four weeks. Intervention: Self-obtained vaginal swab (SOVS) for NG/CT Comparison: Provider performed endocervical sampling swab for NG/CT Outcome: Primary Outcome: Noninferiority of SOVS sensitivity for NG/CT, with noninferiority being demonstrated if sensitivity was 90% or above. Secondary Outcomes: Kappa measurement of the SOVS and PPES, SOVS organism-specific sensitivity for NG and CT, acceptance rate of SOVS, rate of patients worried about doing SOVS correctly, and SOVS refusal rate. Dr. Brian Chinnock This is an SGEMHOP episode which means we have the lead author on the show. Dr Brian Chinnock is Professor in Department of Emergency Medicine at the UCSF-Fresno Medical Education Program, and Research Director. Authors’ Conclusions: “SOVS are noninferior to PPES in NG/CT diagnosis using a rapid NAAT in ED patients and surveys indicate high patient acceptability.” Quality Checklist for Observational Trials: 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? Yes Was the follow up of subjects complete enough? Yes How precise are the results/is the estimate of risk? The results are precise with narrow confidence intervals Do you believe the results? Yes Can the results be applied to the local population? Yes Do the results of this study fit with other available evidence? Yes Results: The researchers found 750 patients eligible for inclusion in the study. The final cohort consisted of 515 patents with completed PPES and the SOVS results. The mean age was 30.7 years of age with 52% Hispanic ethnicity. The overall prevalence for either NG or CT or both was 17% (86/515). Of these patients with STIs, 34% (29/86) had infection with NG, 54% (47/86)) with CT, and 12% (10/87) with coinfection. Key Result: SOVS was non-inferior to PPES Primary Outcome: Noninferiority of SOVS sensitivity for NG/CT SOVS had a sensitivity of 95% (95% CI, 88% to 99%) for the detection of NG/CT when compared to PPES. Secondary Outcomes: Kappa was 93 (95% CI, 0.89 to 0.98), which is excellent. SOVS Sensitivity for NG and CT was 97% (95% CI = 87% to 100%) and 94% (95% CI = 84% to 99%) respectively 93% felt that collecting a self-sample is acceptable 28% who were concerned about doing SOVS incorrectl 26% refused SOVS due to reasons clearly related to the SOVS collection procedure (“uncomfortable performing SOVS,” “worried might do it incorrectly”, “prefers physician”) rather than the consent process. Here are the ten nerdy questions we asked Brian to help us better understand his study. Listen to his respond to each question on the SGEM podcast. 1. Selection Bias: Convenience sample (not overnight). Do you think that could have had an impact on your results? 2. Exclusions: Why were patients excluded if they had been treated for NG/CT in the previous 4 weeks? 3. Non-Inferiority: Why do a non-inferiority study design instead of a superiority design? 4. Endocervical Swabs: These were endocervical swabs used in the provide performed exam but would have been vaginal swabs if done by patients themselves. So, are endocervical swabs not actually required to be endocervical? 5. Power: The power was set based on the manufacturer’s reported sensitivity for PPES using the Cepheid Xpert assay of 99% for NG, 96% for CT and a presumed combination of 97%. Non-inferiority was set at 7% with an assumed prevalence of 14% based on the previous year’s data. This required a target of 571 patients or 615 if you only had a prevalence of 13%. You missed the overall target but did get at least 80 positive patients. Can you explain why you stopped enrollment, and do you think it would impact your study? 6. Aptima: Where I work, we use Aptima endovaginal swabs for STI testing, and I assume this would be even better for self-testing than swabs that require endocervical sampling. Are there other studies that support this hypothesis? 7. Best Swab Type: Is there a list of swab types that would be effective for SOVS vs. PPES? Yours is a 90-minute NAAT swab which is not used in many centers and the swabs used can vary by geographic location. 8. External Validity: In the limitations section, you mention the high proportion of Hispanic (52%) ethnicity as making the study potentially not generalizable to all ED settings. Can you explain why this would be? 9. Qualitative: Can you discuss the qualitative data as to reasons why patients declined to participate in the study and why some still preferred a provider performed exam to a self-obtained swab? 10 Anything Else: We like to have an open-ended question to allow the author to discuss something that we did not address in our nerdy questions. Is there anything else you would like to add about your study? Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions. SGEM Bottom Line: Consider the use of self-obtained vaginal swabs for STI testing and the necessity of performing a pelvic exam for patients presenting with clinical suspicion for NG/CT. Case Resolution: You provide your patient with analgesic for her pain and ask if she would prefer a self-obtained vaginal swab or for you to perform a pelvic exam to obtain a swab. She chooses to perform the swab herself, and you treat her empirically for an NG/CT. Dr. Chris Bond Clinical Application: This was an excellent study that supports the use of self-obtained vaginal swabs for STI testing in the ED and can reduce uncomfortable pelvic exams for patients. It is reasonable to offer this option to patients presenting to the ED who clinically require a swab for STI testing but there is no other need for a pelvic examination. What Do I Tell My Patient? I am concerned that you may have an STI. A vaginal swab should be done to test for this infection. Doing a vaginal swab by yourself is just as accurate as having me perform a pelvic exam. It will also be faster and probably less painful for you. I understand if you are uncomfortable doing it yourself. I am happy to do the exam and get the swab sample. It is your choice and both options are fine. Keener Kontest: Last weeks’ winner was Dr. Sebastian Nemetz from Offenbach, Germany. He knew Dr. Emil Siegle is the German physician is credited with the creation of pneumatic otoscopy? 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 the use of self-obtained vaginal swabs? Tweet your comments using #SGEMHOP.

Date: June 11th, 2021 Guest Skeptic: Dr. Dennis Ren is a paediatric emergency medicine fellow at Children’s National Hospital in Washington, DC. Reference: McLaren SH, et al. Invasive bacterial infections in afebrile infants diagnosed with acute otitis media. Pediatrics 2021 Case: You are working with a medical student at the emergency department when a 2-month-old boy is brought in by his parents for fussiness. They note that he has had upper respiratory symptoms for the past few days and fussier than usual. He has still continued to feed well and make wet diapers. He has not had any fever. Yesterday, they noticed that he seemed to be pulling at his right ear. On exam, he is afebrile, active, and alert. He cries and moves vigorously when you look into his ear. You see a bulging, red tympanic membrane. His left tympanic membrane is clear. The rest of his exam is unremarkable. You turn to the medical student and ask her what she would like to do for this patient. She replies that she thinks the patient has an acute otitis media (AOM) but given his age, she is also thinking about the possibility of an invasive bacterial infection (IBI) and would like to obtain some blood for labs and even consider a lumbar puncture for cerebral spinal fluid. How do you reply? Background: Acute Otitis media is the second most diagnosed illness in children and the most common indication for antibiotic prescription [1-2]. We have covered the of AOM twice on the SGEM: SGEM#132: One Balloon for Otitis Media with Effusion with Dr. Richard Lubell SGEM#278: Seen Your Video for Acute Otitis Media Discharge Instructions SGEMHOP with lead author Dr. Naveen Poonai? In 2013, the American Academy of Pediatrics (AAP) updated recommendations for the diagnosis and management of acute otitis media (AOM) for children older than 6 months. Unfortunately, there is limited guidance for patients younger than 6 months. The diagnosis of AOM becomes more complicated by the concern for concurrent invasive bacterial infections (IBI) in infants less than 3 months of age. Previous studies have demonstrated low prevalence of concurrent IBI in infants with AOM, but sample size has been small and included a mix of afebrile and febrile infants [3-4]. Additionally, the microbiology of pathogens causing AOM has shifted after the implementation of the pneumococcal conjugate vaccine with a higher proportion of patients having culture negative AOM [5]. This uncertainty has led to wide practice variation and controversy surrounding diagnostic testing (blood and cerebrospinal fluid testing), antibiotic administration (IV vs oral), and disposition (discharge vs admission) in infants with AOM. Clinical Question: What is the prevalence of invasive bacterial infections and adverse events in afebrile infants ≤ 90 days of age with acute otitis media? Reference: McLaren SH, et al. Invasive bacterial infections in afebrile infants diagnosed with acute otitis media. Pediatrics 2021 Population: Afebrile infants ≤ 90 days of age with clinically diagnosed acute otitis media across 33 pediatric emergency departments (29 USA, 2 Canadian and 2 Spanish EDs) from 2007 to 2017 Excluded: Temperature ≥38°C and <36°C in the ED or within 48 hours, antibiotic use (other than topical) within 48 hours of presentation, concurrent mastoiditis, evidence of focal bacterial infection, transferred to ED with previous diagnostic testing/antibiotics Intervention: Evaluation of invasive bacterial infections in blood or cerebrospinal fluid (CSF) Comparison: None Outcomes: Primary Outcome: Prevalence of IBI (bacterial meningitis and bacteremia) Secondary Outcomes: Variability in diagnostic testing for IBIincluding blood or cerebrospinal fluid (CSF), parenteral antibiotic administration, and hospitalization. Safety Outcome: AOM-associated adverse events Authors’ Conclusions: “Afebrile infants with clinician-diagnosed acute otitis media have a low prevalence of invasive bacterial infections and adverse events; therefore outpatient management without diagnostic testing may be reasonable.” 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? Unsure Was the exposure (diagnostic testing) accurately measured to minimize bias? Yes Was the outcome accurately measured to minimize bias? Unsure Have the authors identified all-important confounding factors? Unsure Was the follow up of subjects complete enough? Yes How precise are the results? Unsure 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: They screened 5,270 infants from 33 sites to establish a cohort of 1,637 who met inclusion/exclusion criteria. The median age was 68 days and 89% met the simplified American Academy of Pediatrics diagnostic criteria for AOM. Key Result: No infant with blood cultures had bacteremia and no infant was diagnosed with bacterial meningitis by CSF culture. Primary Outcome: Prevalence of Invasive Bacterial Infections 0/278 with blood cultures had bacteremia (95% CI 0%-1.4%) 0/102 with CSF cultures had bacterial meningitis (95% CI 0% to 3.6%) Two infants had adverse events in 30-day follow up and hospitalization history: Culture negative sepsis vs. severe dehydration from milk protein allergy Lymphadenitis (20 days after ED visit) after initial discharge on amoxicillin Secondary Outcomes: Diagnostic Testing, Antibiotic Administration, and Hospitalization Rates. One-fifth (21.7%, 355 of 1637) had ≥1 diagnostic test. One-third (34%, 34 of 100) of infants ≤28 days had a lumbar puncture. For infants with upper respiratory symptoms (n=1179), ~5% had a lumbar puncture, and 13.7% had blood cultures. ~10% received IV or IM antibiotic 90% received a prescription for oral antibiotic (most commonly amoxicillin followed by amoxicillin-clavulanate) 5% were discharged from the emergency department Almost half (47%) of infants 0-28 days were hospitalized 72-hour return rate was 63 (4.3%) of which 15 infants were hospitalized. Most common reason for hospitalization was bronchiolitis Older infants were less likely to have blood cultures, lumbar puncture, and hospitalization compared to younger infants. Ear discharge was significantly associated with diagnostic testing and hospitalization. 1. Diagnostic Uncertainty: The diagnosis of otitis media remains challenging. It is a clinical diagnosis and there is variability amongst clinicians. Here is the American Academy of Pediatrics (AAP) 2013 diagnostic criteria for AOM [6]. But even the AAP concedes that there is no gold standard for the diagnosis of AOM because it exists in a spectrum of findings as the disease process develops. This becomes challenging in a retrospective review as the diagnosis of AOM cannot be verified. The authors chose to use a simplified diagnostic criteria defined by presence of tympanic membrane erythema, bulging tympanic membrane, or otorrhea. Unfortunately, the presence of tympanic membrane erythema alone is not specific for AOM as it can be because the infant is crying. This may falsely increase the number of infants with AOM included in the analysis and underestimate the prevalence of IBI. Although, zero infants in the study had confirmed bacteremia or bacterial meningitis on cultures. 2. Primary Outcomes: They had two primary outcomes, prevalence of IBI (bacteremia and bacterial meningitis) and AOM-associated adverse events. We know from the movie Highlander…There can be only one! Primary outcome. I am uncertain that the two reported adverse events are truly associated with AOM. One patient who was initially discharged on amoxicillin presented 20 days later  with cervical lymphadenitis and perforated AOM. The other patient did grow Staphylococcus aureus from middle ear effusion and was hospitalized for culture-negative sepsis but was also thought to have a severe milk protein allergy. The authors note that this patient presented with severe illness during the index ED visit so was likely not going to be discharged home regardless. 3. Partial Verification Bias: There were several potential biases in this study that could have impacted the results. One was already mentioned in nerdy point number one that there is not a gold standard. This is called the imperfect gold standard bias or the copper standard bias. Another potential bias is partial verification bias. Not all infants in the study underwent the same testing for IBI. This can cause an underestimation of IBI. It is possible that some infants with bacteremia on whom blood cultures were not obtained were treated by oral antibiotics. The authors did try to perform follow up on patients within 30 days by reviewing medical records but acknowledge that this may not fully capture all patients with bacterial meningitis that was seen outside of the index ED or hospital system. 4. Selection Bias: As someone who works mainly in community hospitals, I’m concerned about selection bias. Are the infants who present to free-standing pediatric hospitals the same as those who present to community or rural EDs? Are those in large urban areas more likely or less likely to bring in a “fussy” infant? Are parents in the USA less likely to go to the ED because of co-pays, insurance status or other financial issues? It is unclear how any of these biases could alter the findings in this study. 5. Age: A last point to highlight is that there is a very low number of infants ≤28 days old (n=100, 6.1% of study population). This low number could be due to a variety of reasons.

Date: May 25th, 2021 Guest Skeptic: Dr. Garreth Debiegun is an emergency physician at Maine Medical Center in Portland, ME and clinical assistant professor with Tufts University School of Medicine. He also works at an urgent care and a rural critical access hospital. Garreth is interested in wilderness medicine and is the co-director of the wilderness medicine clerkship at Maine Med, and the medical director for Saddleback Ski Patrol and for Maine Region NSP. At work Garreth imagines himself as a student of evidence-based medicine trying to provide the best care based on the best evidence. References: Suzuki et al. Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic Stroke: The SKIP Randomized Clinical Trial. JAMA 2021 Zi et al. Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke: The DEVT Randomized Clinical Trial. JAMA 2021 Case: A 74-year-old woman presents to your emergency department with 1.5 hours of right-sided weakness, aphasia, and neglect. On rapid bedside assessment you calculate the National Institute of Health Stroke Score/Scale (NIHSS) of 11 and a Field Assessment for Stroke Triage for Emergency Destination (FAST-ED) score of 7; you suspect a large vessel occlusion (LVO) based on the high NIHSS and FAST-ED score >3. A non-contrast CT shows no evidence of intracranial hemorrhage. A CT angiogram plus CT perfusion demonstrate a clot in the left proximal middle cerebral artery (MCA) with a small infarcted area and a large penumbra. Based on your institution’s current guidelines, the patient is a candidate for endovascular therapy, but they are also within the current window for the administration of thrombolytics. You wonder if you gotta be starting something?  Specifically, you wonder if you should give the thrombolytics while waiting for your neurointerventional/endovascular team? Background: Management of acute ischemic stroke has been discussed on the SGEM ever since this knowledge translation project was launched in 2012. My position remains that there is uncertainty as to whether tPA provides a patient-oriented outcome and this was summarized in the downgrading of the NNT recommendation to “yellow” with Dr. Justin Morgenstern from First10EM. The world of stroke management has changed in the last few years the more robust evidence to support endovascular therapy (EVT) for large vessel occlusion (LVO) strokes. The tipping point came with the publication of MR. CLEAN in 2015. It was a multicenter, randomized, unblinded trial of patients with an LVO stroke in the anterior circulation treated in less than six hours after onset of symptoms. The primary outcome was good neurologic function defined as a modified Rankin Scale (mRS) score of 0-2 at 90 days. The trial included 500 patients and reported an absolute risk reduction of 14% (33% EVT vs 19% control) with a NNT of 7. Four other RCTs were stopped early due to the publication of MR. CLEAN.  All of these were published in the NEJM in the following six months. SWIFT PRIME (n=196) NNT of 4 EXTEND-IA (n=70) NNT of 2-5 depending on which outcome you picked REVASCAT (n=206) extended the window to eight hours NNT 6.5 ESCAPE (n=316) extended to 12 hours NNT 4 There are dangers with stopping trials early. Dr. Gordon Guyatt wrote in the BMJ that it can introduce bias towards efficacy. He said you should have a high level of skepticism regarding the findings of trials stopped early for benefit, particularly when those trials are relatively small, and replication is limited or absent. A systematic review and meta-analysis (SRMA) was published by Badhiwala, JH et al in JAMA 2015 looking at EVT for stroke. The first three RCTs reported no superiority. Then came MR. CLEAN and those four additional studies that were stopped early. The forest plot shows a point estimate that favors EVT and the 95% confidence interval does not cross the line of no statistical difference. We do need to be careful in not over interpreting this data because the bias of stopping trials early could have been compounded in the SRMA process. A couple more RCTs were published since the 2015 SRMA: DAWN 2018 (n=206) NNT 3 between 6-24 hours, stopped early DEFUSE 2018 (n=182) NNT 4 between 6-16 hours, stopped early Here is a lists all the studies and the number of patients enrolled/center/year put together by friend of the SGEM, Dr. Salim Rezaie (REBEL EM). The average was 4.6 patients/year from these stroke centres. While the NNT for EVT looks very impressive, it is suffering from denominator neglect. Once the patient is getting the intervention the NNT is in the single digits. However, how many possible stroke patients were screened, and code strokes were called to get the impressive NNTs of the EVT trials? Most of these trials didn’t tell us how many patients they screened to get the patients they registered.  Only one did – EXTEND-IA.  In that RCT, they screened ~7,800 patients, and registered 70. That’s 0.9%, or about 1/110, that were eligible for the treatment. The NNT in MR CLEAN, the largest and arguably the most methodologically sound of these trials, was 7.  If you must screen 110 patients to find one eligible, and need to treat 7 to benefit one, then about one out of every 770 patients having a potential stroke would benefit from this therapy. Therefore, we think the NNT provided by the RCTs suffer from denominator neglect. An NNT of 770 is not nearly as impressive as an NNT of 7. The agenda is in the numerator, but the devil is in the denominator. One major component of LVO management is the use of systemic thrombolytics in patients presenting within the current thrombolytic treatment window prior to endovascular intervention. However, it’s unclear if systemic thrombolytic administration results in better outcomes or if it simply exposes the patient to increased risks at a higher cost. There is a SRMA by Mistry et al published in Stroke 2017 on the issue of EVT +/- tPA. They included 13 studies (n=1,769) with three RCTs (which accounted for only 25% of patients) and ten observational studies (which accounted for the other 75% of the patients). They reported an NNT of 17 for good neurologic outcome (defined as mRS 0-2) with EVT + tPA compared to EVT alone. However, it was not statistically significant if you just looked at the RCT data. This is a problem of combining lower quality observational studies with higher-quality RCTs. We looked at a 2020 RCT by Yang P et al published in the NEJM on SGEM#292. This trial asked if EVT alone was non-inferior to EVT + tPA in stroke patients with LVOs presenting withing 4.5 hours of symptoms. The cohort consisted of 654 patients and the key results was EVT alone was not non-inferior to EVT plus tPA. Our SGEM bottom line was that there does not appear to be a role for systemic thrombolysis in acute ischemic stroke for appropriate patients when EVT is readily available. Two more trials have been published and that is what we are going to review today on the SGEM. Clinical Question: Does intravenous thrombolysis prior to mechanical thrombectomy increase the percentage of patients with LVO who achieve mRS of 0-2 (functional independence) at 90 days? Reference #1:  Suzuki et al. Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic Stroke: The SKIP Randomized Clinical Trial. JAMA 2021 Population: Patients aged 18-85 evaluated at one of 23 stroke centers in Japan within 4.5 hours of onset, who were found to have: NIHSS ≥6, CTA or MRA proven ICA or M1 occlusion, minimal imaging changes of ischemic stroke. Patients had to be previously independent (mRS 0-2) and meet Japanese criteria for thrombolysis. Exclusions: Contraindication for contrast agent or EVT, contraindication for IVT, presence of severe renal disorder, pregnancy or possibility of pregnancy, unlikely to complete the study, such as due to progressive malignant tumor, judged incompatible with the study by the investigators Intervention: Mechanical thrombectomy of LVO without additional thrombolytics Comparison: Alteplase given at a dose of 0.6 mg/kg in addition to mechanical thrombectomy performed within 30 minutes of randomization Outcome: Primary Outcome: mRS evaluated by physical exam or phone interview at 90 days. Secondary Outcomes: Ordinal shift analysis of mRS, mRS 5-6, mRS 0-1, mRS 0-3, 90-day mortality, successful reperfusion, recanalization and adverse events (ICH) Authors’ Conclusions: “Among patients with acute large vessel occlusion, mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, failed to demonstrate noninferiority regarding favorable functional outcome. However, the wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. Unsure The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were treated (per-protocol analysis for non-inferiority trials). 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. Unsure 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

Date: May 28th, 2021 Guest Skeptics: Heather Logan is the executive Strategy lead for the Canadian Agency for Drug and Technologies in Health (CADTH). Dr. Wendy Levinson is the Chair of Choosing Wisely Canada (CWC) and a Professor of Medicine, University of Toronto This SGEM Xtra is based on document created by CADTH and presented at Choosing Wisely Canada National annual meeting May 13, 2021. The title of the report is Using Health Care Resources Wisely After the COVID-19 Pandemic: Recommendations to Reduce Low-Value Care. We have discussed Choosing Wisely before on SGEM Episodes: SGEM#15: Choosing Wisely SGEM Xtra: CAEP Choosing Wisely SGEM Xtra: Right, You’re Bloody Well Right, You’ve got the Bloody Right to Care Choosing Wisely Canada (CWC): Dr. Wendy Levinson It is the national voice for reducing unnecessary tests and treatments in health care. One of its important functions is to help clinicians and patients engage in conversations that lead to smart and effective care choices. Choosing Wisely Canada is led by a team of clinicians and staff based at St. Michael’s Hospital (Toronto), the University of Toronto, and in collaboration with the Canadian Medical Association. Choosing Wisely Canada mobilizes and supports clinicians and organizations committed to embedding campaign recommendations into practice. There are close to 350 documented quality improvement projects across the country that are building capacity for the spread and scale of Choosing Wisely. These efforts are underway in hospitals, long-term care homes, and primary care clinics. Many of these innovative projects, including their evidence-based tools and methods, have been packaged into easy to follow toolkits that are broadly circulated in order to encourage widespread adoption. This has allowed Choosing Wisely Canada to foster a network for those looking to implement campaign recommendations into practice. Canadian Agency for Drug and Technologies in Health (CADTH): Heather Logan It is an independent, not-for-profit agency funded by Canadian federal, provincial, and territorial governments (except Quebec) to provide credible, impartial advice and evidence-based information about the effectiveness of drugs and other health technologies to Canadian health care decision-makers. CADTH believes that credible, objective evidence should inform every important health care decision. When you want to know what the evidence says, ask CADTH. Created in 1989 by Canada’s federal, provincial, and territorial governments, CADTH was born from the idea that Canada needs a coordinated approach to assessing health technologies. The result was an organization that harnesses Canadian expertise from every region and produces evidence-informed solutions that benefit patients in jurisdictions across the country. South Huron Hospital Association (SHHA) is known as the "Little Hospital that Does". SHHA has been choosing wisely since 2012 selecting five items every three years. SHHA Choosing Wisely 2012 Influenza shots for staff with privileges SGEM#20 Use Ottawa ankle and knee rules SGEM#3 and SGEM#5 No routine use of antivirals for Bell’s Palsy SGEM#14 No routine use of antibiotics for simple cutaneous abscesses SGEM#13 No routine use of proton pump inhibitors for upper GI bleeds SGEM#16 SHHA Choosing Wisely 2015 Utilize Canadian CT head rules to guide our decisions on getting CT heads SGEM#106 Utilize Canadian C-Spine rules to guide our decisions on obtaining plain film c-spine imaging SGEM#232 Do not do annual physical exams on asymptomatic adults with no significant risk factors Do not screen women with Pap smears if under 21 years of age or over 69 years of age Do not order echo cardiograms routinely SHHA Choosing Wisely 2018 Only use supplemental Oxygen for STEMI patients that are hypoxic (saturations < 90%) SGEM#193 Use appropriate antibiotic selection for uncomplicated COPD exacerbation ie. Amoxicillin, Septra and Doxycycline Do not start IV unless you are 80% sure that you are actually going to use the IV SGEM#204 Treat Chronic Pain utilizing non-pharmacological means before prescribing an opioid medication Don’t place or leave in place a urinary catheter without reassessment Low-Value Care, Challenges of COVID19, High-Value Care and the Purpose of the CADTH Report Slides from the Choosing Wisely Presentation - May 13th, 2021 CADTH Four Step Approach Recommendations in Six Key Clinical Areas Primary care: Seven recommendations span primary care, including avoiding unnecessary rural transfers, annual exams, and screening and imaging tests Specialty care: Four recommendations address low-value procedures, including chronic dialysis, colonoscopy for constipation, cardiac imaging without high-risk markers, and knee MRIs End-of-life care: Three recommendations emphasize the importance of advance care planning conversations for patients with serious illness and access to palliative care Hospital care: Two recommendations address low-value routine investigations and pre-operative testing in hospital care Long-term care: One recommendation addresses unnecessary hospital transfers from long-term care Blood products: One recommendation addresses the overuse of red blood cells transfusion in hemodynamically stable critical care patients. Nineteen Recommendations for High-Value Care Hospital Care: Routine Investigations: Don't order routine investigations, including chest radiographs or blood tests, in critically ill patients except to answer a specific clinical question. Preoperative Testing: Don’t order baseline laboratory studies (complete blood count, coagulation testing, or serum biochemistry) for asymptomatic patients undergoing low-risk non-cardiac surgery End-of-Life Care: Advance Care Planning Conversations:  Don’t start or continue life-supporting interventions unless they are consistent with the patient’s values and realistic goals of care Don’t delay advance care planning conversations Palliative Care: Don’t delay palliative care for a patient with serious illness who has physical, psychological, social, or spiritual distress because they are pursuing disease-directed treatment Specialty or Outpatient Care: Nephrology: Don’t initiate chronic dialysis without ensuring a shared decision-making process between patients, their families, and their nephrology health care team Gastroenterology: Avoid performing a colonoscopy for constipation in those under the age of 50 years without a family history of colon cancer or alarm features Cardiology: Don’t perform stress cardiac imaging or advanced non-invasive imaging in the initial evaluation of patients without cardiac symptoms unless high-risk markers are present Orthopedics: Don’t order a knee MRI when weight-bearing X-rays demonstrate osteoarthritis and symptoms are suggestive of osteoarthritis as the MRI rarely adds useful information to guide diagnosis or treatment Long-Term Care: Transfer: Don’t send the frail resident of a nursing home to the hospital unless their urgent comfort and medical needs cannot be met in their care home Blood Products: Red Blood Cells Transfusion: Don’t routinely transfuse red blood cells in hemodynamically stable ICU patients with a hemoglobin concentration greater than 70 g/L (a threshold of 80 g/L may be considered for patients undergoing cardiac or orthopedic surgery and those with active cardiovascular disease) Oncology: Palliative: Don’t delay or avoid palliative care for a patient with metastatic cancer because they are pursuing disease-directed treatment Primary Care:  Rural Transfer: Don’t send a patient for a specialist visit that requires several hours of transport if the visit can be done virtually or by a local physician Annual Examinations: Don’t do annual physical exams on asymptomatic adults with no significant risk factors. Unnecessary Screening Tests: Don’t perform population-based screening for 25-OH-vitamin D deficiency. Unnecessary Imaging: Don’t order screening chest X-rays and ECGs for asymptomatic or low-risk outpatients Don’t do imaging for lower back pain unless red flags are present Don’t do imaging for uncomplicated headache unless red flags are present Don’t order a CT scan for uncomplicated acute rhinosinusitis The official CADTH report with all 19 recommendations and additional information  can be downloaded as a PDF. Key Messages from the CADTH Report Low-value tests, treatments, and procedures are an important health care quality problem in Canada and across the world because they provide little clinical benefit, may be harmful for patients, and waste limited resources. Due to the COVID-19 pandemic, health care systems face increased challenges of limited resources, reduced capacity, and a growing backlog of surgeries and other procedures. The pandemic has compelled health care professionals to make challenging decisions to prioritize health care services while coping with increased demand. As Canada emerges from the pandemic and health care systems rebuild and begin to address the backlog of delayed or cancelled services, there is an imperative to introduce lasting changes to reduce low-value care and ensure high-quality care is available to everyone. To help inform efforts for using health care resources wisely and to support decision-making, CADTH and Choosing Wisely Canada convened a 10-member multi-disciplinary panel of clinicians, patient representatives, and health policy experts to review areas of low-value care that can be reduced or limited. This panel reviewed, deliberated,

Date: May 20th, 2021 Guest Skeptic: Dr. Robert Edmonds is an emergency medicine physician in the Air Force in Dayton, Ohio, and a University of Missouri-Kansas City residency alumni from 2016. Reference: Jhunjhunwala et al. Reassessing the cardiac box: A comprehensive evaluation of the relationship between thoracic gunshot wounds and cardiac injury. Journal of Trauma and Acute Care Surgery. September 2017 DISCLAIMER: THE VIEWS AND OPINIONS OF THIS PODCAST DO NOT REPRESENT THE UNITED STATES GOVERNMENT OR THE US AIR FORCE. This SGEM episode was recored live for the Truman Medical Centers Multidisciplinary Trauma Conference. We did the session over zoom as an SGEM Journal Club. If you would like a copy of the slides from the presentation you can download them free open access at this LINK. Case: You receive a call on the Biocom for an incoming Type A trauma, three minutes out.  The patient is an adult male with a gunshot wound to the chest, and they’re combative with emergency medical services (EMS). Upon arrival in the emergency department (ED), the patient is incoherently speaking, has a pulse of 135 beats per minute, blood pressure of 85/50 mm Hg, and an obvious open wound in their left mid-axillary line at the level of the nipple. Background: Penetrating trauma is a major disease burden in the United States, and gunshot wounds cause 30,000 deaths annually [1] . As a country, penetrating trauma accounts for about 10% of all trauma cases [2] , but at some trauma centers it can reach much higher numbers. Here at the Truman Medical Center the average penetrating trauma for gunshot wounds alone represents ~19% of all traumas.  Naturally, patients with a direct cardiac injury from a gunshot wound (GSW) require prompt identification and management, so tools have sprung into existence to attempt to risk stratify patients at a higher risk of an underlying cardiac injury. One of the more common tools is the “cardiac box”. This three-dimensional area is at the highest risk of cardiac injury. The anatomical area is defined anteriorly as between the clavicle and xyphoid, and between the bilateral midclavicular lines. Per the authors, “The dogma of the cardiac box is largely based on small studies with primarily stab wounds. The underlying issue is that stab wounds are low kinetic energy and result from instruments with a fixed length. Thus, most stab wounds usually only result in a cardiac injury if the entrance is in very close proximity to the heart or there is a long weapon. Because these studies did include gunshots, the concept of the “box” was ultimately uniformly applied to all mechanisms. Injuries from high kinetic energy projectiles, however, can cause cardiac injury from entrance wounds to any area of the torso, especially the thorax.” Although it may be obvious to some that injury outside the cardiac box doesn’t rule out injury to the heart, the existence of such a tool colors our language and shifts the perceived risk in the clinician’s head.  According to a recent study in the Journal of Surgical Research [3] , 44% of all penetrating thoracic trauma patients presented to a non-trauma center (not a level 1 or level 2 ACS defined trauma center). For clinicians in these settings, use of the “cardiac box” nomenclature can have a significant impact on the perceived injuries when communicating with an on-call surgeon or when transferring the patient to another facility. If the injury is outside the cardiac box, it can be perceived as less concerning and may give the treating team a false sense of security. Clinical Question: Are the anatomic borders of the cardiac box adequate to predict cardiac injury from gunshot wounds? Reference: Jhunjhunwala et al. Reassessing the cardiac box: A comprehensive evaluation of the relationship between thoracic gunshot wounds and cardiac injury. Journal of Trauma and Acute Care Surgery. September 2017 Population: All patients in the Fulton County (Georgia) Medical Examiner’s autopsy registry who sustained a penetrating torso gunshot wound from January 2011 to December 2013. Excluded: Injuries above the clavicles and below the xyphoid Exposure: Wounds that were in the cardiac box- “defined as the two-dimensional plane covering the anterior surface of the thorax from the level of the clavicle to the tip of the xiphoid… and between the midclavicular lines (laterally).” The authors also included this same region projected onto the posterior thorax as well. Comparison: Patients with wounds outside the “cardiac box” Outcome: Primary Outcome: Cardiac injury Safety Outcome: None (this data all came from autopsy reports) Authors’ Conclusions: “For GSWs, the current cardiac box is inadequate to discriminate whether a gunshot wound will cause a cardiac injury. As expected, entrance wounds nearest to the heart are the most likely to result in cardiac injury, but, from a clinical standpoint, it is best to think outside the “box” for GSWs to the thorax.” 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/No 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? Yes Was the follow up of subjects complete enough? Yes How precise are the results? Very 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 authors identified 263 patients with 735 penetrating torso injuries over three years. They reported 620 (84%) of the injuries were from gunshot wounds (GSW) with a mean of 2.6 GSW/patient. After exclusions, 320 GSWs were included in the study. The mean age was 34% and 87% were male. Half of the patients were pronounced dead at the scene and 46% were dead on arrival. Key Results: The relative risk of having a cardiac injury from a GSW in the cardiac box is low and not statistically different from those outside the cardiac box. Primary Outcome: Cardiac Injury 80/257 (31%) in the box and (14/67) 21% outside the box RR = 0.96; p=0.82 We had a hard time confirming their numbers when we tried to calculate the RR. Also their percentage of GSW was 80% in the abstract and 84% in the result section. These discrepancies and issues made us less confident in the study. 1. Autopsy: The authors touch on the fact that their study was an autopsy study. This would exclude all the patients who suffered survivable trauma. In their patient demographics they list the frequency of dead at scene as 50% and dead-on arrival as 46% of all patients. This has huge implications as the patient population is massively different than the patients who survive long enough to enter the care of the hospital team. Although limiting the study to autopsy did provide opportunity to definitively examine for cardiac injury and to precisely evaluate for the location of wounds, the exclusion of patients with survivable injuries presents a challenge to the generalizability of the data.  It is unknown whether the sort of patient who survives long enough to receive care may have an injury pattern more consistent with the traditional cardiac box, and perhaps the tool performs better.  The authors mention that in their “experience with high volumes of penetrating cardiac injuries, these findings parallel clinical practice and experience,” but this is opinion rather than evidence. 2. Death Bias: This will expand on point #1. We often see survival bias but in this case the opposite is true. The bias is towards those who died. It is a form of selection bias. We do not know the injury pattern (inside or outside the cardiac box) for those patients who had GSWs, did not present to the hospital or presented to hospital and survived. 3. Power: The study doesn’t mention how they determined how many patients to enroll in the study. To adequately power a study to detect a difference between two groups, generally a calculation is performed beforehand (a priori) based on the estimated difference between the exposure group and the control group. The authors don’t comment on a power calculation and don’t mention their pre-trial expectation of a difference in cardiac injury based on anatomic location. Performing a power calculation a priori is based on two variables. One is setting the delta (difference) you assume there is between the two groups. In this case it would be cardiac injuries that are from penetrating injuries inside the cardiac box to those outside the cardiac box. The second is the confidence interval that is traditionally set at 95%. This can be one tailed (5%) or two-tailed (2.5%). Doing a power calculation after data has been collected would be wrong and potentially misleading. It is called observed power or post-hoc power. All it does is restate the p-value. Since observed power is a direct function of the p value it does not provide any additional useful information. Unfortunately, you will still see some journals request a post-hoc power calculation mistakenly thinking it will help them distinguish between “true negatives” from “false negatives”. In other word, to differentiate between the lack of observed effect is due to an ineffective treatment or the study shows no effect because it is too small. If you understand how that is not the case you can see how doing these post-hoc power calculations can be misleading, misinterpreted, and ultimately not helpful [4, 5]. 4. 2D vs. 3D: The authors used a two-dimensional definition of the cardiac box looking at the anterior and posterior surface of the thorax. However,

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.