The EMJClub Podcast

Early Norepinephrine for Septic Shock

Journal Club Podcast #49: April 2019 A brief look at the efficacy of sodium bicarbonate in the management of cardiac arrest… Click Tabs Below to Expand Articles: Article 1: Vukmir RB, Katz L; Sodium Bicarbonate Study Group. Sodium bicarbonate improves outcome in prolonged prehospital cardiac arrest. Am J Emerg Med. 2006 Mar;24(2):156-61. Answer Key. Article 2: Kim J, Kim K, Park J, Jo YH, Lee JH, Hwang JE, Ha C, Ko YS, Jung E. Sodium bicarbonate administration during ongoing resuscitation is associated with increased return of spontaneous circulation. Am J Emerg Med. 2016 Feb;34(2):225-9. Answer Key. Article 3: Kawano T, Grunau B, Scheuermeyer FX, et al. Prehospital sodium bicarbonate use could worsen long term survival with favorable neurological recovery among patients with out-of-hospital cardiac arrest. Resuscitation. 2017 Oct;119:63-69. Answer Key. Article 4: Ahn S, Kim YJ, Sohn CH,et al. Sodium bicarbonate on severe metabolic acidosis during prolonged cardiopulmonary resuscitation: a double-blind, randomized, placebo-controlled pilot study. J Thorac Dis. 2018 Apr;10(4):2295-2302. Answer Key. Vignette: You're working a busy shift in TCC one Sunday afternoon when you get a page that EMS is bringing in a patient in cardiac arrest. The patient is a 57-year-old male with unknown past medical history who collapsed while at church. On EMS arrival at the scene, the patient was in ventricular fibrillation. He was defibrillated twice, devolved into PEA, then went back into ventricular fibrillation two more times en route. He arrives in ventricular fibrillation after a final failed attempt at defibrillation. A bolus of amiodarone has also been given, along with four rounds of epinephrine. You resume CPR as you switch the patient over to your monitor. He is being bagged via a laryngeal airway device with a good waveform on capnography. You defibrillate the patient, which results in PEA. He has now been in cardiac arrest for twenty minutes, and you begin to wonder what other management options you have. You consider whether you should give sodium bicarbonate or calcium chloride given his prolonged cardiac arrest, but your attending tells you that neither treatment is beneficial (though you aren't sure epinephrine is beneficial either, and you keep giving that). After a total of thirty minutes of downtime, the patient is now in asystole and the decision is made to call the code. As you leave the room, you wonder whether you should have given sodium bicarbonate after all. You figure the patient had probably become quite acidotic, which you know decreases catecholamine responsiveness, and think trying to ameliorate that acidosis would help the patient. Not satisfied with your attending's brush-off, you decide to search the literature yourself and see what evidence is out there... PICO Question: Population: Adult patients suffering out of hospital cardiac arrest. Special interest was paid to those with prolonged cardiac arrest Intervention: Sodium bicarbonate administration Comparison: Standard care Outcome: Survival to hospital discharge with good neurologic function Search Strategy: The Clinical Queries tool in PubMed was searched using the terms “bicarbonate AND arrest,” resulting in 555 citations (https://tinyurl.com/yxj2682c). Of these, four articles were chosen. A search of the Cochrane Database did not identify any systematic reviews on this topic. Bottom Line: The debate surrounding the use of sodium bicarbonate in cardiac arrest is longstanding. Early Advanced Cardiac Life Support (ACLS) guidelines recommended routine bicarbonate administration for cardiac arrest, while more recent revisions have recommended against its routine use. Stoking this ongoing debate is a lack of rigorous evidence to direct practice. Those randomized controlled trials on the topic either looked at outcomes of little importance to patients (Vukmir 2006)—such as return of spontaneous circulation (ROSC) or survival to the emergency department (ED)—or enrolled such a small sample of patients that clinical significance could not be determined (Ahn 2018). Vukmir et al found no difference in survival to ED admission (RR 0.99; 95% CI 0.70 to 1.40) among all patients, though they did demonstrate a trend toward improved survival in those patients with prolonged (> 15 minutes) cardiac arrest (RR 2.0; 95% CI 0.92 to 4.5). Unfortunately they did not look at long-term survival or neurologic outcomes. Ahn et al found no difference in ROSC or survival to hospital admission (RR 0.25; 95% CI 0.03 to 2.2), but the confidence intervals are so wide that they do not exclude a potentially clinically significant difference. Larger observational studies have demonstrated conflicting results. Kawano et al (Kawano 2017) found a decrease in rates of survival to hospital discharge with bicarbonate administration (AOR 0.48, 95% CI 0.35-0.65) and a decrease in survival with a favorable neurologic outcome (AOR 0.61, 95% CI 0.43-0.86), after adjustment for multiple confounders. Kim et al (Kim 2016) demonstrated an increase in ROSC with bicarbonate administration (OR of 2.49; 95% CI 1.33 to 4.65) independent of other factors. While Kawano et al looked at more clinically appropriate outcomes, both studies were severely limited by a high risk of selection bias and imbalance with regards to both known and unknown confounders between the groups. While there is not a substantial body of evidence to either support of refute the utility of bicarbonate administration in cardiac arrest, the bulk of the evidence does not suggest any benefit. Instead, providers should focus on those factors that have been shown to improve outcomes, such as high quality chest compressions with minimal interruptions and early defibrillation (when appropriate). Bicarbonate, meanwhile, should be reserved for specific case, such as hyperkalemia or suspected TCA overdose.

Journal Club Podcast #48: February 2019 A look at the utility of history, physical exam, and plain radiography for detecting clinically significant injuries of the thoracic and lumbar spine… Click Tabs Below to Expand Articles: Article 1: VandenBerg J, Cullison K, Fowler SA, Parsons MS, McAndrew CM, Carpenter CR. Blunt Thoracolumbar-Spine Trauma Evaluation in the Emergency Department: A Meta-Analysis of Diagnostic Accuracy for History, Physical Examination, and Imaging. J Emerg Med. 2018 Dec 28. Answer Key. Article 2: Inaba K, DuBose JJ, Barmparas G, Barbarino R, Reddy S, Talving P, Lam L, Demetriades D. Clinical examination is insufficient to rule out thoracolumbar spine injuries. J Trauma. 2011 Jan;70(1):174-9. Answer Key. Article 3: Karul M, Bannas P, Schoennagel BP, Hoffmann A, Wedegaertner U, Adam G, Yamamura J. Fractures of the thoracic spine in patients with minor trauma: comparison of diagnostic accuracy and dose of biplane radiography and MDCT. Eur J Radiol. 2013 Aug;82(8):1273-7. Answer Key. Article 4: Inaba K, Nosanov L, Menaker J, et al; AAST TL-Spine Multicenter Study Group. Prospective derivation of a clinical decision rule for thoracolumbar spine evaluation after blunt trauma: An American Association for the Surgery of Trauma Multi-Institutional Trials Group Study. J Trauma Acute Care Surg. 2015 Mar;78(3):459-65; discussion 465-7. Answer Key. Vignette: You're working a shift at a level II trauma center in the community one rainy afternoon when EMS brings in Mr. Q, a 62-year-old man with hypertension and hyperlipidemia who was involved in a motor vehicle collision. He was the unrestrained driver in a car that hydroplaned on the highway and collided with the concrete barrier. His car spun around and was struck on the driver's side before coming to rest in the median. The driver had LOC and ended up in the passenger side of the car. His only complaint is a headache and chest pain. He arrives awake, alert, with abrasions and contusions to his upper face. He has no midline cervical, thoracic, or lumbar spine tenderness and he is neurologically intact. Your next patient is Ms. P, a 47-year-old female with no significant past history who slipped on the wet stairs outside her apartment building. She ended up falling down four stairs, landing primarily on her buttocks. She complains of coccygeal and left hip pain, but denies back or neck pain. She has no midline tenderness in her cervical or thoracic spine, but does have tenderness in the midline lumbar spine, around L2/3. She is neurologically intact. You consider your imaging options in both of these patients. For the first patient, you are planning to get a CT of his head, face, and cervical spine, and are considering a CT of the chest, abdomen, and pelvis as well, based purely on the mechanism of injury. You wonder if you even need to consider imaging of the thoracic and lumbar spine, given his lack of physical exam findings, and if so, wonder if you should get CT reconstructions or if plain films would suffice. In the second case, in addition to imaging of the pelvis and left hip, you are planning to get plain films of the lumbar spine. Again, you wonder if this is sufficient, or if you need to get more advanced imaging (such as a CT) to evaluate for fracture. The first patient gets a "pan-scan" and is found to have isolated facial bone fractures, for which he is evaluated by ENT and eventually discharged home. The second patient is found to have no fractures on plain films, feels much better after ibuprofen, and also goes home. You still have questions about your imaging choices, and a quick look online directs you to a recent systematic review on the evaluation of thoracic and lumbar spine following blunt trauma. Wondering what other literature there is, you begin to conduct a more thorough search... PICO Question: Population: Adult patients suffering blunt trauma Intervention: Aspects of history (e.g. mechanism of injury) and physical exam, plain radiography Comparison: CT scan, surgical findings, follow-up Outcome: Need for surgical intervention or TLSO bracing Search Strategy: A systematic review and meta-analysis, recently published by a collaboration of physicians that included one Washington University emergency physician and recent graduate of our residency program, was first identified. The bibliography of this review was searched to identify three additional relevant studies. Bottom Line: Evaluation for injury of the cervical spine following blunt trauma was made much easier by the derivation and subsequent validation of key clinical decision rules (NEXUS criteria, Canadian c-spine rule). Unfortunately, no such rule exists for evaluation of the thoracic and lumbar spine. At least one observational study from LA County/USC Medical Center (Inaba 2011) suggested that physical exam alone performed poorly at evaluating for a “clinically significant” injury of the thoracic or lumbar spine, with with a sensitivity of 78.6%, specificity of 83.4%, LR+ of 4.73, and LR- of 0.26. A recent systematic review on this topic (VandenBerg 2018) similarly found that aspects of the history and physical exam (when looked at independently) were inadequate at ruling in or out disease. Mechanism of injury had a pooled LR+ ranging from 0.5 to 1.7 and LR- of 0.63 to 1.25. There was no negative finding on physical examination that significantly reduced the probability of finding a TL-spine fracture, although the presence of a palpable spine deformity was good at ruling in a fracture, with a LR+ of 15.3. Various imaging modalities have also been evaluated, with some studies suggesting that plain films alone are inadequate to detect injury. One study looking at trauma to the thoracic spine (Karul 2013) found that plain radiography had a LR+ of 1.09 and LR- of 0.93, suggesting that such films are useless whether they are positive or negative for fracture. Unfortunately, this study was severely limited by incorporation bias (CT was the ultimate gold standard) and spectrum bias, as the study only included patients with a thoracic spine deformity or step-off on exam who were still having pain within 10 days. This study did not address the utility of plain films in patients at lower risk of injury. The systematic review by VandenBerg et al identified additional studies looking at the diagnostic accuracy of various imaging modalities. Five studies evaluated the accuracy of plain films of T and L-spine, with a pooled LR+ of 25.0 (95% CI 4.1-152.2) and LR- of 0.43 (95% CI 0.32-0.59) for diagnosis of injury. Similar likelihood ratios were found when pooling studies looking only at the thoracic spine or only at the lumbar spine. Studies evaluating CT of the chest, abdomen, and pelvis and those looking at reformatted thoracic and lumbar CT found a high degree of accuracy with either modality. As noted by the authors of the review, this evidence is based primarily on retrospective studies at high risk of incorporation bias. Additionally, many of these studies used as their outcome a “significant injury,” which included both the need for surgery or the need for TLSO bracing. Recent research suggests that TLSO bracing (primarily used for burst fractures) is not beneficial (Bailey 2014), and this outcome may not be as patient-centered as intended. One clinical decision rule has been derived (Inaba 2015), with resulting sensitivity and specificity of 98.9% and 29.0%, respectively. This corresponds to a negative likelihood ratio of 0.04, suggesting the rule could significantly reduce the risk of a clinically significant fracture when negative. Unfortunately, this rule has not been validated (Level IV CDR), and the potential impact of the rule has not been evaluated. The final clinical decision rule consisted of the following criteria: 1. High-risk mechanism 2. Findings of pain, tenderness to palpation, deformity, or neurologic deficit 3. Age ? 60 Future research will be needed to validate this rule in multiple settings, and should be aimed at determining the impact of the rule to ensure it improves outcomes or reduces unnecessary imaging without worsening outcomes. Until then, it seems reasonable to continue using clinical acumen to determine who needs imaging of the thoracic or lumbar spine following blunt trauma, with a lower threshold to at least get plain films in those felt to be at low risk of injury. In patients felt to be higher risk, it seems prudent to forego plain radiography and proceed to CT scanning.

Journal Club Podcast #47: January 2019 The Selleck Maneuver? A brief look at whether cricoid pressure (AKA the Selleck Maneuver) decreases aspiration risk or impedes airway visibility… Click Tabs Below to Expand Articles: Article 1: Bohman JK, Kashyap R, Lee A, He Z, Soundar S, Bolling LL, Kor DJ. A pilot randomized clinical trial assessing the effect of cricoid pressure on risk of aspiration. Clin Respir J. 2018 Jan;12(1):175-182. Answer Key. Article 2: Turgeon AF, Nicole PC, Trépanier CA, Marcoux S, Lessard MR. Cricoid pressure does not increase the rate of failed intubation by direct laryngoscopy in adults. Anesthesiology. 2005 Feb;102(2):315-9. Answer Key. Article 3: Birenbaum A, Hajage D, Roche S, et al. Effect of Cricoid Pressure Compared With a Sham Procedure in the Rapid Sequence Induction of Anesthesia: The IRIS Randomized Clinical Trial. JAMA Surg. 2018 Oct 17. Answer Key. Article 4: Oh J, Lim T, Chee Y, Kang H, Cho Y, Lee J, Kim D, Jeong M. Videographic analysis of glottic view with increasing cricoid pressure force. Ann Emerg Med. 2013 Apr;61(4):407-13. Answer Key. Vignette: You are working a shift in TCC one day when the level 1 pager goes off. EMS is bringing in a forty-year-old male involved in a rollover MVC. He was unrestrained, has a blood pressure of 70/40, and has been intermittently combative. You gather your team, grab the ultrasound, and make sure the CMAC is in the room and ready for intubation. The patient arrives in extremis. His combativeness has resolved as he is now unresponsive. He is breathing spontaneously, does not respond to questions, and has sonorous respirations. His GCS is 5. As the team continues the primary survey, all are in agreement that the patient requires intubation to secure his airway. A quick assessment from the head of the bed, as the nurses draw up medications, reveals a large laceration to the left parietal scalp with minimal bleeding, left periorbital ecchymosis and edema, and 4 mm pupils that are round and reactive to light. He has no signs of neck or intraoral injury. His O2 sat is 98% on a nonbreather and his blood pressure is now 82/38. The meds are ready and the team is prepared for the intubation. As he is paralzyed and sedated, you gently remove the cervical collar and ask your colleague to provide inline stabilization. As you open the airway and begin to insert the laryngoscope, you hear somebody question why no cricoid pressure is being administered. As you are busy trying to keep the patient alive, you ignore the ensuing argument and insert a endotracheal tube between the vocal cords without incident. Later, the team discusses the utility of cricoid pressure (aka the Sellick Maneuver) while the patient is undergoing CT scans of his entire body. You have been taught that cricoid pressure is not really helpful, but wonderful if there is actual evidence to back this up. As you begin to search the internet, you find a very recent article published on the topic, with some very in-depth reviews. Not content with this single article, you diver deeper into the subject... PICO Question: Population: Adults patients requiring endotracheal intubation under RSI in the emergency department for any reason. Intervention: Cricoid pressure (AKA the Sellick Maneuver). Comparison: No cricoid pressure. Outcome: Aspiration pneumonitis, hospital-acquired pneumonia, ventilator associated pneumonia, ease of intubation, hypoxia during intubation attempt, failed intubation. Search Strategy: A PubMed search using the terms "cricoid pressure" OR "Sellick maneuver” resulted in 472 citations (https://tinyurl.com/ycb6v3dl), from which the 4 most relevant articles were selected. The Cochrane Database of Systematic Reviews was also searched; this resulted in a single systematic review. As this review only included one article, the review was omitted. Bottom Line: For years after Dr. Sellick first described his maneuver in 1961 (Sellick 1961), cricoid pressure was touted for use during endotracheal intubation to theoretically prevent the aspiration of stomach contents by compressing the upper esophagus. Despite a lack of clinical evidence, this maneuver was widely used by both anesthesiologists (Howells 1983, Thwaites 1999) and emergency physicians (Kovacs 2004, Gwinnut 2015). Over the years, several studies have evaluated the efficacy and harm associated with cricoid pressure, with varying results. In 2005, Turgeon et al performed a randomized controlled trial evaluating the effect of cricoid pressure on failure to intubate within 30 seconds among patients undergoing elective procedures in the operating room (Turgeon 2005). They found no significant differences in failure rates (RR 1.2, 95% CI .058 to 2.5) with and without cricoid pressure. A cross-sectional study published in 2013 (Oh 2013) evaluated the effect of cricoid pressure on glottic view by recording images of the glottis at varying degrees of cricoid pressure using a video laryngoscope. While they did find a decrease in the medial area of the glottic view with increasing pressure, they did not evaluate the effect of this on the ease or success of intubation. More recently, two randomized controlled trials were undertaken to assess the effect of cricoid pressure on rates of aspiration. In the first of these (Bohman 2018), patients undergoing elective surgical procedures were randomized to receive or not receive cricoid pressure. Following intubation, all patients had 5 mL of sterile saline infused into the endotracheal tube, followed by aspiration via a sterile suction catheter. Pepsin A testing was then performed on the aspirate to determine whether micro-aspiration had occurred or not. The presence of significant pepsin A was similar between the groups (RR 0.77, 95% CI 0.33 to 1.8) suggesting to difference in micro-aspiration rates. There was also no difference in the incidence of healthcare-associated pneumonia or ventilator-associated pneumonia. The second trial published last year (Birenbaum 2018) also randomized patients undergoing surgery to cricoid pressure or sham cricoid pressure. Pulmonary aspiration was defined as either visual detection of aspiration during laryngoscopy or by tracheal aspiration following tracheal intubation. Again, the incidence of aspiration was not difference between the two groups (RR 0.90, 95% CI 0.33 to 2.38). Unfortunately, the study was designed as a noninferiority trial, but the incidence of aspiration was much lower than anticipated (0.5% overall). This resulted in the upper limits of the 1-sided 95% confidence interval exceeding the a priori noninferiority margin of 1.5, and the study could not conclude that omitting cricoid pressure was not inferior to its use. Unfortunately, none of the studies we reviewed was conducted in the emergency department (all were conducted in the operating room) and questions of external validity make it difficult to generalize these results to our patient population. Additionally, while these four studies only represent a small portion of the literature on this topic, there has been no direct evidence that cricoid pressure reduces the risk of patient-centered outcomes (i.e. aspiration pneumonitis, healthcare-associated pneumonia, ventilator-associated pneumonia, ARDS).

Journal Club Podcast #46: October 2018 A look at the evidence for and against the routine performance of pelvic examination for abdominal pain or vaginal bleeding in early pregnancy… Click Tabs Below to Expand Articles: Article 1: Seymour A, Abebe H, Pavlik D, Sacchetti A. Pelvic examination is unnecessary in pregnant patients with a normal bedside ultrasound. Am J Emerg Med. 2010 Feb;28(2):213-6. Answer Key. Article 2: Hoey R, Allan K. Does speculum examination have a role in assessing bleeding in early pregnancy? Emerg Med J. 2004 Jul;21(4):461-3. Answer Key. Article 3: Linden JA, Grimmnitz B, Hagopian L, et al. Is the Pelvic Examination Still Crucial in Patients Presenting to the Emergency Department With Vaginal Bleeding or Abdominal Pain When an Intrauterine Pregnancy Is Identified on Ultrasonography? A Randomized Controlled Trial. Ann Emerg Med. 2017 Dec;70(6):825-834. Answer Key. Article 4: Johnstone C. Vaginal examination does not improve diagnostic accuracy in early pregnancy bleeding. Emerg Med Australas. 2013 Jun;25(3):219-21. Answer Key. Vignette: You are working a busy afternoon shift in EM-2, and have just completed your tenth pelvic exam of the day, when you go in to see yet another patient with a pelvic complaint. You encounter a pleasant, 25-year-old woman who is nine weeks pregnant with a very desired pregnancy. She reports light vaginal bleeding without passage of tissue for the last six hours. She denies any lightheadedness or dizziness and reports only mild, intermittent, lower abdominal cramping. She has only gone through two pads since the bleeding began. On exam she has stable vital signs has no abdominal tenderness to palpation. Her bedside ultrasound reveals a live IUP with a heart rate of 150. Her quantitative HCG is 8,000 and her blood type reveals that she is A positive. You present the patient to your attending and show her the ultrasound images. When she asks you what the pelvic exam revealed, you admit that you haven’t done it yet and dutifully trudge back to patient’s room like a child whose been sent to the principal’s office. The pelvic exam reveals a closed cervical os with minimal blood in the vaginal vault and the patient ends up being discharged with bleeding precautions. As you bid her farewell, you wonder if you really needed to do that pelvic exam at all. You’re pretty sure the patient didn’t enjoy it and you certainly could have done without it, and you wonder if there’s any evidence to support of refute the utility of the pelvic exam in the evaluation of vaginal bleeding in early pregnancy. You vow to do some digging to support your hypothesis that it is an unnecessary, and uncomfortable, waste of time… PICO Question: Population: Pregnant women < 20 weeks gestational age with vaginal bleeding or abdominal pain Intervention: Omission of pelvic (speculum and/or bimanual) examination in the ED Comparison: Standard of care, including full pelvic examination Outcome: Change in management or disposition, missed ectopic pregnancy, need for intervention (e.g. manual vacuum aspiration, dilatation and curettage) Search Strategy: PubMed was searched using the terms “((pelvic OR vaginal) AND examination) AND early pregnancy” limited to clinical trials (https://tinyurl.com/yda24s5t). This resulted in 74 citations, from which four articles were chosen. Bottom Line: Vaginal bleeding and abdominal pain are frequent complaints seen in the ED during early pregnancy. Typical evaluation consists of a pelvic ultrasound to confirm the presence of an intrauterine pregnancy (IUP), often accompanied by a pelvic examination (speculum and bimanual) to evaluate the extent of bleeding and to confirm a closed cervical os. Give the time consumed performing the pelvic examination and the perceived discomfort experienced by the patient, some have called into question the utility of this portion of the work-up. Unfortunately, there is little research into this question, and what evidence exists is mostly of low quality. Three prospective observational studies were identified, though two of these (Johnstone 2013, Hoey 2004) were severely limited by the lack of a pelvic ultrasound during the ED stay to confirm an IUP. Given that our primary diagnostic modality in these patients is ultrasound to confirm an IUP, the results of these studies are of little value (external validity). The third observational study (Seymour 2010) only enrolled pregnant patients of 16 weeks gestational age or less with a confirmed IUP on ultrasound. They found that the pelvic examination did not affect patient disposition, but did not look at the effect on management outside of this (e.g. need for manual vacuum aspiration, dilatation and curettage) or the timing of follow-up. The fourth article reviewed (Linden 2017) was a prospective randomized controlled trial conducted at two academic ED’s in Boston and Washington, D.C. Pregnant patients < 16 weeks gestational age with vaginal bleeding or abdominal pain and with a documented IUP were randomized to either undergo a pelvic examination omitted or to have one performed. The incidence of the primary outcome (a 30-day composite that included need for further treatment or intervention, unscheduled return visits to the ED or clinic, need for hospital admission, emergency procedure transfusion, infection, or subsequent identification of other source of symptoms occurred with similar frequency in the no pelvic exam group (19.6%) and the pelvic exam group (22.0%) for an absolute risk reduction (ARR) of -2.4% (95% CI -11.8% to 7.1%). Unfortunately, this study was limited by its small size as well as its chosen outcomes. While it assessed many sources of comorbidity, it did not address the potential need for an urgent procedure among those patients with limited follow-up, the potential for missed infectious diagnoses, or the long-term effects of delayed treatment and/or diagnosis. While this subject remains controversial, there is insufficient evidence to recommend omitting the pelvic examination in this population of patients.

Journal Club Podcast #45: August 2018 A look at the use of BNP to differentiate cardiac from non-cardiac causes of syncope... Click Tabs Below to Expand Articles: text Article 1: Pfister R, Hagemeister J, Esser S, Hellmich M, Erdmann E, Schneider CA. NT-pro-BNP for diagnostic and prognostic evaluation in patients hospitalized for syncope. Int J Cardiol. 2012 Mar 8;155(2):268-72. Answer Key. Article 2: Reed MJ, Newby DE, Coull AJ, Prescott RJ, Jacques KG, Gray AJ. The ROSE (risk stratification of syncope in the emergency department) study. J Am Coll Cardiol. 2010 Feb 23;55(8):713-21. Answer Key. Article 3: Reed MJ, Newby DE, Coull AJ, Jacques KG, Prescott RJ, Gray AJ. Role of brain natriuretic peptide (BNP) in risk stratification of adult syncope. Emerg Med J.2007 Nov;24(11):769-73. Answer Key. Article 4: Isbitan A, Hawatmeh A, Elnahar Y, et al. Utility of brain natriuretic peptide assay as a predictor of short term outcomes in patients presenting with syncope to the emergency department. Cardiovasc Diagn Ther. 2016 Jun;6(3):234-40. Answer Key. Vignette: You are working an evening shift in your ED as the senior resident when you encounter Mr. Drop, a 58-year-old male presenting with syncope. He was sitting at the dinner table, getting ready to eat, when he suddenly lost consciousness and fell face-first into his mashed potatoes. He had no seizure activity and awoke within a few seconds. His wife helped him clean the mashed potatoes off his face and brought him to the ED. His past medical history includes hypertension and diet-controlled diabetes, and he endorses a family history of coronary artery disease in both parents. He denies chest pain, shortness of breath, or palpitations, and his vital signs and physical exam are currently normal. You go to put in orders, including an ECG, BMP, CBC, and troponin, when your large Russian attending, whose hairstyle reminds you of Eddie Munster, suggests you order a BNP, “to help determine if this is cardiac syncope.” In your years of training, this is the first time anyone has suggested such a thing, but not wanting to anger this dangerous-looking attending, you comply without question. Later, when you’re certain he’s not looking, you open up PubMed and begin searching the evidence to see if there is actually any correlation between BNP levels and cariogenic syncope… PICO Question: Population: Adult patients presenting to the ED with syncope of unclear etiology Intervention: BNP testing Comparison: Standard ED workup Outcome: Diagnostic accuracy of BNP for potentially life-threatening causes of syncope (e.g. arrhythmia or structural cardiac disease), impact of BNP testing on admission rates, impact of BNP on diagnostic testing. Search Strategy: PubMed was searched using the terms “(BNP OR “brain natriuretic peptide”) AND syncope” (https://tinyurl.com/yc4ta5e9). This resulted in 35 citations, from which the 4 most relevant articles were chosen. Bottom Line: Syncope is a common presenting complaint in the ED with a large number of potential underlying causes, ranging from the very benign (e.g. vasovagal syncope, orthostasis) to potentially life-threatening causes (e.g. cardiac arrhythmia). While studies have demonstrated a broad range for rates of serious outcomes, as wide as 1.2% to 36.2%, there is very little objective data to help the emergency physician determine who is safe for discharge and who requires admission to prevent morbidity and mortality. Several clinical prediction rules have been developed to assist with disposition decisions; unfortunately, none of these has performed well when external validation has been attempted (Birnbaum 2008, Serrano 2010, Safari 2016). As a result, investigators continue to search for potential prognostic factors to help differentiate those syncope patients at high risk of adverse outcome from those safe for discharge. Brain natriuretic peptide (BNP) and its analogs are typically elevated in the setting of structural heart disease, but has also been show to increase following certain cardiac arrhythmias. As a result, BNP has been proposed as a possible test to help differentiate cardiogenic from non-cardiogenic causes of syncope. A small, prospective, observational study conducted in Scotland in 2007 (Reed 2007) demonstrated a significant association between BNP values and serious adverse outcome. Unfortunately, the test characteristics for this association were rather poor. To predict a serious outcome at 3 months (including death, MI, life-threatening arrhythmia, implantation of a pacemaker or defibrillator, PE, CVA, intracranial hemorrhage, need for blood transfusion or need for acute surgical procedure or endoscopic intervention), a BNP > 100 had a positive likelihood ratio (LR+) of 2.21 and a negative likelihood ratio (LR-) of 0.48, suggesting that neither a positive nor negative test at this threshold would have any significant impact on post-test probability. For a threshold of 1000, BNP had a LR- of 0.51, which again would be of little help. While the LR+ was infinity, there were only 3 patients with a BNP this high. A larger study would need to confirm the potential utility of a BNP this elevated, though it would likely impact only a small percent of patients presenting with syncope (most of whom would likely be admitted anyway). Based on this observed association, these authors conducted an additional study (Reed 2010) in which they attempted to derive and validate a clinical decision rule employing BNP results as one of the criteria. They developed the ROSE rule, which employed the following criteria: BNP level ? 300 pg/mL Bradycardia ? 50 in ED or pre-hospital Rectal examination with fecal occult blood Anemia (hemoglobin ? 90 g/L) Chest pain associated with syncope ECG showing Q-wave (not in lead III) Saturation ? 94% on room air This rule was derived in 529 ED patients presenting with syncope. In the derivation cohort, the rule had a LR+ of 3.5 and LR- of 0.1 , suggesting that it may be useful in reducing the probability of a serious outcome in patients with none of the criteria, with a small increase in the probability in patients for whom the rule is positive. The rule performed slightly less well in the validation cohort (N = 550), with a LR+ of 2.5 and LR- of 0.2. Unfortunately, these results are skewed by several sources of bias: only 13% of patients underwent rectal examination (which was a component of the rule); a non-consecutive sample of patients was enrolled, with 35% and 40% of eligible patients not approached for enrollment in the derivation and validation cohorts, respectively; and the rule was derived and validated at a single study site, requiring additional validation at multiple sites before it can be used safely. Previously, the San Francisco syncope rule was validated at a single site, but then failed to validate when tested at additional sites. Two additional prospective studies evaluating the diagnostic accuracy of BNP or its analogs were reviewed. The first of these (Pfister 2012) enrolled patients with syncope admitted to a cardiac unit in Cologne, Germany. They evaluated the accuracy of NT-pro-BNP for identifying patients with an arrhythmia or structural cardiac/cardiopulmonary abnormality. With 161 patients enrolled, the study found a LR+ of 1.86 and LR- of 0.20. The second study (Isbitan 2016) enrolled patients at two emergency departments in New Jersey and evaluated the accuracy of BNP at determining “serious outcomes” (which were similar to those listed for the two studies by Reed). Using a cutoff of 250, the authors found a LR+ of 5.02 and LR- of 0.57. Again, these two studies demonstrate rather poor positive and negative likelihood ratios which would not be expected to have a significant effect on probability. Additionally, the first study likely suffers from spectrum bias, as it was conducted on a cohort of patients already admitted to a cardiac unit rather than undifferentiated ED patients. Overall, the current evidence for the use of BNP in the work-up of syncope is rather limited and not very promising. All of the studies were limited by the lack of a clear gold standard in the evaluation of syncope and by a non-uniform application of additional testing leading to differential verification bias and partial verification bias. The diagnostic accuracy of BNP in these studies was poor, with a LR- ranging from 0.2 to 0.57 and LR+ ranging from 1.86 to 5.02; although LR+ was infinity when a high enough BNP threshold was used, such a cutoff would likely be of little value, as it would be unlikely to change management and would apply to a rather small number of patients. The ROSE rule, while promising on derivation, had a LR- of 0.2 when validated; additional validation in other clinical settings would be needed to determine whether it would be reasonable to use. For now, BNP and the ROSE rule should not be used to determine disposition or direct further evaluation of patients presenting to the ED with syncope.

Journal Club Podcast #44: July 2018 A (somewhat)restrained rant on the importance of looking at the details and not combining outcomes to improve precision... Click Tabs Below to Expand Articles: Article 1: Self WH, Semler MW, Wanderer JP, et al; SALT-ED Investigators. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):819-828.Answer Key. Article 2: Semler MW, Self WH, Wanderer JP, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):829-839. Answer Key. Article 3: Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan MS, Setoguchi S, Beadles C, Lindenauer PK. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit Care Med. 2014 Jul;42(7):1585-91. Answer Key. Article 4: Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012 Oct 17;308(15):1566-72. Answer Key. Vignette: It’s another busy day TCC, when an elderly female rolls in from triage with fever, cough, and a new oxygen requirement. Her vitals are T 38.3 BP 90/42, HR 115, RR 24, SpO2 88% on RA. Even before you see the patient you are concerned for pneumonia with severe sepsis. You institute early antibiotics, fluids, serial lactates and systematically begin to aggressively resuscitate her. The patient requires nearly five liters of normal saline before her blood pressure stabilizes. Proud of your resuscitation, you tweet out #crushingsepsis and #normalsaline4life which gets an immediate response from Dr. Evan Schwarz, who happened to be trolling your twitter feed. He tweets “More like #increasedrenalfailure and #trybalancedfluids”. Inspired by his tweets (and his article published in EPMonthly) you perform a brief literature review on the topic of ‘balanced fluid’ resuscitation. PICO Question: Population: Adult patients receiving IV crystalloid (admitted patients, critically ill patients, patients with severe sepsis or septic shock) Intervention: Balanced (chloride-restricted) crystalloids such as Lactated Ringer’s or Plasma-Lyte Comparison: Normal Saline Outcome: Mortality, renal failure, need for renal replacement therapy Search Strategy: Two recently published, highly publicized articles (Self 2018 and Semler 2018) were chosen for inclusion. In order to identify two additional articles, the previous journal club covering this topic (November 2015) was searched and the two most relevant articles chosen. Bottom Line: Normal saline has long been the “go to” fluid of choice for resuscitation in the ED for critically ill patients. However, the use of such “chloride rich” or “unbalanced” fluids has been controversial for decades, with many calling for the use of fluids that more closely resemble the tonicity of human blood. Aggressive resuscitation with isotonic saline has been shown to decrease serum pH, without affecting serum osmolality (Williams 1999), and has been suggested to increase the risk of renal dysfunction (Lobo 2014). The clinical significance of these and similar effects has been called into question over the last decade. We sought to evaluate the evidence for and against the use of balanced fluid resuscitation in ED patients, particularly those with severe sepsis or septic shock. The first paper we reviewed was a retrospective before-and-after study conducted at a single ICU in Melbourne Australia (Yunos 2012). This study demonstrated an decreased risk of acute kidney injury (OR 0.52, 95% CI 0.37-0.75) and need for renal replacement therapy(OR 0.52 95% CI 0.35-0.76) with the use of balanced fluids. Unfortunately, this study was not only limited by its methodological design, but is not externally valid to our patient population, as only 22% of patients were admitted from the ED, half were post-operative, and nearly a third were admitted following elective surgery A less methodologically robust, retrospective study was identified that at least enrolled patients more similar to those in our setting (Rhagunathan 2014). This study was conducted using a retrospective cohort of patients from 360 US ICUs with sepsis requiring vasopressor therapy. Unfortunately, as this was retrospective, the two treatment groups were unbalanced, and statistical methods had to be employed to balance the two cohorts. Patients receiving any amount of balanced fluid were propensity matched to patients receiving only unbalanced fluids during the same time period. Patients who received some balanced fluids saw a decrease in in-hospital mortality (RR 0.86, 95% CI 0.78-0.94; NNT 31) with no difference in AKI or need for dialysis. A dose-response relationship was also observed, in which the relative risk of in-hospital mortality was lowered an additional 3.4% on average for every 10% increase in in the proportion of balanced fluids received. More recently, two large quasi-randomized studies looking at the use of balanced fluids were published out of Vanderbilt University Medical Center. The first of these (Self 2018) enrolled patients receiving at least 500 mL of intravenous isotonic crystalloid in the ED who were later admitted to a non-ICU bed (i.e. non-critically ill patients). Patients were "randomized" based on calendar month, alternating between saline and balanced cystalloids. There was no difference in the primary outcome (number of hospital-free days to day 28) between the two groups. There was small decrease in risk of the secondary outcome, major adverse renal events—a composite of doubling of creatinine from “baseline,” need for renal replacement therapy, and death—with an adjusted odds ratio of 0.98 (95% CI 0.92-1.04), a risk reduction of 0.9%, and a NNT of 111. This slight difference was entirely driven by the decreased risk of a doubling of the creatinine, with no actual difference in need for renal replacement therapy or death. In fact, the statistical significance achieved was also entirely due to the use of a composite outcome to increase the incidence of any outcome (thereby narrowing the 95% CI), with no actual statistically significant difference in the risk of doubling of creatinine when looked at in isolation (RR 0.86, 95% CI 0.73-1.01). It shouldn’t be surprising that no real difference in outcomes was observed in this study, given that these were relatively healthy patients receiving a rather small amount of fluid (median volume of ~ 1 liter during the entire hospitalization). The results are made even more suspect by the fact that over a third of patients did not have a baseline creatinine in the system for comparison, but rather had a baseline creatinine estimated based solely on age, race, and gender. The second study out of Vanderbilt (Semler 2018) was similar in methodology, but enrolled only adult patients admitted to one of five participating ICUs. In this case, the primary outcome was the composite incidence of major adverse renal events, as defined for the previous study. The authors again found a small reduction in the incidence of major adverse renal events, with an adjusted OR of 0.90 (95% CI 0.82-0.99), a risk reduction of 1.1%, and a NNT of 91. As in the prior study, there was no statistically significant difference for any of the individual components of this composite outcome; by combining outcomes, the authors were able to increase the incidence and hence decrease the 95% CI, allowing them to achieve statistical significance. In this case, the difference was only observed after statistical adjustment for known confounder; when looking at unadjusted data, there was no statistically significance difference between the groups (RR 0.93, 95% CI 0.86-1.00). Interestingly, the median volume of fluid administer was about 1 liter, similar to the study conducted on non-critically ill patients, and it quite likely that a more pronounced effect would be seen in patients receiving a larger volume of fluid. In fact, a fairly large treatment effect was observed in subgroup analysis of patients with sepsis, with a risk difference of 5.1% (NNT ~20). The bulk of this evidence suggests that when administered broadly, the use of saline versus balanced fluids does not have any real impact on meaningful outcomes. However, when larger volumes of fluid are administered (such as in patients with sepsis), there does seem to be a trend, at least, towards improved outcomes. Rather than continue to research the use of balanced fluids in non-critically ill patients or in all patients admitted to an ICU, regardless of medical condition, further research should attempt to confirm the apparent benefit in those patients likely to receive a larger volume of IV fluids. Likewise, despite the low cost and lack of harm associated with Lactated Ringer’s solution, it would be difficult to broadly recommend its use over normal saline, but rather to consider its use when two or more liters of fluid are expected to be given.

Journal Club Podcast #43: May 2018 A brief look at the evidence for and against the use of steroids in patients sepsis and septic shock... https://www.textfixer.com/html/convert-word-to-html.php Click Tabs Below to Expand Articles: Article 1: Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. Answer Key. Article 2: Keh D, Trips E, Marx G, et al; SepNet–Critical Care Trials Group. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016 Nov 1;316(17):1775-1785. Answer Key. Article 3: Venkatesh B, Finfer S, Cohen J, et al; ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808. Answer Key. Article 4: Annane D, Renault A, Brun-Buisson C, et al; CRICS-TRIGGERSEP Network. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809-818. Answer Key. Vignette: You’re working the weekend shift in TCC when you get a page: triage patient to 3L for low BP. You meet the patient in the room and find a critically ill-appearing 55-year-old female with one week of cough and increased shortness of breath. Her vital signs are: HR 125 BP 65/30 SpO2 89% on room air RR 28 She is struggling to breathe, getting out 2 to 3 word sentences, and is oriented only to self. You immediately ask the nurses to get two large-bore IVs and hang two liters of normal saline on pressure bags while you prepare to intubate. Following intubation (during which you administer two boluses of phenylephrine, 100 mcg each, for dropping blood pressure), you get a stat portable chest x-ray showing multifocal pneumonia. After your initial two liters of fluid have been administered, followed by a third (and broad-spectrum antibiotics), the patient’s blood pressure is still only 80/45. You place a right-sided internal jugular central line under ultrasound guidance and start a norepinephrine drip. Your deftly placed arterial line begins to demonstrate an improved BP and MAP and you find the patient a bed in the medical ICU. As the patient is being transferred, you begin to wonder whether steroids would be beneficial in this patient with clear septic shock. After all, you know that much of the problem in sepsis is the inflammatory response, which would theoretically be mitigated by steroid administration. You begin to search the literature and realize this has been a controversial topic dating back over 10 years... PICO Question: Population: Adults patients with either severe sepsis without septic shock of with septic shock. Intervention: IV steroids, administered as an intermittent bolus or a continuous infusion. Comparison: Placebo and standard of care. Outcome: Mortality, resolution of septic shock, development of septic shock, ICU and hospital length of stay, duration of mechanical ventilation, need for renal replacement therapy. Search Strategy: PubMed was searched using the terms “steroids AND sepsis” and limiting the results to clinical trials (https://tinyurl.com/y9wswub5). This strategy yielded 363 studies, from which the four most relevant articles were chosen. The Cochrane Database of Systematic Reviews was also searched in an attempt to find a meta-analysis of results, but no such article was identified. Bottom Line: In 2002, a landmark study published in JAMA (Annane 2002) demonstrated a significant reduction in 28-day mortality with the use of low-dose steroids among patients with septic shock who did not respond appropriately to a corticotropin stimulation test (adjusted odds ratio [OR] 0.54, 95% CI 0.31-0.97). Despite adjusting outcomes for baseline characteristics in this randomized controlled trial (with no difference in outcomes looking at raw data), the authors concluded that steroids were beneficial in non-responders. Since this study was published, several studies have been conducted to reevaluate the effects of steroids on the course of septic shock. We looked at four such articles, including two high-impact articles published earlier this year. In 2008, the CORTICUS trial was published as a follow-up to the initial 2002 study. This international, multicenter trial again evaluated the efficacy of steroids in both corticotropin non-responders and responders with septic shock, and found no difference in 28-day mortality among either group (relative risk [RR] 1.09, 95% CI 0.77 to 1.52 and RR 1.09, 95% CI 0.84-1.41, respectively). The authors therefore concluded that “hydrocortisone cannot be recommended as general adjuvant therapy for septic shock (vasopressor responsive), nor can corticotropin testing be recommended to determine which patients should receive hydrocortisone therapy.” Given the different outcomes observed in these two early studies, further research has since been completed to attempt to obtain a more definitive answer. Earlier this year, two studies were published in the New England Journal of Medicine, again with differing results. The ADRENAL study enrolled 3800 patients with septic shock requiring mechanical ventilation, but did not test corticotropin responsiveness. Patients were randomized to either placebo or a continuous infusion of hydrocortisone for up to 7 days, and there was no difference in 90-day mortality between the groups (OR 0.95, 95% CI 0.82-1.10). Similar to the CORTICUS trial, they did find a faster time to resolution of shock in the hydrocortisone group (median 3 vs. 4 days; hazard ratio [HR] 1.32, 95% CI 1.23-1.41), but this again is of unclear importance to the patient. The APPROCCHSS trial, published soon after the ADRENAL trial, again enrolled patients with septic shock, but was designed to test the efficacy of both combined hydrocortisone-fludrocortisone therapy AND drotrecogin alfa. As drotrecogin alfa was removed from the market several years into the study, an adjustment was made and the study ended with a two-parallel-group design. Unfortunately, due to this adjustment, the study was halted twice for prolonged periods, and hence was completed over a seven-year period, during which multiple changes in the management of sepsis occurred (see Journal Club July 2015, Journal Club October 2010). While this trial found a decrease in 90-day all-cause mortality with steroid administration (RR 0.88, 95% CI 0.78-0.99) its logistical issues make these results difficult to interpret. While these studies had differing results, the APPROCCHSS study at least suggests that it is reasonable to administer stress-dose steroids to patients with sepsis and refractory shock, as in this study, only patients requiring vasopressors for at least 6 hours were eligible for enrollment. This is likely not a significant change from current management in many ICUs. An additional study was identified that looked at the ability of steroids to prevent progression to shock in patient with severe sepsis (the HYPRESS trial). A total of 353 patients with sepsis and evidence of organ dysfunction without shock were enrolled and randomized to received placebo (mannitol) or a continuous infusion of hydrocortisone for 5 days, followed by a taper. There was no significant difference in rates of progression to shock between the two groups (absolute risk reduction [ARR] -1.8%, 95% CI -10.7% to 7.2%), or in 28-day, 90-day, 180-day, ICU, or in-hospital mortality. There was also no difference in ICU or hospital length of stay, need for mechanical ventilation, or need for renal replacement therapy. This final study suggests no benefit with the administration of steroids in patients with sepsis but without shock.

Journal Club Podcast #42: April 2018 A brief recap of four articles selected for review by the critical care folks... Click Tabs Below to Expand Articles: Article 1: Jakob SM, Ruokonen E, Grounds RM, et al; Dexmedetomidine for Long-Term Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012 Mar 21;307(11):1151-60. Answer Key. Article 2: Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017 Jun;151(6):1229-1238. Answer Key. Article 3: Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis. 2013 May;13(5):426-35. Answer Key. Article 4: Glajchen M, Lawson R, Homel P, Desandre P, Todd KH. A rapid two-stage screening protocol for palliative care in the emergency department: a quality improvement initiative. J Pain Symptom Manage. 2011 Nov;42(5):657-62. Answer Key. Search Strategy: Four articles relevant to the critical care medicine in the emergency department were selected by the critical care medicine section. No formal literature search was performed. Bottom Line: PGY-1 These two blinded, randomized controlled trials comparing dexmedetomidine with midazolam and propofol demonstrated noninferiority of dexmedetomidine with regards to the proportion of time spent at the desired level of sedation, with a decreased in duration of mechanical ventilation compared to midazolam, but no difference compared to propofol. Imbalances in dosing, resulting in lower levels of sedation among patients receiving dexmedetomidine compared to the standard drugs, and lack of objective criteria for weaning of mechanical ventilation and extubation suggest that there may be issues with both internal and external validity. Additionally, patient-centered outcomes and cost were not assessed in this study, nor was the incidence or degree of delirium. PGY-2 This single-center, before and after study demonstrated a rather large reduction in morality among patients with severe sepsis and septic shock treated with IV vitamin C, hydrocortisone, and thiamine. The results of this study are quite profound, and hence should be confirmed with additional prospective, randomized controlled trials. If this intervention is truly this beneficial, and truly reduces mortality to less than 10% in this patient population, routine use of this therapy should be initiated immediately. PGY-3 In this meta-analysis evaluating the diagnostic capability of serum procalcitonin in the differentiation of sepsis from non-infectious SIRS, the reported pooled sensitivity and specificity correspond to positive and negative likelihood ratios of 3.7 and 0.29, which will only result in small changes in disease probability. Therefore, caution will need to be exercised when interpreting test results. Interval likelihood ratios may provide more clinically useful information, but were not provided. If procalcitonin is to become a relevant aspect of sepsis care, additional research will need to identify a particular clinical role with an improvement in patient-oriented outcomes. PGY-4 This study suggests that an ED protocol to screen elderly patients with functional decline who would benefit from palliative care or hospice is feasible, but highly cost-ineffective. Additional means of implementing this protocol in a way that does not involve hiring additional, full-time staff should be sought and studied.

Journal Club Podcast #41: March 2018 A look at the PESIT trial, which suggests a very high rate of PE in syncope patients, followed by a look at the rest of the evidence... Click Tabs Below to Expand Articles: Article 1: Prandoni P, Lensing AW, Prins MH, et al; PESIT Investigators. Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope. N Engl J Med. 2016 Oct 20;375(16):1524-1531. Answer Key. Article 2: Costantino G, Ruwald MH, Quinn J, et al. Prevalence of Pulmonary Embolism in Patients With Syncope. JAMA Intern Med. 2018 Jan 29. Answer Key. Article 3: Frizell A, Fogel N, Steenblik J, Carlson M, Bledsoe J, Madsen T. Prevalence of pulmonary embolism in patients presenting to the emergency department with syncope. Am J Emerg Med. 2018 Feb;36(2):253-256. Answer Key. Article 4: Oqab Z, Ganshorn H, Sheldon R. Prevalence of pulmonary embolism in patients presenting with syncope. A systematic review and meta-analysis. Am J Emerg Med. 2017 Sep 14. pii: S0735-6757(17)30740-4. Answer Key. Vignette: You’re working a TCC shift with Dr. Cohn, sitting right beside you. He’s drinking a Diet Coke, having not offered you one. You decide to go see your next patient, a 78 year old female, complaining of “feeling woozy”. She endorses syncope, shortness of breath, and leg pain. She is saturating 89% on room air, tachycardic to 104, and BP 117/76. She has many other reasons other than a pulmonary embolism to be feeling this way, but the syncope has you thinking. You remember reading an article that was all the rage a few months ago regarding syncope as a presenting complaint for PE. It was fake news, you said. So vague. But here you are. You’ve got a minute, and Dr. Cohn by your side. You search the literature and gently fall into the rabbit hole… PICO Question: Population: Adult patients presenting to the ED with syncope and those patients who were admitted to the hospital for syncope. Intervention: Routine testing for pulmonary embolism (PE) Comparison: Standard of care with PE workup based on clinical gestalt Outcome: Prevalence of PE among these patients, mortality, development of CTEPH, adverse reaction to IV contrast, cancer rates. Search Strategy: PubMED was searched using the terms "pulmonary embolism" AND prevalance AND syncope (https://tinyurl.com/y7x4gs2u). This resulted in 93 citations, from which 4 relevant articles were chosen. Bottom Line: In 2016, the PESIT study from Italy, published in the New England Journal of Medicine, demonstrated an extremely high prevalence of pulmonary embolism (PE) among patients admitted to the hospital for syncope (Prandoni et al). The 17.3% prevalence observed in this study was shocking, and several editorials attempted to rationalize these findings (EPMonthly, R.E.B.E.L.EM, NUEMBlog). As a result, several studies have been published in the interim attempting to either replicate or refute these findings. We looked not only at the PESIT study, but two of these additional studies and a meta-analysis of data in an attempt to place these results in a broader context. Two retrospective studies were identified, one involving patients from five separate longitudinal administrative databases from Canada, Denmark, Italy, and the United States (Costantino 2018), the other involving patients prospectively enrolled in a syncope database at the University of Utah Hospital (Frizell 2018). Both studies failed to demonstrate such a high prevalence of PE. In the former study, the rate of PE diagnosis among all ED patients ranged from 0.06% to 0.55% in the different databases, while the rate among hospitalized patients ranged from 0.15% to 2.10%. In the latter study, the prevalence of PE among all ED patients with syncope was 0.6%, while the rate among admitted patients was 2.3% (including 2 patients presumably diagnosed with PE within 30 days after hospital discharge, both of whom had a negative CT scan for PE while in the ED). The meta-analysis we reviewed (Oqab 2017) included 9 studies involving 6608 ED patients and 3 studies involving 975 admitted patients, and demonstrated a similarly low prevalence of PE. The prevalence among all ED patients was 0.8%, and the prevalence among patients hospitalized for syncope was 1.0%. Interestingly, this study specifically excluded the PESIT trial from its meta-analysis. Inclusion of the PESIT study would likely increase the pooled prevalence, though likely not by a significant amount. The PESIT study itself is the only prospective study of its kind in which all patients being admitted to the hospital for syncope were evaluated for PE. They used an algorithm in which a simplified Well's score for PE was calculated and a d-dimer was drawn in all patients. Those with a low-risk Well’s score and a negative D-dimer underwent no further testing, while anyone with a high-risk Well’s score or a positive D-dimer underwent either CT pulmonary angiography (CTPA) or ventilation-perfusion testing (V/Q). Interestingly, the enrolled population seems to be a very high-risk cohort. Nearly 11% of patients had cancer, 7% had recent prolonged immobility, and 5% had recent trauma or surgery. Of those patients diagnosed with PE, 45% were tachypneic, a third were tachycardic, a third were hypotensive, and 40% had clinical signs of DVT. The authors note that 24 patients diagnosed with PE had no clinical manifestations of the diagnosis, including tachypnea, tachycardia, hypotension, or clinical signs or symptoms of DVT. Excluding patients with signs concerning for thromboembolic disease, the rate of PE among remaining patients was only around 5%. If you further excluded patients at high risk of PE (i.e. those with cancer, recent immobilization, or recent surgery) this number would likely be even lower. Previous calculations have estimated the test threshold for PE as low as 1.8% (Kline 2004), or as high as 5.5%. Based on this study, even excluding patients with obvious signs of PE or DVT, the prevalence of disease is still likely above the test threshold. However, all of the other evidence suggests that the actual prevalence of PE among patients in the ED, or even being admitted to the hospital, is much lower, and is very likely to be below this threshold. For now, PE should certainly be considered in the differential for any patient presenting with syncope, but routine testing is not likely to benefit patients. Rather, patients with clinical signs or symptoms concern for PE, or significant risk factors, should undergo risk stratification via the PERC rule, modified Well’s score, or Geneva score, with additional testing based on pre-test probability.

Journal Club Podcast #40: January 2018 A little discussion about the evidence for amiodarone in atrial fibrillation, stable V-tach, and shock-refractory VF/VT in cardiac arrest... Click Tabs Below to Expand Articles: Article 1: Ortiz M, Martín A, Arribas F, et al; PROCAMIO Study Investigators. Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study. Eur Heart J. 2017 May 1;38(17):1329-1335. Answer Key. Article 2: Chevalier P, Durand-Dubief A, Burri H, Cucherat M, Kirkorian G, Touboul P. Amiodarone versus placebo and class Ic drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis. J Am Coll Cardiol. 2003 Jan 15;41(2):255-62. Answer Key. Article 3: Kudenchuk PJ, Brown SP, Daya M, et al; Resuscitation Outcomes Consortium Investigators. Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2016 May 5;374(18):1711-22. Answer Key. Article 4: Kudenchuk PJ, Leroux BG, Daya M, et al; Resuscitation Outcomes Consortium Investigators. Antiarrhythmic Drugs for Nonshockable-Turned-Shockable Out-of-Hospital Cardiac Arrest: The ALPS Study (Amiodarone, Lidocaine, or Placebo). Circulation. 2017 Nov 28;136(22):2119-2131. Answer Key. Vignette: Working in TCC can be draining, and on one particularly busy afternoon, you begin to suspect your own sanity. After back-to-back cardiac arrest patients, you wonder if perhaps you should have done something less stressful with your life, like maybe become a lobster boat captain or an ice road trucker. Your first code is a middle-aged female who suffered cardiac arrest while watching Alabama beat Clemson during the Sugar Bowl (yeah...that's right!!!). She was initially noted to be in ventricular fibrillation (VF), and remained so after three rounds of defibrillation. As she arrives in the trauma room, you immediately continue CPR and set up to shock her again. Your attending orders amiodarone, and even though you remember hearing that this may not be very effective, you realize it's not the time to argue. The patient ends up with ROSC and goes to the cath lab when her ECG reveals an anterior STEMI. Your second patient is an elderly male who was initially found to be in PEA by EMS, but then later developed fine VF after three rounds of epinephrine en route. You shock him three times in the trauma room without effect, and once again your attending calls for amiodarone. After twenty more minutes of CPR, the patient reverts to asystole and the code is soon called. You end up giving amiodarone twice more in your shift, once to a patient with new-onset a-fib who ends up getting admitted after not converting to a sinus rhythm, and later to a patient with stable, wide-complex tachycardia (which you're pretty sure was ventricular tachycardia [VT]), and you start to wonder if your attending owns stock in the company that makes it. You search online after your shift and find an excellent rundown on the limits of amiodarone on RebelEM, which prompts you to perform your own literature search. PICO Question: Population: Adults patients with either new-onset atrial fibrillation, hemodynamically stable ventricular tachycardia (VT), or cardiac arrest due to ventricular fibrillation (VF) or VT Intervention: IV Amiodarone Comparison: Placebo or any alternative antiarrhythmic Outcome: Conversion to normal sinus rhythm, need for hospital admission, survival, functional neurologic outcome, hypotension. Search Strategy: Three articles were chosen from the RebelEM blog (Ortiz 2017, Chevalier 2003, Kudenchuk 2016). A fourth article was chosen by reviewing the “similar articles” list for the Kudenchuk article (Kudenchuk 2017). Bottom Line: Amiodarone, which was first approved by the FDA in 1985, became a mainstay of arrhythmia management after being added to the ACLS guidelines in 2000. At that time, amiodarone was recommended ahead of lidocaine for management of hemodynamically stable wide-complex tachycardia but was only included as a consideration for refractory VF and pulseless VT. In the 2010 update, amiodarone was recommended as a “first line anti arrhythmic agent” in refractory VF/pulseless VT, based on limited evidence for improved rates of ROSC and hospital admission. In addition, amiodarone been recommended for use in recent-onset AF for over twenty years (Hou 1995). Given the rise in prominence of procainamide use in AF (see Ottawa Aggressive Protocol by Stiell et al), and an increased focus on longer term outcomes in cardiac arrest, we decided to review evidence for a variety of amiodarone indications frequently seen in the ED. Stable Ventricular Tachycardia PROCAMIO, a small, multicenter randomized controlled trial conducted at several hospitals in Spain enrolled 74 patients with hemodynamically stable, wide-complex tachycardia and randomized them to receive either IV amiodarone or IV procainamide over twenty minutes. Major cardiac events (clinical signs of hypoperfusion, dyspnea, hypotension, or acceleration of heart rate) occurred less frequently among patients receiving procainamide (OR 0.1; 95% CI 0.03 to 0.6). These patients also had a much higher rate of cardioversion (OR 3.3; 95% CI 1.2 to 9.3). Unfortunately, this was a very small study in which only a fifth of the number of planned patients was actually enrolled. Despite this limitation, it seems reasonable to use procainamide as a first line agent for hemodynamically stable wide-complex tachycardia rather than amiodarone. Recent Onset Atrial Fibrillation Procainamide has been used successfully in the management of recent-onset AF, with a previously documented conversion rate of around 60%, occurring at a median of 3 hours following drug infusion (Stiell 2010). In one systematic review and meta-analysis comparing IV amiodarone to placebo and class Ic antiarrhythmics (Chevalier 2003), amiodarone did not have a significantly higher rate of cardioversion compared to placebo at 1 to 2 hours, but did have a higher rate at 6 to 8 and 24 hours. Compared to class Ic antiarrhythmics, amiodarone was less effective at 1 to 2 and 6 to 8 hours, but had similar efficacy at 24 hours. Cardioversion with amiodarone by 6 to 8 hours occurred in 48-62% patients (depending on the individual study), which is fairly comparable to previously reported rates for procainamide. Given the lack of studies comparing procainamide to amiodarone head-to-head, it seems reasonable to consider either drug, though concerns regarding hypotension with amiodarone may sway many to use procainamide instead. Refractory VF or Pulseless VT A recent multicenter, randomized controlled trial conducted at 55 EMS services in North America sought to compare the effectiveness of amiodarone, lidocaine, and placebo in patients with out of hospital cardiac arrest (OHCA) due to refractory VF/pulseless VT. After excluding patients whose initial rhythm was not VF or VT, 3026 patients were enrolled and evenly split between groups. The authors found no significant difference in survival to hospital discharge between patients receiving amiodarone and placebo (ARR 3.2%; 95% CI -0.4% to 7.0%) and no difference between those receiving lidocaine and placebo (ARR 2.6%; 95% CI -1.0% to 6.3%). Unfortunately, despite the large number of patients enrolled, the outcome was fairly rare, which resulted in relatively wide 95% CIs. As a result, a potentially clinically meaningful survival improvement (3.2% for amiodarone and 2.6% for lidocaine) could not be shown to be statistically significant. In a follow-up study, the authors of the previous study also looked at those patients initially enrolled but excluded because VF/pulseless VT was not their initial rhythm (i.e. those patients with an initially non-shockable rhythm). Again, they did not observe any statistically significant difference in survival to discharge between the three groups (1.9% for the placebo group, 3.1% for the lidocaine group, and 4.1% for the amiodarone group). Also, despite not finding a statistically significant difference, the study was not sufficiently powered to detect a potentially clinically significant improvement in mortality of 2% with amiodarone. Given this limitation for the last two studies, and the lack of any downside in this subset of patients, it seems reasonable to continue amiodarone use for patients with refractory VF/pulseless VT for both OHCA and in-hospital arrest.

Journal Club Podcast #39: October 2017 A discussion of the controversial practice of shoving a tube down someone's nose and sucking out stomach contents... Click Tabs Below to Expand Articles: Article 1: Pateron D, Vicaut E, Debuc E, et al; HDUPE Collaborative Study Group. Erythromycin infusion or gastric lavage for upper gastrointestinal bleeding: a multicenter randomized controlled trial. Ann Emerg Med. 2011 Jun;57(6):582-9. Answer Key. Article 2: Aljebreen AM, Fallone CA, Barkun AN. Nasogastric aspirate predicts high-risk endoscopic lesions in patients with acute upper-GI bleeding. Gastrointest Endosc. 2004 Feb;59(2):172-8. Answer Key. Article 3: Palamidessi N, Sinert R, Falzon L, Zehtabchi S. Nasogastric aspiration and lavage in emergency department patients with hematochezia or melena without hematemesis. Acad Emerg Med. 2010 Feb;17(2):126-32. Answer Key. Article 4: Huang ES, Karsan S, Kanwal F, Singh I, Makhani M, Spiegel BM. Impact of nasogastric lavage on outcomes in acute GI bleeding. Gastrointest Endosc. 2011 Nov;74(5):971-80. Answer Key. Vignette: It is a typical Saturday afternoon in TCC when you are roomed a patient with a history of COPD and GERD who appears short of breath. When they bring him back from triage in a wheelchair, you watch him shakily stand and transition to the stretcher, appearing dizzy when he does so. As you go in to greet the patient, you ask the nurse to get him started on the monitor. You can hear wheezing on your exam. HR 116 RR 24 BP 88/54 Sat 100% Temp 36.3 During the review of systems, your patients embarrassedly admits to having several large bowel movements over the past two days that appeared dark and have progressively gotten more tarry throughout the day. He has had smaller episodes in the past, but nothing so large or frequent. He denies any vomiting, and specifically has had no hematemesis. DRE reveals black, heme positive stool. His respiratory rate improves a little with a nebulizer, but he still appears short of breath. His labs are significant for a hemoglobin of 6.8, so you initiate your resuscitation. The patient’s vital signs improve slightly but do not normalize. When you hear back from your GI consult, he asks you to admit the patient for serial CBCs overnight after performing a nasogastric lavage. However, you remember reading an editorial about NG lavage in evaluating GI bleeds in patients without hematemesis that was not entirely flattering. On top of that, you are concerned about worsening your patient’s already existing respiratory distress (or risk aspiration) if it is unnecessary. You decide to perform a quick search to see if there are any articles that might help you weight the pros and cons... PICO Question: Population: Adult patients with potential upper GI bleeding Intervention: NG tube lavage Comparison: No NG tube placement Outcome: Mortality, transfusion requirement, need for surgery, gastric visualization at endoscopy, triage of patients Search Strategy: No formal search strategy was used. Two emergency medicine residents used multiple sources to identify articles that evaluated the use of NG lavage in potential upper GI bleeding with regards to any outcome. Bottom Line Considered to be one of the more painful procedures performed in the ED, nasogastric tube (NG) insertion is also associated with complication rates of 0.3% to 0.8% (Pillai 2005). NG tubes are often placed in patients with a known or suspected upper GI bleed, with potential goals of determining if the source is upper or lower, improving endoscopic visualization of the gastric fundus by lavage, and potentially triaging patients to urgent vs. non urgent endoscopy (particularly off hours). Unfortunately, very little evidence exists to support routine NG tube placement or lavage in these patients. We therefore sought to broadly evaluate the potential benefits of NG tube placement in patients with suspected or known upper GI bleeds. One of the earlier studies performed sought to evaluate the predictive ability of NG lavage (NGL) in predicting the presence of a high risk lesion (spurting, oozing of blood, or a visible non-bleeding vessel) at endoscopy (Aljebreen 2005). A total of 520 patients with known upper GI bleeding were enrolled from the Canadian Registry of patients with Upper Gastrointestinal Bleeding undergoing Endoscopy (RUGBE). When considering a bloody NGL as a positive test (and coffee-ground, clear, or “other” aspirate as negative), the positive likelihood ratio (LR) was 2.00 and the negative LR was 0.68. When bloody or coffee-ground NGL was considered positive, the positive LR decreased to 1.20 and the negative LR decreased to 0.63. Overall, these likelihood ratios are quite poor, and would do very little to alter the probability of the disease, no matter the results. Another study, conducted in Paris, France, compared NGL and erythromycin in terms of ability to clear the stomach and improve gastric visualization during endoscopy (Pateron 2011). In this randomized, controlled trial, 253 patients were randomized to either NGL until clear, a dose of IV erythromycin, or both NGL and erythromycin. The mean visualization score at the time of endoscopy was similar between all 3 groups, with no difference in duration of endoscopy, need for hemostasis, ability to identify the source of bleeding, or need for a second endoscopy. A third study, undertaken in the West Los Angeles VA system, attempted to compare outcomes between patients with GI bleed who underwent NGL and those who did not (Huang 2011). This retrospective study included 632 patients, of whom 378 patients underwent NGL. The authors used propensity score matching to try and achieve prognostic balance between the two groups by balancing for several known confounding factors. Following propensity matching, two groups with 193 patients in each were compared. There was no significant difference in mortality (OR 0.84, 95% CI 0.37 to 1.92), mean length of stay (difference 0.80 days, 95% CI -1.4 to 3.0), need for emergency surgery (OR 1.51, 95% CI 0.42 to 5.43), or mean blood transfusion requirement (difference -0.18 units, 95% CI -0.98 to 0.62). Of note, significantly more patients in the NGL group underwent endoscopy (OR 1.71, 95% CI 1.12 to 2.62) and were more likely to undergo earlier endoscopy, suggesting that significant imbalance remained between the groups in spite of propensity matching. This finding significantly limits the internal validity of the study. Finally, a systematic review was identified from 2010 that attempted to determine the accuracy of NGL in differentiating upper from lower GI bleeds in patients with hematochezia or melena without hematemesis (Palamidessi 2010). The authors identified 3 articles; unfortunately, one of these (Aljebreen 2005) did not actually address the question being asked, as it only included patients with upper GI bleeds. For the remaining two article, positive LRs were 4.74 and 4.44, while negative LRs were 0.2 and 0.65. As before, these likelihood ratios (with the exception of the negative LR of 0.2) suggest that the results of the test would do little to change the probability of an upper (or lower) GI hemorrhage. In all, there is very little evidence to support the routine use of NG lavage in patients presenting to the ED with suspected upper GI hemorrhage. The only potential benefit not explored was the triage of patients to emergent, urgent, or non-urgent endoscopy, which would likely only be helpful during off hours. Given the poor ability of lavage to identify patients with high risk lesions, and given the significant discomfort associated with the procedure, this seems like a fairly soft reason to place an NG tube. Additional factors associated with poor outcomes in upper GI hemorrhage, such as older age, presence of upper GI malignancy, and variceal disease (Roberts 2012), in addition to signs of clinical instability may provide better triage of these patients, and should be considered prior to NG tube placement.

Journal Club Podcast #38: August 2017 A brief discussion on contrast-induced nephropathy and some of the evidence that suggests it may be as real as Sasquatch himself... Click Tabs Below to Expand Articles: Article 1: Hinson JS, Ehmann MR, Fine DM, Fishman EK, Toerper MF, Rothman RE, Klein EY. Risk of Acute Kidney Injury After Intravenous Contrast Media Administration. Ann Emerg Med. 2017 May;69(5):577-586.e4. Answer Key. Article 2: Mitchell AM, Jones AE, Tumlin JA, Kline JA. Incidence of contrast-induced nephropathy after contrast-enhanced computed tomography in the outpatient setting. Clin J Am Soc Nephrol. 2010 Jan;5(1):4-9. Answer Key. Article 3: McDonald JS, McDonald RJ, Carter RE, Katzberg RW, Kallmes DF, Williamson EE. Risk of intravenous contrast material-mediated acute kidney injury: a propensity score-matched study stratified by baseline-estimated glomerular filtration rate. Radiology. 2014 Apr;271(1):65-73. Answer Key. Article 4: McDonald JS, McDonald RJ, Comin J, Williamson EE, Katzberg RW, Murad MH, Kallmes DF. Frequency of acute kidney injury following intravenous contrast medium administration: a systematic review and meta-analysis. Radiology. 2013 Apr;267(1):119-28. Answer Key. Vignette: It was a clear black night, a clear white moon...and you're stuck working in EM-2 instead of out regulatin'! One of your patients is Ms. Z, a 52-year old woman with left lower quadrant abdominal pain. She's quite tender and has some localized guarding, but no rebound. Her WBC is 14.5. You're worried about diverticulitis, possibly with rupture and an abscess, and would like to get a CT scan, but her creatinine is 1.7, which is her baseline. Additionally, she has a history of diabetes and hypertension, and you worry about causing contrast-induced nephropathy (CIN) if you give contrast for the CT. Your attending assures you that there's no such a thing as CIN, that it's as made up as Santa Claus and the Easter Bunny (EmLitofNote: The Latest Myth: Contrast-Induced Nephropathy; EMCrit: Do CT Scans Cause Contrast Nephropathy). As you fight back the tears, your childhood fantasies destroyed, you call the radiologist to discuss what to do. The radiologist shares your concerns and suggests that in this "not overly skinny" woman, contrast shouldn't be necessary. Lo and behold, the CT shows uncomplicated diverticulitis, and Ms. Z goes home on oral antibiotics, her remaining nephrons safe and secure. But as you end your shift, eyes heavy with fatigue, you wonder: was your attending right about CIN (and the poor little Easter Bunny), or was the radiologist right to be concerned? You head home, crash, wake up refreshed, and begin to search the literature… PICO Question: Population: Adult patients undergoing computed tomography (CT) scan Intervention: Administration of intravenous contrast for enhancement of CT scan Comparison: No contrast administration for enhancement of CT scan Outcome: Acute kidney injury, chronic kidney disease, need for dialysis, mortality Search Strategy: An article published in a recent issue of Annals of Emergency Medicine (Hinson 2017) was chosen as the impetus for this journal club. A meta-analysis referenced in this article, along with two primary research studies, were chosen for inclusion as well. Bottom Line: Iodinated contrast media was once cited as the third most common cause of iatrogenic acute kidney injury (Hou 1983). Previous research on the incidence of contrast-induced nephropathy (CIN) associated with intravenous contrast for CT scans in the ED has found the rate to be around 11%, with much lower rates of severe renal failure (1%) and death due to renal failure (0.6%) (McDonald 2014). Other studies have reported similar rates (Mitchell 2007, Mitchell 2012). The problem with these cohort studies is that while they demonstrate the incidence of AKI in patients receiving IV contrast, they do not necessarily establish contrast as the cause of the AKI. Patients receiving IV contrast typically have some issue requiring them to undergo CT scanning or angiographgy, and some percentage of these patients would develop AKI independent of contrast administration. As a result, several observational studies have been undertaken to compare the incidence of AKI and other outcomes in patients receiving contrast to the incidence in patients not receiving contrast. While some older studies have demonstrated an increased incidence of AKI among patients receiving IV contrast when compared with controls (Heller 1991, Polena 2005) these studies have failed to control for potential confounders. Studies that have controlled for such confounder, typically using propensity score matching, have found no increased incidence of AKI, severe kidney failure, or death due to renal failure compared to patients not receiving contrast (McDonald 2014, Hinson 2017). A meta-analysis of all such studies, performed in 2013, similarly failed to demonstrate a statistically significant increase in the incidence of AKI (McDonald 2013). While the bulk of data thus far does not suggest a clear association between IV contrast administration and acute kidney injury (AKA CIN), no randomized controlled studies have performed up to this point. While more recent studies have used methods such as propensity matching to help control for known confounding factors, these studies are not able to control for unknown confounders, and similarly have not controlled for potentially renal protective interventions undertaken after contrast administration (e.g. IV fluid administration and bicarbonate administration, withholding of potentially nephrotoxic drugs). It would therefore be difficult to advocate for a change in clinical practice without such randomized controlled trials. There have been several barriers to performing such studies, including the assumption that IV contrast is harmful. The current evidence may help break that barrier, establishing that there is clinical equipoise regarding this issue, but other issues remain. Perhaps the most significant is the potential harm in withholding IV contrast in patients undergoing CT who would benefit from contrast enhancement, making it unethical to randomize patients to a non-contrast arm in such a study. Unfortunately, until further evidence is available, it seems prudent to consider withholding IV contrast in patients felt to be at high risk of developing AKI, with the caveat that in some emergent cases (i.e. possible aortic dissection), the risks of withholding contrast may outweigh the risks of developing kidney injury.

Journal Club Podcast #37: July 2017 A brief discussion of several of the controversies that have popped up in the last few years regarding the diagnosis and management of cellulitis... Click Tabs Below to Expand Articles: Article 1: Peterson D, McLeod S, Woolfrey K, McRae A. Predictors of failure of empiric outpatient antibiotic therapy in emergency department patients with uncomplicated cellulitis. Acad Emerg Med. 2014 May;21(5):526-31. Answer Key. Article 2: Pallin DJ, Camargo CA Jr, Schuur JD. Skin infections and antibiotic stewardship: analysis of emergency department prescribing practices, 2007-2010. West J Emerg Med. 2014 May;15(3):282-9. Answer Key. Article 3: Weng QY, Raff AB, Cohen JM, Gunasekera N, Okhovat JP, Vedak P, Joyce C, Kroshinsky D, Mostaghimi A. Costs and Consequences Associated With Misdiagnosed Lower Extremity Cellulitis. JAMA Dermatol. 2016 Nov 2. Answer Key. Article 4: Moran GJ, Krishnadasan A, Mower WR, Abrahamian FM, LoVecchio F, Steele MT, Rothman RE, Karras DJ, Hoagland R, Pettibone S, Talan DA. Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. JAMA. 2017 May 23;317(20):2088-2096. Answer Key. Vignette: You're moonlighting in a local ED one afternoon, when you encounter Mrs. X, a 40-year-old woman with rheumatoid arthritis, for which she takes Methotrexate. She was gardening three days prior to presentation when she suffered a small cut to her left ankle from a misplaced spade. The following day, there was some mild erythema around the wound, which has progressed. She now has redness, warmth, and mild swelling to the lateral ankle and distal calf, with no signs of lymphangitis and no fluctuance. The ankle joint moves easily and without pain. As she is afebrile and well appearing, you discuss with her PMD and send her out on Bactrim and Keflex, to cover both Strep species and MRSA. The very next patient you meet is Mr. Y, a 50-year-old obese male with CHF. He has had swelling in both his legs for quite some time, chalked up in the past to chronic lymphedema and CHF, but now has redness and pain to both ankles and lower legs. Given the severity of the redness and swelling, you elect to treat the patient for cellulitis and order vancomycin, then place an admission order. The hospitalist muses that perhaps the patient has venous stasis dermatitis, but admits that it's probably worth treating for potential cellulitis. Thinking back to both patients later in the day, you begin to worry about your treatment plans. Should the immunosuppressed woman have been admitted for her cellulitis? What factors make patients more prone to treatment failure? Do you always need to prescribe both Bactrim and Keflex for cellulitis (see IDSA guidelines for SSTIs)? And finally, could the second patient have had stasis dermatitis, and if so, did he really need antibiotics and admission? You decide to look into the evidence to try to answer these questions, and dive right into the literature... PICO Question: Given the nature of the journal club this month, no specific PICO questions was devised. Instead, we looked at several controversial issues surrounding the management of cellulitis, including diagnostic accuracy, antibiotic selection, risk factors for treatment failure, and prescribing practices. Search Strategy: Again, due to the nature of the journal club, no specific search strategy was undertaken. Recent high-impact articles were selected from the medical literature, some due to their highly controversial nature. Bottom Line: Cellulitis, a common skin infection, results in around 2.3 million ED visits in the US annually. This number has risen over the years with the increasing prevalence of community-acquired MRSA (CA-MRSA) (Pallin 2008). Despite these rising numbers, there remains significant controversy regarding the diagnosis and management of this common condition, in part due to the lack of objective diagnostic criteria, the presence of several hard to distinguish mimics (Weng 2016), and difficulties in determining the bacterial etiology in the majority of cases (Jeng 2010). The most recent guidelines from the Infectious Diseases Society of America (IDSA) do not recommend adding MRSA coverage for the management of mild or moderate non-purulent skin and soft-tissue infections (i.e. cellulitis and erysipelas). The PGY-4 paper (Moran 2017) found that among patients treated as an outpatient for cellulitis, cephalexin alone resulted in similar cure rates to cephalexin plus trimethroprim-sulfamethoxazole, supporting the IDSA recommendations. However, it should be noted that this recommendation does not apply to patients with fever or leukocytosis, or in immunocompromised patients. In our PGY-2 paper (Pallin 2014), the authors determined, among other things, that 63% of patients with cellulitis were given antibiotic regimens that included CA-MRSA coverage. Unfortunately, they did not attempt to determine how many of these patients had criteria that would exclude them from the IDSA recommendation, but instead insinuate that nearly all of them were being treated inappropriately. They even go so far as to recommend using this as a reported quality measure for Medicare’s Physician Quality Reporting System, a suggestion that is both premature and potentially dangerous. Our PGY-3 article (Weng 2016) went a step further, attempting to determine the costs associated with misdiagnosis of lower extremity cellulitis in the US. They report that 30.5% of patients admitted to the hospital with lower extremity cellulitis in their study were misdiagnosed, and that the majority of these patients did not require hospital admission. Using a literature review, they therefore determined that such misdiagnoses cost between $195 and $515 million dollars annually throughout the US. Unfortunately, all of these conclusion are based on a highly methodologically flawed retrospective study in which final diagnosis was determined by chart review out to thirty days post-discharge. It is quite likely that the retrospective conclusion of misdiagnosis was, in many cases, itself a misdiagnosis. Additionally, the authors offer no direction on how to avoid such proposed misdiagnosis, failing to consider the amount of data available 30 days after presentation that would not be available to the ED physician at the time of presentation (e.g. response to treatment), and fail to note that among misdiagnosed patients who were deemed not to require hospital admission at all (determined retrospectively by dermatologists), the mean length of stay was over 4 days! This information suggests that either these patients did, in fact, need to be admitted, or that the ability to differentiate cellulitis from “pseudocellulitis” did not become evident until several days of observation had passed. An editorial written in response to this review notes many of these issues, but also calls for improved diagnostic capabilities and discussion between the ED and admitting physicians (Moran 2017), which seems more than reasonable. Our PGY-1 paper (Peterson 2014) found that fever (odds ratio [OR] 4.3), chronic leg ulcers (OR 2.5), chronic edema or lymphedema (OR 2.5), prior cellulitis in the same area (OR 2.1), and cellulitis at a wound site (OR 1.9) were all predictors failure of outpatient management of cellulitis. All of this evidence suggests that cellulitis can be a difficult diagnosis fraught with controversy. Care should be taken when diagnosing lower extremity cellulitis, as there are many mimics that do not require antibiotics. Care should also be taken in those patients with risk factors for failed outpatient therapy, with close follow-up and good return precautions given to such patients. Additionally, improved adherence to current IDSA guidelines would likely result in use of fewer antibiotics with fewer adverse effects.

Journal Club Podcast #36: June 2017 Dr. Chris Carpenter and Marco Sivilotti bridge the US-Canada border to bring us a new podcast on the diagnostic approach to atraumatic SAH... Click Tabs Below to Expand Articles: Article 1: Sensitivity of early brain computed tomography to exclude aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis, Stroke 2016; 47: 750-755). (http://pmid.us/26797666) Answer Key. Article 2: False-negative interpretations of cranial computed tomography in aneurysmal subarachnoid hemorrhage, Acad Emerg Med 2016; 23: 591-598. (http://pmid.us/26918885) Answer Key. Article 3: Spontaneous subarachnoid hemorrhage: A systematic review and meta-analysis describing the diagnostic accuracy of history, physical examination, imaging, and lumbar puncture with an exploration of test thresholds, Acad Emerg Med 2016; 23: 963-1003. (http://pmid.us/27306497) Answer Key. Article 4: Determination of a testing threshold for lumbar puncture in the diagnosis of subarachnoid hemorrhage after a negative head computed tomography: A decision analysis, Acad Emerg Med 2016; 23: 1119-1127. (http://pmid.us/27378053) Answer Key. Vignette: Mrs. Z. is a healthy 30-year-old female who presents to your emergency department 2-hours after onset of “the worst headache of my life” which peaked within 1 minute of onset but was not “thunderclap”. She describes the headache as diffuse with associated nausea, but no photophobia, neck stiffness, vomiting, focal motor-sensory deficits, or fever. She reports no recent viral or febrile illness, blunt trauma, travel history, or sick contacts. Nobody else at home or work has had a headache recently. Her immunizations are up-to-date and she denies any significant PMH including no history of migraine (or other) headache disorders, cerebral aneurysm, stroke, HIV or other immunocompromising disorder, pseudotumor cerebri, malignancy, bleeding diatheses, or meningitis. She denies recent alcohol use or any history of intravenous or illicit substance abuse. She has not tried any medications for her headache. She is a secretary and lives at home with her husband and 3 year old child. In the ED, her vitals are BP 106/55, P 58, RR 18, T 37.2°C, and 100% oxygen saturation on room air. She is in no acute distress, and her exam is unremarkable. As you consider the diagnosis of subarachnoid hemorrhage and await her CT, you weigh the value of a post-CT lumbar puncture. You recall a recent meta-analysis discussed on your favorite “podcast” Emergency Medical Abstracts (listen here) as well as an episode of McMaster’s Textbook of Internal Medicine (watch here) and wonder how other researchers and specialties interpret the best evidence. Realizing that there are two distinct questions for the ED diagnosis of SAH, you develop two PICO questions. PICO Question: PICO Question #1 Population: ED patients with sudden onset severe headache concerning for aneurysmal SAH (aSAH) Intervention: Computed tomography within 6 hours of symptom onset Comparison: No comparator Outcome: CT sensitivity, specificity, positive/negative likelihood ratio for aSAH PICO Question #2 Population: ED patients with sudden onset severe headache concerning for aneurysmal SAH (aSAH) Intervention: Lumbar puncture following unremarkable CT Comparison:No comparator Outcome: LP sensitivity, specificity, positive/negative likelihood ratio for aSAH Search Strategy: Using these PICO questions, you devise a PubMed search using Clinical Queries (diagnosis/broad) and the search term “aneurysmal subarachnoid hemorrhage” which identifies 2891 studies (see http://tinyurl.com/zrvgc3s) from which you select the 4 studies below from last year. Bottom Line: Needle in a Haystack Headaches represent about 2% of emergency department (ED) visits annually. While severe headache patients presenting with altered mental status, fevers, or associated trauma usually generate sufficient concern to justify further diagnostic evaluations, most other sudden onset headache cases ultimately prove to result from benign, non-life threatening causes like migraine headache. The myriad causes of sudden onset headaches include cough, exertion, and post-coital, but can also include potentially life-threatening conditions like sinus thrombosis, vascular dissection, intracerebral hemorrhage, vasospasm, and aneurysmal subarachnoid hemorrhage. [Landtblom 2002, Delasobera 2012, de Bruijn 1996, Pascual 1996, Dodick 1999] Observational studies indicate that migraine headaches are at least 50-times more common than SAH amongst ED headache patients, so SAH represents a needle in a haystack for a very common chief complaint. [Edlow 2003] Missed SAH diagnosis occurs between 12%-53% of cases with ED providers estimated to miss 5% of them. [Edlow 2000, Vermeulen 2007] Up to 80% of SAH cases result from a ruptured cerebral aneurysm. Other causes of SAH include low-pressure perimesencephalic bleeds, cerebral amyloid angiopathy, vasculitis, sickle cell disease, and cocaine or amphetamine abuse. [Carpenter 2016] One-fourth of aneurysmal SAH victims die within one-day and 50% of SAH survivors never return to work. Correctly identifying SAH early can reduce these adverse outcomes if subsequent neurosurgical interventions (coiling or clipping) occur emergently. [Schievink 1997] Therefore, the possibility of aneurysmal SAH must be considered in ED patients presenting with severe headaches. Understanding the SAH diagnostic evidence available for bedside evaluation, advanced imaging, and the role for lumbar puncture (LP) is therefore essential and the landscape is shifting. Non-Contrast Cranial CT Computed tomography (CT) became widely available for the evaluation of headache patients about 30 years ago. Early CTs were 4-slice and radiologists’ interpretative learning curves were steep. These early CTs were imperfect (sensitivity ~90%) for identifying small amounts of blood in the subarachnoid space, so textbooks, guidelines, and several generations of emergency medicine trainees advised against a CT-only approach to rule-out aneurysmal SAH. Instead, SAH could only be ruled out when a negative CT was followed immediately by a LP demonstrating cerebrospinal fluid (CSF) without either red blood cells or (at least 12 hours post-headache onset) xanthochromia. However, in 2017 there are three problems with that approach: (1) contemporary CTs are far better at identifying blood in the subarachnoid space; (2) LP’s frequently identify blood that is not in the subarachnoid space (traumatic LPs); and (3) CSF xanthochromia is not an accurate diagnostic test for SAH. A rule of thumb to define sufficient diagnostic accuracy to rule-in a disease as positive is likelihood ratio (LR+) > 10 or negative likelihood ratio (LR-) < 0.1 to rule-out a disease. Both Perry 2011 and Backes 2012 demonstrate acceptably safe CT accuracy for SAH when imaging is obtained within 6-hours of headache onset (summary LR+ 235, summary LR- 0.01). Beyond 6-hours CT is still accurate to rule-in SAH (summary LR+ 223) but less impressive to rule out SAH (summary LR- 0.07, 95% CI 0.01-0.61). These studies used neuro-radiologists to interpret the CT, which opens the question as to whether general radiologists’ accuracy would equate these studies. Recent studies indicate that general radiologists’ are just as accurate for the diagnosis of SAH as neuro-radiologists. Post-CT LP– Quantifying Benefits and Harms Most European hospitals use spectrophotometry to evaluate the presence or absence of xanthochromia, whereas 99% of North American hospitals use visible inspection. Recent meta-analyses indicate that visible xanthochromia can rule-in SAH (LR+ 25) but is less accurate to rule it out (LR- 0.22). At least four spectrophotometric methods to evaluate xanthochromia exist and most ED headache studies report different methods, but spectrophometry using any method doesn’t appear to be significantly better than visible xanthochromia to rule-in or rule-out SAH. [Carpenter 2016, Chu 2014] At a threshold of 2000 x 106 red blood cells per liter in the final tube of CSF collected, the LR+ is 10.3 and the LR- is 0.07 (95% CI 0.01-0.49). [Perry 2015] Importantly, up to 30% of patients experience worsening post-LP headache, in addition to the risks of post-LP back pain, epidural bleeding, and introduction of skin flora into the central nervous system. [Seupaul 2005] Patients are not the only reluctant participants in this exercise; physician barriers to routine post-CT LP include inadequate time in the busy ED and expectation of normal or non-diagnostic results in most patients (low diagnostic yield). In fact, up to 1 in 6 LPs are traumatic (blood detected from skin or superficial soft tissue, not from the subarachnoid space). Consequently, LP is not performed in over half of acute headache patients in whom a CT is obtained. [Perry 2010, Perry 2013] The ultimate objective is not to understand test accuracy; instead, the goal is to deliver the appropriate care to the right patients. How is a busy ED physician supposed to interpret all of these numbers and communicate with patients meaningfully to allow shared decision making? One approach to balance the harms and benefits of post-CT LP is to hypothesize test- and treatment-thresholds. The test-threshold describes the probability of a diagnosis (aneurysmal SAH) below which continuing to test for the diagnosis will harm more patients than it will help, whereas above the threshold additional testing will benefit more patients than will be harmed. This threshold is derived from the test accuracy (CSF xanthochromia or RBC), risk of the test (post-LP headache, infection, or epidural bleed), benefit of the treatment for those with disease, and harms of the treatment for those without disease (since false-positives will receive the treatment and have no possibility of benefit since they don’t actually have the disease). Based upon one recent diagnostic meta-analysis, the threshold at which post-CT LP would benefit patients is quite narrow (2-4% for CSF RBC or 2%-7% for visible xanthochromia). Doubling the risk of benefit and halving the risk of harm was used to further evaluate these thresholds and the thresholds didn’t change significantly. Still not convinced? Thinking about the benefit of LP alone (and neglecting the potential for harms associated with LP), the Number Needed to LP (NNLP) to identify one CNS infection in acute onset headache patients is 227 [Brunell 2013] while the NNLP to identify one additional aneurysmal SAH upon which neurosurgical intervention occurs and which was missed by CT within 6 hours ranges from 250 [Perry 2011, Sayer 2015] to 15200! [Blok 2015] Journal Club Discussion Between Neurosurgery & Emergency Medicine Here is the synopsis of the Journal Club discussion between Neurosurgery and Emergency Medicine, including Dr. Sivilotti the senior author of the PGY-III meta-analysis. PGY-I CT within 6 hours of thunderclap headache onset is sufficiently sensitive to rule out SAH without LP, if the CT is 16 slice or greater with cuts < 5mm. PGY-II Non-contrast head CT is an excellent test for ED headache patients in whom SAH is a concern, but like every other test that exists it is not 100% sensitive. Scenarios in which false negative CTs occur include imaging more than 6 hours after the onset of the headache, less severe bleeds (as measured by Hunt-Hess classification), anemia (Hg <10), and non-neuro-radiologists readers. In those scenarios, patient shared decision making about additional testing (CTA or LP) is warranted but should include informed consent about anticipated benefits and potential harms. PGY-III Less than one in 10 headache patients concerning for SAH are ultimately diagnosed with SAH in recent studies. While certain symptoms and signs increase or decrease the likelihood of SAH, no single characteristic on history/physical exam is sufficient to rule in or rule out SAH. Within 6 hours of symptom onset, noncontrast cranial CT is highly accurate, while a negative CT beyond 6 hours substantially reduces the likelihood of SAH. Based on anticipated treatment benefit of 80% with immediate aneurysmal SAH (aSAH) diagnosis, LP risk of 1% (including significant post dural headache, discomfort, and infection), and total (cancer + other) risk for angiography of 2%, LP would only be helpful in a pre-LP probability of aSAH range of 2-7% (if using visible xanthochromia) or 2-4% (if using CSF RBC > 1000). Therefore, LP appears to benefit relatively few patients within a narrow pretest probability range. Scenarios in which false negative CTs occur include imaging more than 6 hours after the onset of the headache, less severe bleeds (as measured by Hunt-Hess classification), anemia (Hg <10), and non-neuro-radiologists readers. In those scenarios, patient shared decision making about additional testing (CTA or LP) is warranted but should include informed consent about anticipated benefits and potential harms. With improvements in CT technology and an expanding body of evidence, test thresholds for LP may become more precise, obviating the need for a post-CT LP in more acute headache patients. Existing SAH clinical decision rules await external validation, but offer the potential to identify subsets most likely to benefit from post-CT LP, angiography, or no further testing. PGY-IV Decision analysis using accepted methods but sparse, low quality evidence-basis demonstrates post-CT LP test threshold that is significantly higher than the majority of ED headache patients in whom SAH is considered. Nonetheless, the similar test-threshold point-estimate for post-CT LP in comparison to Carpenter et al (which used very different methods to derive a test-threshold), indicates that current textbook and guideline recommendations (which advocate post-CT for everyone) merit revision. The discussion amongst the Journal Club attendees focused around two issues. 1) Some neurosurgeons expressed concerns about the risk of aneurysmal re-bleeding within 24 hours, which has been recognized to be about a 6% risk since observational studies were conducted in the 1950’s. Some of the neurosurgeons also noted that no test is perfect, so their traditional approach has been that more testing is generally better for patients and providers. Dr. Sivilotti made the point that attempts to attain diagnostic perfection (0% miss rate) leads to operational inefficiencies for the hospital and at eventually harms some patients. 2) Some noted uncertainty about how to derive the initial pre-test probability estimate by which to guide post-CT decision-making about the benefits vs. harms of LP. It was noted that the PGY-III meta-analysis included weighted average prevalence of SAH of 7.5% in recent prospective studies of headache patients in whom SAH is a concern. This meta-analysis prevalence is one evidence-based estimate of pre-test probability. The point was then made that the 7.5% probability of SAH falls within the 2%-7% range for which LP benefits outweigh risks, but the meta-analysis authors noted that the 7.5% prevalence estimate is pre-CT. Whether a CT is obtained less than 6-hours post-headache onset (summary LR- = 0.01 so post-CT probability of SAH = 0.1%) or later than 6-hours (summary LR- = 0.07 so post-CT probability of SAH = 0.6%). Either way, the post-CT probability of SAH is far below the lower margin of benefit (2%). The issue with CT diagnostic accuracy beyond 6-hours is the 95% Confidence Interval which extends to 0.61, so these situations require more careful contemplation and perhaps offer a role for CT angiography – a proposal to which neurosurgery eagerly agreed requires additional research at Washington University. Future Research Priorities Carpenter et al. was grounds for practice-change for many ED diagnosticians, but has also received criticism – mainly based on philosophical grounds. Is the role of emergency medicine to definitively rule-in or rule-out particular diagnoses or simply to exclude (or minimize) life-threats without putting a label of certainty on symptom etiology? Based upon the personal observations that thunderclap headache represents a potential life-threat that is not SAH in over half of cases and that a CT/LP approach alone will fail to identify other life-threats without consulting Neurology and/or Neurosurgery with additional advanced imaging at the discretion of these consultants, some argue that diagnostic research based upon ruling-in or ruling out SAH alone is inherently flawed and not worthy of altering the long-standing practice paradigm of CT then LP if CT is non-diagnostic. However, this approach neglects to consider the potential harms of LP, the number of additional studies required to save one additional life or avert one bad outcome, or the role for shared decision-making. It is worth noting that the perspective that thunderclap headache more commonly represents a non-SAH life-threatening diagnosis than SAH or migraine is counterintuitive to most ED research. This phenomenon likely reflects spectrum bias in that sicker patients with more likelihood of life-threatening disease and poor outcomes are being labeled as “thunderclap headache” than is the norm in published research and common practice. Indeed, a subset of acute headache patients who do benefit from post-CT LP almost certainly exists, including those with hemoglobin less than 10 g/dL (increased risk of false-negative CT), significant delay between headache onset and CT, and those in whom diagnoses like CNS infection or pseudotumor cerebri are being contemplated. The art of medicine is identifying the individual patients who are more likely to benefit from additional testing rather than applying a one-size fits all that mandates routine post-CT LP. Many questions remain unanswered. Can general radiologists rule-out aneurysmal SAH as well as neuro-radiologists? Will clinical decision aids provide an additional risk-stratification mechanism by which to identify subsets more likely to benefit from post-CT LP? Is there a role for CT angiography (CTA) following a non-diagnostic non-contrast CT? If so, which patients would benefit from CTA? Bottom Line: The decades old dogma that acute headache patients in whom SAH is a consideration must uniformly undergo an LP following a non-diagnostic CT appears is unnecessary for a large subset of these patients and may leads to harms via additional downstream testing that results from the imperfect, non-specific findings in CSF.

Journal Club Podcast #35: May 2017 After a brief interlude where I shamelessly self-promote my new novel, I talk about the risks of delayed bleeding in head injury patients on warfarin... Click Tabs Below to Expand Articles: Article 1: Menditto VG, Lucci M, Polonara S, et al. Management of minor head injury in patients receiving oral anticoagulant therapy: a prospective study of a 24-hour observation protocol. Ann Emerg Med 2012;59:451-455. Answer Key. Article 2: Swap C, Sidell M, Ogaz R, Sharp A. Risk of Delayed Intracerebral Hemorrhage in Anticoagulated Patients after Minor Head Trauma: The Role of Repeat Cranial Computed Tomography. Perm J. 2016 spring;20(2):14-6. Answer Key. Article 3: Chauny JM, Marquis M, Bernard F, Williamson D, Albert M, Laroche M, Daoust R. Risk of Delayed Intracranial Hemorrhage in Anticoagulated Patients with Mild Traumatic Brain Injury: Systematic Review and Meta-Analysis. J Emerg Med. 2016 Nov;51(5):519-528. Answer Key. Article 4: Nishijima DK, Offerman SR, Ballard DW, et al. Immediate and delayed traumatic intracranial hemorrhage in patients with head trauma and pre-injury warfarin or clopidogrel use. Ann Emerg Med2012;59:460-468. Answer Key. Vignette: You are working a moonlighting shift at a local level II trauma center when you meet Mr. X, a 68 year old gentleman with a history of atrial fibrillation, for which he takes diltiazem for rate control and warfarin for anticoagulation. He sees his primary care physician on a regular basis and has his international normalized ratio (INR) checked once a week. It has been between 2.0 and 3.0 consistently for the last 6 months. This morning, while walking his dog, a rare crossbreed known as a great doodle (a cross between a great Dane and a poodle), he was tripped up by the leash and fell forward, striking his forehead on the concrete. He suffered no loss of consciousness, has a mild headache, and has had no nausea or vomiting. His wife states that he has had no altered mental status since the fall. On exam he has a GCS of 15, a superficial abrasion to his forehead with a small 4 cm hematoma, no cervical spine pain or tenderness, and a normal neurologic examination. His INR today is 3.2. Being an astute reader of the literature, you remember that the studies on the Canadian Head CT rules excluded patients on anticoagulation, and proceed to order a head CT, which is read as normal by the attending radiologist (not a neuroradiologist). After updating the patient’s tetanus booster you discharge him home in the care of his wife. That night after your shift, you begin to worry about your patient and his risk of delayed intracranial hemorrhage given his anticoagulant use. You also wonder if his risk would be higher if he were on one of the novel anticoagulants (rivaroxaban, apixaban, etc). Unable to sleep, you head online and begin to search the literature for answers. PICO Question: Population: Patients on anticoagulation therapy suffering minor head injury Intervention: Observation and/or repeat CT scan of the head CT Comparison: Discharge after normal initial head CT Outcome: Risk of delayed intracranial hemorrhage leading to a change in management Search Strategy: A previous journal club covering delayed intracranial bleeding in the setting of anticoagulation was conducted in 2012 (http://emed.wustl.edu/Journal-Club/Archive/August-2012). The online archive was searched and two of the articles were chosen for inclusion. PubMed was searched using the terms anticoagulation AND “delayed intracranial hemorrhage”, resulting in 7 articles (http://tinyurl.com/y9yjn3go). Among these, a systematic review and meta-analysis was chosen as well as one of the articles included in the systematic review. Bottom Line: Traumatic brain injury results in just over 1.3 million emergency department (ED) visits, 275,000 hospitalizations, and 52,000 deaths annually in the United States alone, with an increase in the combined rate of ED visits, hospitalization, and death from 521 per 100,000 in 2001 to 823.7 per 100,000 in 2010 (CDC TBI Report). In elderly patients suffering a fall, long-term anticoagulation has been shown to increase not only the incidence of intracranial hemorrhage (ICH) compared to those not on anticoagulation (8.0% vs. 5.3%, p < 0.0001), but to also increase mortality in those with ICH (21.9% vs. 15.2%, p = 0.04) (Pieracci 2007). Additionally, the use of warfarin prior to blunt head trauma has been shown to increase mortality compared to those not taking anticoagulants, with an odds ratio of 2.008 (95% CI 1.634-2.467) (Batchelor 2012). Unfortunately, the rate of pre-injury warfarin use has been increasing in trauma patients in the US, from 2.3% in 2002 to 4.0% in 2006 (P < .001); in patients older than 65 years, use increased from 7.3% in 2002 to 12.8% in 2006 (P < .001) (Dossett 2011). Given the increasing number of head injury patients seen in the ED, and the increase in concomitant anticoagulant use, the clinical dilemmas surrounding these patients have become more and more relevant. Studies in patients taking warfarin who suffer minor head injury have shown incidences of ICH ranging from 6.2%-29% (Li 2001, Gittleman 2005, Brewer 2011), leading some authors to conclude that most, if not all, such patients should undergo routine cranial CT scanning on presentation (Brewer 2011, Cohen 2006, Fabbri 2004). One important question surrounds the prognostic implications of a normal cranial CT in head injury patients on anticoagulant therapy. While some European guidelines suggest that all anticoagulated patients with head injury should be admitted for a period of routine observation (Vos 2002, Ingebrigtsen 2000), these recommendations are not based on studies of the prevalence of delayed ICH. In the three primary studies reviewed, the incidence of delayed ICH following normal CT scan in patients taking warfarin ranged from 0.6% to 6%; the meta-analysis revealed a pooled risk of 0.6%. However, if a diagnosed ICH has no affect on the patient’s outcome or treatment, then it would be considered a surrogate outcome, which is often “used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives (Thomas 1995).” As such outcomes are often found to be clinically insignificant, their use has been questioned in the literature (Guyatt 2011, Fleming 1996), and the incidence of patient important outcomes should be considered instead. In these studies, the majority of patients found to have delayed ICH required no neurosurgical intervention and had no adverse outcome documented. The incidence of death or neurosurgical intervention ranged from 0 to 1.1%, with a pooled incidence of 0.13% in the meta-analysis. The authors of one of the articles reviewed suggest that “our data support the general effectiveness of the European Federation of Neurological Society’s recommendations for 24-hour observation followed by a repeated head CT scan for anticoagulated patients with a minor head injury” (Menditto 2012). However, this conclusion is based on the incidence of delayed ICH (6%) rather than the incidence of clinically important outcomes (1.1%). In this study, only one patient out of 87 suffered clinically significant delayed ICH. It is mentioned in the study that one patient showed signs of neurologic deterioration, however they do not say if this was the same patient who required neurosurgical intervention. If so, this would suggest that observation alone would suffice to detect any clinically significant delayed ICH. Additionally, the authors do not perform a cost-effectiveness analysis to support their conclusion. In a subsequent editorial appearing in the same journal, it is suggested that a protocol of 24-hour observation and routine repeat CT scanning would cost an average of just over $1 million per patient saved (Li 2012). The author of the editorial suggests that home observation and phone call follow-up would be more cost-effective, and likely as safe, though this has not been studied. While the current literature does not support routine hospital observation for 24 hours or repeat cranial CT scans in all anticoagulated patients with head injury, this may be warranted in those at increased risk of delayed bleeding, such as those with supratherapeutic INR levels or concomitant antiplatelet therapy. Further studies are needed to identify these higher risk patients for delayed bleeding to determine appropriate management. Furthermore, as newer anticoagulants enter the market and begin to replace warfarin, such as apixaban, dabigatran, and rivaroxaban, further studies on the risk of delayed hemorrhage may be necessary to determine the best management strategy for patients on these medications.

Journal Club Podcast #31: October 2016 A short discussion of optimal blood pressure management in ICH, looking at intensive BP control vs. guideline-based control... Click Tabs Below to Expand Articles: Article 1: Tsivgoulis G, Katsanos AH, Butcher KS, Boviatsis E, Triantafyllou N, Rizos I, Alexandrov AV. Intensive blood pressure reduction in acute intracerebral hemorrhage: a meta-analysis. Neurology. 2014 Oct 21;83(17):1523-9. Answer Key. Article 2: Qureshi AI, Palesch YY, Barsan WG, et al; ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med. 2016 Sep 15;375(11):1033-43. Answer Key. Article 3: Butcher KS, Jeerakathil T, Hill M, et al; ICH ADAPT Investigators. The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial. Stroke. 2013 Mar;44(3):620-6. Answer Key. Article 4: Anderson CS, Heeley E, Huang Y, et al; INTERACT2 Investigators. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013 Jun 20;368(25):2355-65. Answer Key. Vignette: It's a slow Sunday morning in TCC when you get a page that a fifty-year-old patient with a sudden onset of confusion is en route. Per the page, the patient's BP is 210/110, with a heart rate of 85. The patient arrives to the ED awake, alert, but clearly confused. He answers all questions inappropriately and only follows commands with repeated questioning. His BP is still elevated (208/113). After getting a finger-stick blood sugar, which is 105, a normal ECG, and sending off labs, you rush the patient for a head CT. The CT shows an intraparenchymal hemorrhage in the left basal ganglia without intraventricular extension. The volume of blood is about 30 mL. You immediately place a consult to neurology while the patient is transported back to the room. The nurse rechecks the patient's BP, which is now 218/115, and asks what you would like to do to treat this hypertension. You remember learning that when managing BP in intracerebral hemorrhage (ICH) there is a balance between reducing further bleeding and perfusing the rest of the brain, but you aren't sure what the optimal goal BP is or how quickly you should try and achieve this goal. After discussing this with the neurologist, you decide to do a quick literature search and see what the evidence shows... PICO Question: Population: Adult patients with spontaneous ICH and elevated BP Intervention: Aggressive lowering of blood pressure Comparison: Standard lowering of blood pressure (i.e. SBP below ~180 mmHg) Outcome: Death, functional status, quality of life, cost, length of stay Search Strategy: A PubMed “Clinical Queries” search was performed using the terms “intracerebral hemorrhage” AND “blood pressure” with category set to Therapy and scope to Broad. The search was then limited to studies published in the last 5 years using human subjects (http://tinyurl.com/zhj7zgs). This strategy resulted in 143 articles, of which 3 randomized controlled trials and 1 meta-analysis were chosen. The Cochrane database of systematic reviews was also searched, but did not identify an additional meta-analysis. Bottom Line: Optimal blood pressure management in patients with spontaneous intracerebral hemorrhage (ICH) is complicated by the balance between hematoma size and cerebral perfusion. An association between maximum systolic blood pressure and hematoma enlargement has been shown (Ohwaki 2004), but must be tempered by the opposing risk of reduced cerebral blood flow with overly aggressive reductions in blood pressure (Butcher 2003). A small study published in 2013, however, found no difference in relative perihematoma blood flow in patients treated with more aggressive BP goals (SBP < 150 mmHg) compared to traditional goals (SBP < 180 mmHg). This finding opened the door to further clinical research on the effects of aggressive BP lowering in ICH. In 2010, the AHA guidelines for management of ICH suggested that in patients with significantly elevated blood pressure (SBP > 180 or MAP > 130), a “modest reduction” in BP should be considered (SBP < 160, MAP < 110). This arbitrary BP goal was challenged in 2013 by the publication of the INTERACT2 trial. This seminal trial compared traditional BP management to more intensive BP lowering (goal SBP < 140 mm Hg within one hour), and found no statistically significant improvement in the primary outcome of functional status. The authors performed a post hoc analysis of the data, however, and did find an improvement in functional status using the newly popularized “ordinal analysis” of the data. This finding spurred further debate, resulting in additional studies on this subject. A meta-analysis published in 2014 sought to shed further light on this subject, pooling the results of the INTERACT2 trial with its pilot study (INTERACT1), the ICH ADAPT study, and one additional study that lacked the funding to devise a kickass acronym. This meta-analysis confirmed the results of the INTERACT2 trial, which is far from surprising when you consider that the vast majority of patients (~85) came from that particular study. Earlier this year, the ATACH-2 trial was published. Using similar methodology to the INTERACT2 trial investigators, the authors of this international, multi-center trial also found no statistically significant improvement in functional outcomes with more aggressive BP reduction, thereby confirming the prior results of INTERACT2 and the pursuant meta-analysis.

Journal Club Podcast #31: September 2016 A brief discussion of the growing literature on the use of tamsulosin (and sometimes nifedipine) in ureteral colic... Click Tabs Below to Expand Articles: Article 1: Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007 Nov;50(5):552-63. Answer Key. Article 2: Vincendeau S, Bellissant E, Houlgatte A, Doré B, Bruyère F, Renault A, Mouchel C, Bensalah K, Guillé F; Tamsulosin Study Group. Tamsulosin hydrochloride vs placebo for management of distal ureteral stones: a multicentric, randomized, double-blind trial. Arch Intern Med. 2010 Dec 13;170(22):2021-7. Answer Key. Article 3: Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015 Jul 25;386(9991):341-9. Answer Key. Article 4: Furyk JS, Chu K, Banks C, Greenslade J, Keijzers G, Thom O, Torpie T, Dux C, Narula R. Distal Ureteric Stones and Tamsulosin: A Double-Blind, Placebo-Controlled, Randomized, Multicenter Trial. Ann Emerg Med. 2016 Jan;67(1):86-95.e2. Answer Key. Vignette: You are working in TCC one busy evening, kicking ass and saving lives. In the middle of the primary survey of a critically ill level one trauma, you are suddenly hit by a sharp, 10 out of 10 pain in your right side. Thinking that Doug Schueurer might have punched you, you turn around swiftly and see that he is on the other side of the room. After the patient is stabilized, you run to bathroom and begin vomiting. Dr. Wagner knocks on the door and tells you to quit being dramatic and get back to work, which you faithfully do. The pain continues though to the end of your shift, at which time you check yourself in as a patient. You vitals are stable, with a heart rate of 105. You have some improvement in your pain with IV morphine and toradol. Your creatinine is normal and your UA shows a moderate amount of blood, with no signs of infection. An ultrasound (which you remember from a previous journal club is useful for diagnosing ureteral stones) reveals a 4 mm stone in the right distal ureter with mild hydronephrosis. After tolerating a PO challenge (and yes, eating one of our turkey sandwiches is a challenge), you are ready to home. You leave with prescriptions for zofran, vicodin, and Flomax. Having heard horror stories about people developing orthostatic hypotension while taking Flomax, you wonder if there is any real efficacy. When you get home, you decide to do a literature search and see what the evidence shows. PICO Question: Population:Adult patients with ureteral stones not requiring urgent surgical intervention Intervention: Tamsulosin Comparison: Usual treatment (oral hydration, pain control, etc.) Outcome: Time to stone passage, pain level, need for surgical intervention, quality of life, patient satisfaction Search Strategy: The articles chosen for the 2008 journal club were reviewed, and the meta-analysis used at that time was chosen as one of the articles. PubMed was then searched using the terms “tamsulosin AND (stones or colic)” limited to the last 10 years (http://tinyurl.com/jj8qysm). This results in 167 studies, of which 3 relevant randomized controlled trials were selected. Bottom Line: In 2008, the Washington University emergency medicine journal club looked at the efficacy of medical expulsive therapy in the management of ureteral stones. The conclusion at that time, based largely on a systematic review and meta-analysis from the Annals of EM the year before, was that tamsulosin and nifedipine may “improve moderate sized (more than 5mm) distal kidney stone expulsion rates compared with standard medical therapy.” This review did suggest the need for further large randomized controlled trials to further evaluate this topic, given that the results were based largely on “Low-quality RCT’s.” Since then, several larger RCT’s have been performed. One study with mostly small stones (70% being 2-3 mm in diameter) found that tamsulosin did not improve time to stone expulsion or need for urgent intervention (Vincendeau 2010). This finding was supported by a subsequent trial in which ~75% of stones were < 5 mm in diameter (Pickard 2015). Despite a trend toward improved spontaneous stone passage at 4 weeks (the primary outcome) in patients with stones > 5 mm in size receiving tamsulosin, the authors of this paper haughtily conclude that “further trials involving these agents for increasing spontaneous stone passage rates will be futile.” Ignoring this advice, an additional study was recently published in Annals of EM (Furyk 2016). While this study also did not demonstrate improved stone passage when considering all patients (absolute risk reduction 5.1%; 95% CI -3.0% to 13.0%), a prespecified subset analysis of patients with stones 5-10 mm in diameter resulted in a significant improvement in this outcome (ARR 22.4%; 95% CI 3.1% to 41.6%; NNT = 4.5.) This body of data, overall, suggests that tamsulosin likely provides no benefit to patients with small kidney stones (i.e. those smaller than 5 to 6 mm in diameter), but does seem to provide benefit in larger stones. A recent meta-analysis that includes all of these studies came to a similar conclusion (Wang 2016). For patients with stones 5-10 mm in diameter, this meta-analysis found an ARR of 22% (95% confidence interval 12% to 33%) with a NNT of 5.

Journal Club Podcast #30: August 2016 A quick review of the literature on anticoagulation in isolated below the knee DVTs, and why we still don't have an answer... Click Tabs Below to Expand Articles: Article 1: Schwarz T, Buschmann L, Beyer J, Halbritter K, Rastan A, Schellong S. Therapy of isolated calf muscle vein thrombosis: a randomized, controlled study. J Vasc Surg. 2010 Nov;52(5):1246-50. Answer Key. Article 2: Lagerstedt CI, Olsson CG, Fagher BO, Oqvist BW, Albrechtsson U. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet. 1985 Sep 7;2(8454):515-8. Answer Key. Article 3: Utter GH, Dhillon TS, Salcedo ES, Shouldice DJ, Reynolds CL, Humphries MD, White RH. Therapeutic Anticoagulation for Isolated Calf Deep Vein Thrombosis. JAMA Surg. 2016 Jul 20:e161770. Answer Key. Article 4: Horner D, Hogg K, Body R, Nash MJ, Baglin T, Mackway-Jones K. The anticoagulation of calf thrombosis (ACT) project: results from the randomized controlled external pilot trial. Chest. 2014 Dec;146(6):1468-77. Answer Key. Vignette: Mr. M is a 53-year-old patient with a history of high blood pressure and high cholesterol who flew back to St. Louis from Shanghai five days ago. Two days after getting back he noted pain and swelling in his left calf, which he thought was due to a muscle strain while getting off of the airplane. Since then, the swelling has remained constant while the pain has worsened slightly. He reports a dull ache that is worse with ambulation and improves with rest. He denies shortness of breath or chest pain. On physical exam his vitals are normal, his lungs are clear, and he has a normal S1 and S2 without a cardiac murmur or gallop. He has mild swelling noted to the left calf with focal calf tenderness. There is no erythema, warmth, or induration, and his pulses are symmetric bilaterally. Concerned for a possible DVT given his recent long flight, you obtain lower extremity dopplers which reveal echogenic material in the peroneal and soleal veins consistent with acute DVT, but no signs of DVT proximal to the calf. You call the patients PMD to discuss management, and she recommends sending the patient home with no therapy because, "It's just a calf DVT. You don't treat those." While you understand that has been the classic teaching, you also remember listening to an ERCAST Podcast in the last couple of years that spoke about the controversy surrounding this dogma. You send Mr. P home and recommend repeat dopplers in 5-7 days, but later decide to search the literature in order to make your own evidence-based decision... PICO Question: Population: Adult patients with isolated calf DVT distal to the popliteal veins Intervention: Therapeutic anticoagulation (heparin, low molecular weight heparin, factor Xa inhibitor, direct thrombin inhibitor, or vitamin K antagonist) Comparison: No anticoagulation. Outcome: Propagation of clot to the popliteal veins or beyond, PE, bleeding, death, cost, patient satisfaction, quality of life. Search Strategy: An advanced PubMed search was conducted using the strategy “calf AND (thrombosis OR DVT) AND anticoagulation” (http://tinyurl.com/hx4onng) with 180 articles resulting. From these, the four most relevant articles were chosen. Bottom Line: The management of DVTs isolated to the calf veins has remained a controversial topic for many years. The 2008 guidelines produced by the American College of Chest Physicians (ACCP) recommended long-term (3 month) anticoagulation for all patients with DVT, regardless of proximal extension. Updated ACCP guidelines produced this year, on the other hand, make no specific recommendation, offering options of either treating or not treating isolated calf DVTs, as long as surveillance ultrasounds are performed. This lack of a firm recommendation seems based less on actual evidence, as it is on the low quality of evidence, which we will review. This clinical conundrum has persisted for decades, with research extending at least into the 1980s. In 1985, Lancet published a randomized, controlled trial from Sweden (Lagerstedt 1985), in which patients with DVT isolated to the calf vein (as detected by phlebography) received either warfarin or no further anticoagulation (following a 5-day course of IV heparin in both groups). With 52 patients randomized, the authors found that the risk of recurrent clot was significantly lower in the warfarin group, with a NNT of 3.5 (95% CI 2.2 to 8.5). Unfortunately, this does not seem to be a very patient-centered outcome, and no patient in either group developed a PE. In 2010, an article published in the Journal of Vascular Surgery (Schwarz 2010) randomized patients with isolated calf muscle vein (soleal or gastrocnemius) DVT to naroparin or compression therapy alone. They found no difference in progression of clot into either deep calf veins (peroneal or posterior tibial) or proximal veins, with a RR of 0.98 (95% CI 0.14 to 6.7). Unfortunately, this small study was poorly reported and failed to adhere to CONSORT guidelines, making assessment of internal validity nearly impossible. Additionally, the inclusion of calf muscle veins only, which may be less likely to propagate or result in PE, would not detect benefit in patients with deep calf vein clot. A recent pilot randomized, controlled trial conducted in the UK (Horner 2014) randomized patients with any isolated calf DVT to either warfarin or anti-inflammatory medication. Seventy patients were analyzed, and for the composite outcome of proximal propagation, symptomatic PE, VTE-related sudden death, or major bleeding, they found a statistically nonsignificant trend towards benefit with anticoagulation (absolute risk reduction 11.4%, 95% CI -1.5% to 26.7%). Although the study was small, it was designed to demonstrate the feasibility of a much larger study, which is currently underway. Such a study will provide the best evidence to date regarding this treatment. The most recent evidence on this subject was a retrospective observational study conducted at UC Davis. Outcomes of patients with isolated calf DVT were assessed based on whether or not there was an intention for them to receive any form of anticoagulation. The composite outcome of proximal DVT or PE was less likely in those treated with anticoagulation (RR 0.36, 95% CI 0.15 to 0.84). This benefit persisted after adjustment was made for several confounders. Unfortunately, observational studies are never able to control for the unknown confounders, and such evidence does little to inform us of whether anticoagulation provides any actual benefit. Also, less than half the patients in the study underwent repeat testing to assess for propagation of DVT, and such testing was more likely to occur in the control group, biasing the results in favor of the treatment group. The study also included primarily inpatients, and less than 4% were from the ED. The evidence reviewed here is notably lacking in large, randomized controlled trials of good methodology, making it difficult to make firm recommendations. The current Chest guidelines make sense given this lack of evidence, and the decision to treat or not treat isolated calf DVTs should be based on several factors, including location (muscle vs. deep veins), need for ongoing immobilization, and bleeding risk. Emergency physicians will have to work closely with primary care physicians and admitting teams when making such decisions, given the controversy surrounding this topic.

Journal Club Podcast #29: July 2016 A short monologue on the advantages and disadvantages of high sensitivity troponins and a 0/1 hour algorithm to rule-out and rule-in MI... Click Tab to Expand Articles: Article 1: Jaeger C, Wildi K, Twerenbold R, et al. One-hour rule-in and rule-out of acute myocardial infarction using high-sensitivity cardiac troponin I. Am Heart J. 2016 Jan;171(1):92-102.e1-5. Answer Key. Article 2: Mueller C, Giannitsis E, Christ M, et al; TRAPID-AMI Investigators. Multi center Evaluation of a 0-Hour/1-Hour Algorithm in the Diagnosis of Myocardial Infarction With High-Sensitivity Cardiac Troponin T. Ann Emerg Med. 2016 Jul 68(1):76-87.e4. Answer Key. Article 3: Neumann T, Sorensen N, Schemer T, et al. Diagnosis of Myocardial Infarction Using a High-Sensitivity Troponin I 1-Hour Algorithm. JAMA Cardiol. 2016 June. Answer Key. Article 4: Reichlin T, Twerenbold R, Wildi K, et al. Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a high-sensitivity cardiac troponin T assay. CMAJ. 2015 May 19;187(8):E243-52. Answer Key. Vignette: You are working your first ever shift as an intern in the Barnes-Jewish Emergency Department on July 1st when you encounter Mrs. P, a forty-year old woman whose chief complaint is chest pain. She reports that 1 hour prior to arrival, while sitting at her desk at work, she developed a sharp, stabbing pain in the left side of her chest. The pain was not worse with deep inspiration or with exertion, but has continued since then. It is currently rated a 7 out of 10 and has not radiated or migrated. She notes mild subjective shortness of breath and denies diaphoresis or lightheadedness. Mrs. P tells you she a history of hypertension and high cholesterol and takes amlodipine and atorvastatin. She has never had any cardiac issues, but her father had his first MI in his early seventies. Her ROS is negative except as noted above and physical exam is completely normal, including no tenderness to palpation of the chest, no leg swelling, and no calf tenderness. Her ECG has already been performed and is normal, and her initial troponin (ordered in triage) is < 0.03. After discussion with your attending, you decide she is low risk enough that you can forego a stress test, but your attending does think you should keep her for a repeat troponin to rule out MI. Since her pain began so recently, your attending suggests waiting the prerequisite 6 hours before doing so. As you explain this to the patient, she is baffled at why she has to wait so long. As you explain that it takes time for troponin to reach detectable levels in the bloodstream, you remember that the sensitivity of troponin has increased with newer assays, and that in Europe they use an ultra-high sensitive troponin. You wonder if using such an assay would allow you to rule out MI more quickly without adding the risk of missed disease. After your shift, you head to Google and being your search... PICO Question: Population: Adult patients presenting to the ED with chest pain Intervention: One-hour serial troponin using a high sensitivity assay Comparison: Traditional 6-hour (or 4-hour or 3-hour or 2-hour) serial cardiac enzymes Outcome: Missed MI, major adverse cardiac event (MACE), or death Search Strategy: An advances PubMed search was performed using the terms troponin AND high-sensitivity AND myocardial infarction, all limited to article title (http://tinyurl.com/zluqok8). This resulted in 106 articles, from which the following four were chosen. Bottom Line: Chest pain is a one of the most common chief complaints among patients presenting to emergency department (ED) in the US, representing around 5% of all ED visits. Despite widespread testing, around 2-3% of patients with myocardial ischemia or infarction are discharged home from the ED, and missed MI accounts for more malpractice dollar awarded than any other single diagnosis. It is likely that risk of malpractice lawsuits has at least in part led to the high admission rates for chest pain seen in the US, which ranges from around 40% to as high as 80% in some institutions according to data from medicare beneficiaries. This is in spite of data suggesting that only 13-23% of patients presenting to the ED will ultimately have a diagnosis of acute coronary syndrome. The most recent AHA guidelines suggest that patients with symptoms suggestive of myocardial infarction should have serial cardiac troponin I or T levels drawn at presentation AND 3 to 6 hours after symptom onset to detect any rise in the level over that time. However, high-sensitivity troponin assays used in Europe have shown the potential to allow a more rapid rule-out/rule-in approach in which serial enzymes are checked only 1 hour apart. This approach could potentially lead to more rapid disposition of patients from our already overcrowded EDs. The European Society for Cardiology (ESC) has already embraced these newer troponin assays, incorporating a 0/1 hour algorithm into their recommended diagnostic approach. We sought, therefore, to review the evidence supporting these high-sensitivity troponin assays and their use in 0/1 hour algorithms. The four studies identified were all very similar in design. Two of the studies assessed troponin I assays (Jaeger 2016, Neumann 2016) while two assessed troponin T assays (Mueller 2016, Reichlin 2015). All four studies used some kind of algorithm with specific cut-offs for the assay as well as cut-offs for the change in value between 0 and 1 hour. Using the cut-offs, patients were either assigned a “rule-in” status, a “rule-out” status, or were considered to be in a gray zone if could not be placed in either of these groups. For example, the two studies evaluating high-sensitivity troponin T used the following definitions: • Patients with initial hs-cTnT < 12 ng/L and ?1 hour < 3 ng/L were assigned to rule out status. • Patients with initial hs-cTnT ? 52 ng/L and ?1 hour ? 5 ng/L were assigned to rule in status. • All other patients were considered to be in the observation group. Use of this algorithm (and similar algorithms in the articles evaluating high-sensitivity troponin I) resulted in high negative predictive values for ruling out patients in all 4 studies, ranging from 98.9% to 100%, and allowed anywhere from 39% to 63.4% of patients to be ruled out within one hour. The positive predictive values for ruling patients in were significantly lower, ranging from 70.4% to 87.1%. While this evidence suggests that use of high-sensitivity troponin assays would allow the rapid rule-out of many patients presenting to the ED with chest pain, there are some valid concerns remaining. These include the relatively low positive predictive values of the algorithms (which may lead to unnecessary procedures such as cardiac catheterization), and the lack of a clear plan for patients in the observation or gray zones (which may again lead to inappropriate testing in these patients). Additionally, the articles themselves are prone to significant bias, in part because of the heavy use of industry funding in all four studies (Ioannidis 2016). In all of the studies, for example, the adjudicated final diagnosis was based primarily on the results of the serial high-sensitivity cardiac troponin assays themselves, raising the specter of incorporation bias. Most importantly, the current evidence is limited to providing negative and positive predictive values for the various algorithms. Future studies will need to assess the clinical impact of using the algorithms on decision making, disposition times, and patient outcomes in order to demonstrate efficacy and safety. It likely the lack of such studies that has kept these algorithms out of our practice in the US, and out of the AHA guidelines.