TRIMming Transfusions

The Gist:  Transfusions aren't benign and Transfusion Related Immunomodulation (TRIM) may play a role in complications associated with transfusions.  Data suggest that allogenic blood transfusions (ABTs) may have immunosuppressive properties [1-6]. Yet, TRIM is a vague controversial entity without easily identifiable clinical markers or pathogenesis and is predominantly based on observational and animal data [3,8].   Keep this entity in mind, not withholding blood products when indicated, but when contemplating the risks and benefits for those patients with borderline indications.  Give the patient all the blood they need, but not one drop more.

Free Open Access Medical education (FOAM) sources have increasingly mentioned this entity, TRIM, over the past few years, including this recent Maryland Critical Care Project podcast.  On a recent FOAMcastwe reviewed the core content associated with adverse effects of transfusions; yet, we did not encounter TRIM overtly in the review of Rosen's and Tintinalli.  Thus, I needed to find out more about this entity I had only learned about through podcasts.

TRIM has not made its way into many classrooms, likely secondary to the lack of understanding of the clinical significance and etiology of TRIM.  The development of pneumonia in the weeks following a transfusion is more difficult to attribute to a single etiology than a hemolytic reaction occurring during the transfusion.  Furthermore, much of the data are observational are observational and animal based with uncertain clinical implications.  As we see transfusion triggers decrease with equivalent or superior outcomes, it may be helpful to keep an eye on TRIM and, when we are tempted to transfuse individuals who are just above the transfusion threshold or give 2 units of red cells empirically, recall that blood product transfusions are actually transplants.  Perhaps we should have the same obsession with transfusions as we do fluid responsiveness summed up eloquently in the words of Dr. Paul Marik, "give that patient all the fluid they need, but not one drop more."

Clinical effects attributed to TRIM

Increased risk of infection
  • Contamination of blood products with infectious particles is not common and ranges from 1 in 1-3 million for HIV and hepatitis C, to 1 in 2000 for bacteria in platelets [11].  Studies, including the recent JAMA meta-analysis by Rhode et al, demonstrate more infections in individuals with higher transfusion targets.  Thus, some postulate that the increase in infections is a result of the immunomodulatory effects of transfusions. 
Tumor growth/Cancer - The roots of this notion, particularly an association with lymphoma, lie in retrospective and observational studies [6]
  • Randomized controlled trials (RCTs) looking at leukoreduced blood products did not demonstrate an increase in cancer  [1,2,6]
Multi-organ failure - this is one of the effects we care about most clinically and studies of various quality demonstrate an association between multi-organ failure/short-term mortality and transfusion [1].
  • Studies confounded by the underlying severity of illness of the patients, which itself predisposes the patients to multiorgan failure. 
  • The most consistent effects of TRIM are in RCTs involving cardiac surgery patients [1]
Improved survival in renal transplants - In the 1970's, patients awaiting renal transplants were given one or more ABT, leading to increased graft survival [1].
  • Immunosuppressive pharmaceuticals such as cyclosporine have replaced this practice.
Decreased spontaneous abortions [2]

Pathophysiology of TRIM -   These are postulated theories and associations since the exact etiology isn't clear.  Texts tend to agree that TRIM is the result of a complex inflammatory and immunosuppressive happenings that may result from downregulation of cellular immunity, induction of humoral immunity, and altered inflammatory responses. TRIM may depend on:

Degree of contamination of transfused blood with leukocytes - this is one of the reasons the FDA recommends leukoreduction of all blood [12].  Transfusions with leukoreduced blood have demonstrated varying results.
  • The beneficial effects of TRIM have been attributed to donor dendritic cells (or Allogeneic Mononuclear Cells - AMCs), which may invoke a tolerance among recipient cells and downregulate T cells.
  • Leukocytes release reactive oxygen species and proteolytic chemicals that may cause an inflammatory cascade and tissue injury [1].
  • Not the the sole culprit as trials in which one group received leukoreduced blood do not consistently demonstrate a difference [2].
Soluble components or "mediators" - This includes things like histamine, cytokines, and proteins in the plasma or released from the white cell membranes and granules are released upon degradation.  Also, there's some thought that plasma contains soluble class I HLA molecules, which may be partially responsible.
  • These "soluble mediators" may inhibit proper T cell function and ability of neutrophils to work properly [1].  
  • Higher levels of cytokines such as IL-10 have been demonstrated in patients receiving more blood in the peri-operative period.  It's theorized that these cytokines, whether they're generated by the recipient in response to a stimulus or from the donor, play an immunosuppressive effect [7].
  • However, filtration of these products before storage has not demonstrate a difference in "TRIM effects" (OR 1.06 (0.91-1.24)p>0.05), indicating that these are not the sole mediator of TRIM [2]. 
Storage time - This is not an exact etiology but may amplify the effects of the above proposed mediators.  This is purported secondary to the release of soluble mediators during storage of blood products.  Some studies have found increased infection, morbidity, or mortality with older red blood cells (RBCs) but the totality of the literature is inconclusive. Most of the studies have small numbers, have differing definitions of "old" RBCs, and are retrospective or observational in nature; however, results from the RCTs ABLE and RECESS may clarify [13].
  • Leukocytes degrade during the first two weeks of storage and release chemicals called soluble mediators.  RCTs that filtered leukoreduced and non-leukoreduced blood still demonstrated an increased incidence of infection in the non-leukoreduced blood (OR 2.25 (1.12-4.25) p<0.05) [2]
  • Free Iron - blood undergoes a degree of hemolysis during prolonged storage, freeing iron which is biologically reactive.   
So, we're not sure precisely what TRIM is, whether TRIM is clinically significant, or what may cause TRIM.  The bottom line is that transfusions likely have effects beyond what we currently understand, so it is prudent to treat this type of transplant with respect.

References:
1. Vamvakas EC, Blajchman MA. Transfusion-related immunomodulation (TRIM): an update. Blood Rev. 2007;21(6):327–48. 
2. Blajchman MA, Vamvakas EC.  (2009).  Transfusion-related immunomodulation In Pamphilon DH (ed). Practical Transfusion Medicine (pp. 98-106).  Blackwell Publishing
3. Zimring JC, Nester T.  (2013). Transfusion Related Immunomodulation In Shaz BH (ed.) Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects, Elsevier Science, Chapter 69.
4.  Chen W, Lee S, Colby J, et al.The impact of pre-transplant red blood cell transfusions in renal allograft rejection. Rockville, MD, USA: Agency for Healthcare Research and Quality. Technology Assessment Report; Project ID RENT0610; 2012.
5. Scornik JC, Bromberg JS, Norman DJ et al. An update on the impact of pre-transplant transfusions and allosensitization on time to renal transplant and on allograft survivalBMC Nephrology 2013, 14:217 
6. Gilliss BM, Looney MR, Gropper MA. Reducing noninfectious risks of blood transfusion. Anesthesiology. 2011;115(3):635–49. 
7. Theodoraki K, Markatou M, Rizos D, et al. The impact of two different transfusion strategies on patient immune response during major abdominal surgery: a preliminary report. J Immunol Res. 2014;2014:945829. 
8.  Geiger T. Transfusion-associated immune modulation: a reason to TRIM platelet transfusions? Transfusion. 2008 Sep;48(9):1772-3.  doi: 10.1111/j.1537-2995.2008.01860.x.
9. Rohde JM, Dimcheff DE, Blumberg N et al. Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA. 2014 Apr 2;311(13):1317-26. 
10. Sparrow RL. Red blood cell storage and transfusion-related immunomodulation. Blood Transfus. 2010;8 Suppl 3:s26–30.
11.Hillyer CD, Josephson CD, Blajchman CJ et al.  Bacterial Contamination of Blood Components: Risks, Strategies, and Regulation.  ASH Education Book January 1, 2003 vol. 2003 no. 1 575-589
12. Food and Drug Administration.   Guidance for Industry: Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion. U.S. Department of Health and Human Services, Center for Biologics Evaluation and Research.  September 2012
13.Aubron et al. Age of red blood cells and transfusion in critically ill patients.  Annals of Intensive Care 2013, 3:2

"I heard it on a podcast once.."

The Gist:  In the medical and clinical arenas, it may often be unwise to simply quote an expert as justification, whether it's an expert on a podcast or something heard at a national conference lecture.  Use Free Open Access Medical education (FOAM) as a springboard for deeper learning and consider eliminating the phrase "I heard this on a podcast.." from one's arsenal.
  • Note: This is not an evidence based post, rather it's entirely opinion from the powerful experiences I've had failing at using FOAM (and other traditional, peer reviewed sources) juxtaposed with successes.  
The Case:  A trainee at Janus General took care of a patient with hyperkalemia secondary to polypharmacy (spironolactone, ibuprofen, and TMP-SMX).  When admitting the patient, the attending asked why sodium polystyrene (kayexalate) had not been administered and requested it be given in the emergency department.  The trainee replied, with a smug voice, "Well, I heard on a podcast that we don't need to give this, so I'm not going to."

Issues:  Repeating an authority figure's opinion without due diligence can be dangerous, whether it's in a podcast, on a blog, or in a lecture hall.


Eminence versus evidence.  The post, The Matthew Effect, demonstrates examples of how sometimes things that are quoted, both in FOAM and the literature, aren't always as .

Local standard of care.  Practice patterns vary for a myriad of reasons including: health care delivery models, availability of resources, geography, the practice of consultants, the legal system, and patient expectations.  As a result, things heard from experts may not apply, may not work within the framework of the local system, or may take time to implement.  Thus, it's important to keep this in mind while simultaneously pushing for the best, evidence based care for our patients.

A Few Fixes
:
Effective learning involves hard work.  As such, these "fixes" relegate slightly more responsibility on the learner, or whomever is process and potentially using the information.  

Read.  Good podcasts and blogs cite the references for their assertions.  When one encounters a controversial or innovative bit of information from a podcast or blog, spend extra time processing the information as quality and an author's spin may vary.  Furthermore, the "cutting edge" components of podcasts are often rooted in core texts and these can be used for both perspective and leverage.  This post delves more into establishing our thresholds to change our clinical practice.
  • Example:  "As you're aware, literature such as the 2010 Cochrane review and the American College of Gastroenterology guidelines on proton pump inhibitors (PPIs)  in patients with upper gastrointestinal bleeds didn't show any patient oriented benefit.  So, while I think this patient needs admission for endoscopy and further management, I feel comfortable holding off on this intervention at this time."   
Pose a question.  It is fun to bust myths and “lyse dogma” yet this can be off-putting and interventions may not work or be appropriate within the local system or standards of care.  It’s often helpful to generate a discussion on the subject under investigation, regardless of the medium - a new article, blog, or heard on a podcast or conference.
  • Example:  "Some physicians, including some in the nephrology literature, question the efficacy and utility of sodium polystyrene compared with the other interventions we have - with some potential for harm.  How does that fit in here?" Or, "What do you think of this study by Sterns et al in the Journal of the American Society of Nephrology?" 
Disclaimer.  Often, the tacit information shared on podcasts precedes supporting literature, if it exists.  For example, in January 2011, Dr. Scott Weingart published a podcast on delayed sequence intubation (DSI).  In the podcast and lectures on DSI at national conferences, Dr. Weingart has given a clear disclaimer regarding the paucity of peer reviewed evidence on this topic.  Weingart's paper addressing DSI was published online in 2010, yet the print version surfaced over a year later in June 2011, with cases published by Lollgen et al and Schneider et al in 2013-2014.
  • Example:  "I think we should maximize pre-oxygenation in this patient and, while it's not an evidence based technique, some people such as Dr. Scott Weingart, suggest that there may be times when procedural sedation can help with pre-oxygenation as we prepare to intubate."  
The Real World:  Now, it is impossible to perform individual deep dives on every clinical topic.  We do need filters and reliable, trustworthy sources.  Sometimes it can be difficult to parse these out.   There are potential solutions in the FOAM world.  For example, Dr. Seth Trueger offers the following in jest, but it may be helpful to approach information that one counters with the assumption that the accuracy isn't always what it seems.

Also, an excellent new FOAM search-engine, iClickEM (still in beta-testing; however, I recommend getting on the waitlist), pairs peer-reviewed sources alongside a set of curated FOAM sources.  The engine also uses fancy algorithms to create relevant and trusted results.

Engage in dialogue with colleagues, mentors in training programs, or content experts.  Reference FOAM resources such as podcasts and blogs and cite these works appropriately.  Yet please, consider refraining from prefacing a statement with, "I read it on a blog" or "I heard it on a podcast once."  

Breadth and Length – Antibiotics in Uncomplicated Cellulitis

The Gist:  Many cases of uncomplicated, non-purulent* cellulitis can be treated with a five day course of oral antibiotics, such as cephalexin or dicloxacillin, without covering for MRSA.  The Infectious Disease Society of America (IDSA) and core emergency medicine texts support this recommendation, with provisions for extended coverage (duration and/or MRSA antibiotics) in high-risk or sicker patients [1-3]. Despite these recommendations, providers often prescribe lengthier courses with broader spectrum coverage, which may have lead to adverse effects, increased cost, or resistant microbes [4-6,8].

The Case:  A 38 year old female presents to the emergency department (ED) with right lower extremity erythema and warmth, progressing over the past four days.  She has no known trauma, no prior history of cellulitis or abscesses, and her history was remarkable for "borderline" diabetes, hypertension, and depression.  Vital signs are within normal limits and examination reveal a diffusely erythematous area of approximately 7 x 4 cm, warm to touch, with some edema but no induration or drainage.  This patient seems to be an ideal candidate for outpatient therapy.  Should the provider write for cephalexin for 5 days? 7 days? Does the patient also need TMP-SMX or clindamycin?

Despite revolutionizing medical care, antibiotics prescribed for skin and soft tissue infections are not benign as patients incur costs and may develop allergic reactions, yeast infections, antibiotic associated diarrhea, or provoke resistant pathogens.  In national survey data, antibiotics have been associated with nearly 1 in 5 ED visits for adverse drug events and more than 1 in 4 similar events in the pediatric population [5,6].  Antibiotics prescribed for skin and soft tissue infections have been associated with a large proportion of these events, at least in children [7].  As a result, there's an increasing emphasis on using appropriate antibiotics for the minimum duration needed to treat the infection.

Duration of therapy: In 2005, the IDSA issued a recommendation a 5 day course of treatment for uncomplicated cellulitis and this is offered up as an option in core EM texts [1,3,6].  However, many practitioners prescribe an initial 7-10 day course of treatment. Interestingly, the most recent iterations of both Tintinalli and Rosen's do not hazard a suggestion for antibiotic duration for any skin and soft tissue infections [2,3].

The five day recommendation** is based on study by Hepburn et al.  Outpatients presenting to the clinic or ED (n=121) with uncomplicated cellulitis were treated with levofloxacin for 5 days and then randomized (n=87), at a 5 day visit, to receive either 5 additional days of antibiotics or placebo. Patients were reevaluated at an appointment between days 10-14 and then at 28 days by telephone.  Treatment success was not different between groups, with 98% resolution in both arms [8].
  • Diabetes was not an exclusion criteria and was present in 5% (n=12) and 7% (n=16) in the treatment and placebo groups, respectively.
  • At the time of randomization (day 5), patients were allowed to have persistent erythema and warmth, as long as it had not worsened and seemed marginally improved.  This was somewhat subjective.  
  • Patients were enrolled within 24 hours of diagnosis and treatment so some patients received different antibiotics during the first 24 hours.  
  • Levofloxacin isn't routinely used for cellulitis in most populations. 
Choice of antibiotics:  Most non-purulent cellulitis is caused by streptococcus (strep), even in areas with a high prevalence of MRSA.  As such, the IDSA and core texts recommend targeting strep only for most uncomplicated, non-purulent cellulitis [1].  Literature suggests these low risk patients do no better on coverage for both strep and staph [9].  In higher risk patients or those with purulence that do require staph coverage, it is recommended that providers use anti-MRSA antibiotics in areas with high prevalence of MRSA [1-4].  Use of anti-MRSA antibiotics in high risk groups including those with history of MRSA, diabetic ulcers, systemic illness, IVDU, and other higher risk patients is less controversial and more broadly supported [1-4].

A study comparing monotherapy with cephalexin versus TMP-SMX have demonstrated that in systemically well, uncomplicated patients, cephalexin monotherapy suffices [9]. Review of the study. A trial comparing TMP-SMX, placebo, cephalexin, or combination was completed in July 2013, with no posted results at this time [11].

Of note, studies examining the microbiology of cellulitis may be skewed by selection bias, as staph and MRSA tend to cause more purulent infections which may be more likely to be cultured [12]. Furthermore, cultures are only indicated and, theoretically obtained, in the sicker patients and in those with comorbidities which may further also skew the results.

Do we prescribe antibiotics appropriately? Not commonly.
Hurley et al conducted a retrospective cohort study in Denver of ED patients and outpatients in 2010-2011 that measured the frequency of "avoidable antibiotic exposure." The authors defined "avoidable" antibiotics with a broad spectrum of gram-negative activity (beta-lactam/beta-lactamase inhibitor combinations, second, third, or fourth-generation cephalosporins, fluoroquinolones, carbapenems, or aminoglycosides); combination therapy (2 antibiotics or more); or treatment for more than 10 days.
    • n=364 of whom 155 had cellulitis
    • Only 7% (n=8) of patients with cellulitis received 5 days of antibiotics and 47% (n=54) received 10 or more days of antibiotics
    • 61% of patients with cellulitis received MRSA coverage [9]
Also, there's no benefit to a single dose of IV antibiotics in the ED and blood cultures aren't helpful in these patients.  On a more controversial note, a recent retrospective chart review by Paolo et al found that blood cultures may not significantly alter management in cases of complicated cellulitis as the contaminant rate (3%) was roughly equivalent to our true positive rate (4%).

*Complicated - varies by reference, but typically includes immunocompromised, those with signs of systemic illness, extremes of age, or diabetes.
Purulent - drainage or signs of abscess. History of abscess and eschar are also associated with staphylococcus (staph).  
**It's difficult to determine what, precisely, the 7 and 10 day historical attachments are based on other than history and familiarity.
    References:
    1.  Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41(10):1373–406. 
    2.  Kelly EW, Magilner D.  "Soft Tissue Infections."  Tintinalli's Emergency Medicine: A Comprehensive Study Guide.  7th ed. p 1017-1018.
    3 .Marx JA, Hockberger RS, Walls RM.  Rosen's Emergency Medicine , Eighth Edition. Chapter 137, 1851-1863.e1
    4. Meislin HW, Giusto G.  Rosen's Emergency Medicine , Seventh Edition. Chapter 135, 1836-1838. 
    5.  Shehab N1, Patel PR, Srinivasan A, Budnitz DS. Emergency department visits for antibiotic-associated adverse eventsClin Infect Dis. 2008 Sep 15;47(6):735-43. 
    6.  Bourgois FT, Mandl KD, Valim C et al.  Pediatric Adverse Drug Events in the Outpatient Setting: An 11-Year National AnalysisPediatrics. Oct 2009; 124(4): e744–e750.
    7. Goldman JL, Jackson MA, Herigon JC et al.  Trends in Adverse Reactions to Trimethoprim-Sulfamethoxazole.  Pediatrics. Jan 2013; 131(1): e103–e108.
    8. Hepburn MJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis.  Arch Intern med 2004; 164, 1669-1674
    9. Hurley HJ, Knepper BC, Price CS, et al. Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting. Am J Med. 2013;126(12):1099–106. 
    10. Pallin DJ, Binder WD, Allen MB et al.  Clinical Trial: Comparative Effectiveness of Cephalexin Plus Trimethoprim-Sulfamethoxazole Versus Cephalexin Alone for Treatment of Uncomplicated Cellulitis: A Randomized Controlled Trial.  Clin Infect Dis. (2013) 56 (12): 1754-1762.
    11.  ClinicalTrials.gov: A Service of the U.S. National Institutes of Health (NCT00729937). 
    12.  Ray GT1, Suaya JA, Baxter R. Microbiology of skin and soft tissue infections in the age of community-acquired methicillin-resistant Staphylococcus aureus. Diagn Microbiol Infect Dis. 2013 May;76(1):24-30.

    We Don’t Know What We Don’t Know

    The Gist:  Overestimation of our level of mastery is common and is referred to as the Dunning-Kruger effect [1-3].  This effect persists in medicine and may have deleterious effects both at the bedside and in the training process [4-6].  Use of practice testing or simulation, metacognition, and the push of information to an individual may mitigate the dangers of unconscious incompetence by identifying areas of weakness and keeping the practitioner skilled.

    "Ignorance more frequently begets confidence than does knowledge" - Charles Darwin [6]

    The Case:  A 48 year old female with hypertension presented to Janus General with the sensation of the room spinning and feeling off balance for the past day.  The resident performed a head impulse, nystagmus type, test of skew (HINTS) exam, which demonstrated the presence of a saccade during the head impulse component. and determined that the patient likely had a central cause.  The patient was admitted to the hospital for questionable TIA/CVA workup, which was negative.
    • The problem: a saccade during the head impulse component is suggestive of a peripheral cause of vertigo.  While use of the HINTS exam by emergency providers has not been validated and is outside the bounds of this discussion, this example demonstrates the overconfidence of the resident in their skills and interpretation and the potential for perpetuation of this misunderstanding.  
    The Dunning-Kruger Effect - These researchers demonstrated a large discrepancy between the way incompetent people actually perform and the way they perceive their own performance level.  This discrepancy appears smaller for highly skilled individuals, who may underestimate their mastery. The studies demonstrating this effect often result in a graph akin to the one below.


    The Danger in Medicine - A little knowledge is a dangerous thing.  In medicine, a balance exists between the confidence to commit and act and the insight to see that we have uncertainty or lack the appropriate skill set.  In emergency medicine this line may be particularly difficult to walk as patients often require immediate intervention at times when data is limited, clouding certainty.
    • Diagnostic Error -  Overconfidence may result in premature closure, confirmation bias, or failure to use clinical aids such as practice guidelines or decision aids.  It turns out that compared with tempered attendings and insecure medical students, residents may be most susceptible to diagnostic overconfidence [8]. 
    • Unsafe Procedures - An attending once told me, "Procedures in emergency medicine exist to keep us humble."  After a novice learner's first string of successful intubations, it's tempting to believe we've become "good" at intubations.  However, this hubris may cause us to expose patients to harm if we take short cuts in preparation or fail to continue to maintain contingency plans.  Furthermore, in emergency medicine, we must be able to cue up live saving procedures at any moment that we may only see or perform once in a career.  Without accurate awareness of our competence, we may we fail to recognize that our skillsets are weak or a procedure/tools/kits have changed leading to suboptimal outcomes.  
    “Real knowledge is to know the extent of one's ignorance” – Confucius

    Mitigating the Effect
    • Practice Testing (or retrieval practice) - While the quality of the evidence is poor, Davis et al write that physicians are particularly not keen at assessing themselves [6].  As a result, we are unlikely to identify our areas of incompetence ourselves.  Assessment through practice testing, however, may identify weak areas in our knowledge base or skill set that we may otherwise not identify. In this way, we may decrease the discrepancy between what we think we know and what we actually know.
    • Simulation - Practice and rehearsal can identify weak areas in procedures or situations we may not often encounter or, conversely, give us the confidence in our ability to act when needed.  This doesn't require mannequins and computers - simply rehearsing procedures and scenarios in our minds works quite well.  Dr. Cliff Reid eloquently stated, “We have the most powerful, 3D, high-fidelity simulator in the known universe," reference the mental simulator.
    • Information Push - Most of us only review topics we believe we have previously mastered when we discover a weak spot in our understanding or make a mistake.  However, when information is pushed to the us, we encounter a wider array of information.  
      • Free Open Access Medical education (FOAM) serves as a prime example of the concept of information push, as topics collated in RSS aggregators such as Feedly and delivered by subscriptions to podcasts or twitter feeds cover information not intentionally sought by the learner.  So, while some find FOAM overwhelming, it can be used in an interesting way to strengthen the areas that we don’t know that we don’t know.
    • Metacognition - Awareness of weak points in our reasoning or systemic traps may help us overcome overconfidence, particularly with regard to diagnostics.  The post, Metacognition For the Pragmatist, discusses ways in which we can overcome our cognitive biases.  
    • Remain skeptical of the feeling of complete ease and mastery, which may cause to stop working and striving to improve.  In his talk “The Path to Insanity” at SMACC 2013, Dr. Scott Weingart advises that we "never assume your own excellence" [9]. 
    What's the underpinning of the Dunning-Kruger effect?
    • It's difficult to estimate the quality of one's performance.
    • Self-enhancement bias - We tend to think we're better than we actually are.  For example, very few bad drivers actually recognize the fact that they, in fact, are the poor drivers.
    • Regression to the mean - This explanation exists as one of the primary criticisms of the Dunning-Kruger Effect and argues that the effect may be, in part, statistical artifact.  When people are asked to evaluate themselves, incompetent people may simply regress toward the mean when asked to evaluate their own performance. On the other hand, people who have extremely high levels of performance, those who have mastery in a given area, are also less likely to underestimate their skills to the degree that those who are incompetent.
    “I know that I know nothing” – Socrates
    References:
    1. Dunning D, Heath C, Suls JM. Flawed Self-Assessment: Implications for Health, Education, and the Workplace. Psychol Sci Public Interes. 2004;5(3):69–106. doi:10.1111/j.1529-1006.2004.00018.x.
    2. Kruger J, Dunning D. Unskilled and unaware of it: how difficulties in recognizing one’s own incompetence lead to inflated self-assessments. J Pers Soc Psychol. 1999;77(6):1121–34. 
    3. Dunning D, Johnson K, Ehrlinger J, Kruger J. Why people fail to recognize their own incompetence. Curr Dir Psychol Sci. 2003;12(3):83–87. doi:10.1111/1467-8721.01235.
    4. Edwards RK, Kellner KR, Sistrom CL, Magyari EJ. Medical student self-assessment of performance on an obstetrics and gynecology clerkship. Am J Obstet Gynecol. 2003;188(4):1078–1082. 
    5. Hodges B, Regehr G, Martin D. Difficulties in recognizing one’s own incompetence: novice physicians who are unskilled and unaware of it. Acad Med. 2001;76(10 Suppl):S87–9.
    6.  Davis DA, Mazmanian PE, Fordis M, Harrison R Van, Thorpe KE, Perrier L. CLINICIAN ’ S CORNER Accuracy of Physician Self-assessment Compared A Systematic Review. 2006;296(9).
    7. Darwin C. 1871. The Descent of Man, and Selection in Relation to Sex, 1st edition. London: John Murray.
    8. Berner ES, Graber ML. Overconfidence as a cause of diagnostic error in medicine. Am J Med. 2008 May;121(5 Suppl):S2-23. doi: 10.1016/j.amjmed.2008.01.001.
    9. Weingart S.  EMCrit.  Podcast 105.  August 20, 2013.  Available at: emcrit.org/podcasts/path-to-insanity/

    The (Un)Learning Process

    The Gist:  Despite Harvard's medical school dean, Dr. Burwell, warning students, "Half of what we are going to teach you is wrong, and half of it is right. Our problem is that we don't know which half is which," medical education doesn't do a very good job preparing us for unlearning the wrong half.  Recent publications revealing the reversal of common medical practices demonstrate the need for this skill among clinicians [1-4]. Although unlearning is a part of the learning process, it is difficult, can feel personal, and may mirror the stages of grief [6].  Recognizing the obstacles to unlearning and arming ourselves with an enhanced awareness of ways in which we can overcome these barriers may mitigate our difficulty unlearning.

    A study by Prasad et al examined studies testing the "standard of care" in publications in the NEJM and found that 40.2% of articles testing a practice that existed as "standard of care" reversed the practices, whereas 38% of articles testing the practice reaffirmed the standard [1].  The follow up commentary demonstrate that physicians should be open to unlearning and should treat studies with skepticism [2,3].  This is not to say that trainees and physicians should perform full, independent critical appraisals of each article they read but rather, beware of the barriers to scrutinizing our practice.  Through Free Open Access Medical Education (FOAM), one may keep a finger on the pulse of medical literature, through the primary literature and voyeurism into how others process the information.

    The Case:  I read the Nielsen et al paper on therapeutic hypothermia (TH) in cardiac arrest in the New England Journal of Medicine with astonishment after the FOAM world exploded with chatter on the paper.  Just days before, the residency conference featured a presentation outlining the evidence behind TH, including the landmark papers by Bernard et al and by The Hypothermia After Cardiac Arrest Study Group.
    This paper made me feel uncomfortable.  Medical school, Rosen's, and Tintinalli's made no mention of this aspect of medicine - how to unlearn something well ingrained. This is not to say I think we need to unlearn TH, but to re-examine the cherished practice to identify parts that create a difference in patient care. Less than one year into my residency, there have been countless interventions, diagnostic algorithms, or pathophysiologic explanations, taught to me as a medical student, that are now widely accepted as untrue or bad practice:  activated protein C in sepsis, the pathophysiology behind the hypoxic drive in COPD, the new left bundle branch block in a not so sick patient. I am not an expert, but these struggles with unlearning (or relearning) caused me to develop practices to keep my mental flexibility in check.

    Stages of Unlearning and Practices to Overcome These Barriers
    1.  Denial - We gravitate towards literature, dogma, experts, and practice patterns that reflect our own biases.  Thus, we may not come into contact with the information prompting a change in our practice or, alternatively, we may outright dismiss the assertion or data without a solid look.
    Action:
    • Remind ourselves that publications may lead us astray if we are not careful [4,5].  
      • The first study makes the biggest splash but the second (third, fourth, etc) are the most important - don't overlook these [4].  After all, replication is the key to science, the foundation of medicine. 
      • Pay particular attention to "negative" studies, which are published far less frequently than positive studies.
      • Statistics may be easily manipulated.  This exists as data dredging, too much reliance on clinically meaningless statistics such as the p value, or misrepresentation of data or statistics in conclusions [4,5].   
    • Stay abreast of current literature which may include using others to help curate and manage the influx of evidence Examples in FOAM, such as use of Twitter, Emergency Medicine Literature of Note, Richard Lehman's Journal Scan, EM Nerd, can be found at the end of this post
    2.  Anger - We tend to become defensive when our beliefs and practices come under scrutiny or are challenged - it can feel like we're being attacked.
    Action:
    • Accept that we will do things that may, in hindsight, be called "wrong" even though this was not known at the time.
      • This takes a certain level of intellectual and emotional vulnerability.  Historically, this is not only an issue at the individual level, but also a barrier for institutions to unlearn a practice [6].  
    • Reassure ourselves that medical interventions do not define us as providers.  Recognize that evolution of medical practice involves a continuous state of learning and unlearning, despite our best research and efforts. Do not take individual medical interventions personally; rather, attempt to take our overall commitment to good, patient-centered medicine seriously.  
    • Beware of zealotry for a medical intervention.  If question over one of an intervention causes us unease, it may indicate that we are tied more to an idea than to patient care.  For example, I had a visceral response when prompted to re-work my thinking and use IVC ultrasound, in isolation, as a marker of fluid responsiveness.  It was scary to think how I had become so invested in a practice as a medical student.  This may be more difficult for individuals with industry ties or research embedded in one nidus of interest.
    3.  Bargaining - We may engage in mental trade-offs with the evidence, using our own experiences/anecdotes or mental frameworks in an effort to trump the data driving the unlearning.  We may utter something along the lines of, "But, I saw Drug X work, in front of my very eyes," despite data demonstrating lack of efficacy.
    Action:
    • Recognize the cognitive biases we have developed, our heuristics and anecdotes that may cause us to anchor in our learned practice patterns, and attempt to set these aside while we examine the data.  These cognitive short cuts and experiences certainly comprise part of one's clinical gestalt; yet, there may be times in which they act as a crutch.  Once we have a successful, miraculous clinical story of an intervention or diagnosis, we are at risk to become unconsciously attached to the steps that led us to the victorious save.  We have a similarly intense reaction when we experience a negative outcome.  Clinical experience and the best available evidence may work in concert but they also often have a tenuous relationship, filled with bargaining.
    • Similarly, recognize the familiar crutches of pathophysiology based answers or surrogate markers/endpoints.  When we dredge up complicated explanations that we were taught in medical school, with several extrapolations to fit the current thinking, this is frequently a marker that our understanding, to that point, was incomplete to begin with (and therefore, should be prime for re-examination).
    4.  Depression - We may feel guilty or defeated by this unlearning process and assume that it translates into either a reflection on ourselves or demonstration of the futility of medicine, research, or evidence based medicine.
    Action:
    • Recall that while we have a seemingly innate desire to intervene, sometimes even apparently harmless interventions carry risks.  
    • Reinforce that this is part of the process of practicing medicine, which is a dynamic environment teeming with uncertainty.
    5.  Acceptance - Once we acquiesce to the notion that it's necessary to unlearn a practice or thought process in medicine, we are at risk of becoming complacent and failing to unlearn yet again, resulting in a vicious cycle.  Perhaps we should never be fully comfortable with the support for what we do, as that may allow us to become complacent and think that we understand when we don't. We may share in creating a dogma to replace the one we have just unlearned.
    Action:  
    • Given the changing landscape of medical practice, it's likely wise to regard all of our practices with a skeptical and curious eye. This may allow us the mental flexibility to alter our practice when warranted. 
    • FOAM may play a role in allowing one voyeurism into how others are adopting or processing studies so we can identify interventions that may be nearing an inflection point for reversal.
      • The use of a filter and "sounding board" for literature does have limitations:
        • Selection bias - perhaps only papers in specific areas of interest/popularity are disseminated.  Furthermore, one may only encounter those disseminated by others with similar opinions, serving only to confirm our own biases.  
        • Premature adoption - As Ioannidis and Prasad warned, medical interventions undergo reversal frequently so aggressive adoption may expose patients to harms and providers to a bruised ego [1-3].  There's an elusive "sweet spot" between changing/unlearning a practice at a dangerously early time and too late. A previous post addresses the use of FOAM and local "authority" to change practice, and the cautions regarding changing practice discussed therein are also apply here.
        • Predigested information can make staying current on literature and ramblings in the medical community easy and practical for busy clinicians but deprives one of the importance of thinking for oneself - it's in this area of work and effort that learning actually takes place.  It's also tempting to simply nod behind others with similar opinions or adopt an expert's view, although this is certainly an issue outside of FOAM as well (e.g. local experts, clinical policies, etc).
    References:
    1. Prasad V, Vandross A, Toomey C, et al. A decade of reversal: an analysis of 146 contradicted medical practices. Mayo Clin Proc. 2013;88(8):790–8.
    2.  Ioannidis JP a. How many contemporary medical practices are worse than doing nothing or doing less? Mayo Clin Proc. 2013;88(8):779–81.
    3.  Vinay Prasad V, Ioannidis JP.  Evidence-based de-implementation for contradicted, unproven, and aspiring healthcare practices.  Implement Sci. 2014; 9: 1.
    4.  Ioannidis JP a. Why most published research findings are falsePLoS Med. 2005;2(8):e124. 
    5.  Nuzzo R.  Scientific method: Statistical errors Nature 506, 150–152 (13 February 2014) doi:10.1038/506150a 
    6.  Rushmer R, Davies H. Unlearning in health care.  Qual Saf Health Care. 2004 December; 13(Suppl 2): ii10–ii15.

    ‘Roid Rage – Right Route and Dose?

    The Gist:  For many indications, such as croup, asthma, and anaphylaxis, oral steroids are equally as effective and work as quickly as intravenous steroids and the effective doses are likely lower than we frequently give.   Check out this free steroid converter to prevent preposterously high doses of methylprednisolone or dexamethasone.

    The case: A 13 month old presents to the ED with a harsh, barky cough.  Parents report a few days of prodromal upper respiratory symptoms but the child has good oral intake and vital signs.  The child is playful, with a snotty nose and intermittent stridor.  Given the clinical diagnosis of croup, how much dexamethasone do you give?  These bits of Free Open Access Medical education (FOAM) served as the impetus behind the development of my steroid in croup practice: EM PEM podcast, HQMedEd videoEmergency Medicine Literature of Note post

    Croup (laryngotracheobronchitis)- A single dose of steroids in croup is the mainstay of treatment in mild to moderate disease as they decrease return visits (RR 0.5, 95%CI 0.3-0.7) and hospital length of stay compared with placebo [1].  The number needed to treat (NNT) is 11 in the ED population (or 5 for improvement in a clinical score).  The historically touted dose of dexamethasone is 0.6mg/kg orally as this is the most studied dose; however, lower doses have demonstrated non-inferiority and have even made it into textbook recommendations [2,3]. The 0.6mg/kg dose of dexamethasone is equivalent to ~3.75mg/kg of prednisone - overkill for this disease process?
    • Dexamethasone 0.15mg/kg PO (can give IV solution orally)
    A Cochrane Review demonstrates no significant difference in return visits between "high dose dexamethasone" (0.6mg/kg) and 0.15mg/kg with a risk ratio of 1.04 (95%CI 0.62-1.75) [1]. Hospitals, particularly in Australia where the bulk of the steroid in croup literature originates, have used 0.15mg/kg routinely for the past 18 years, and observational data demonstrates a decline in admissions [3,4].

    Limitations - the studies are all pretty small and are not powered to detect small differences.  Are these small differences clinically significant?  Croup also tends to be a self-limiting disease so these studies may be far underpowered to capture rare complications.  Furthermore, many of the studies only look at mild to moderate croup so selection bias may demonstrate.  Yet Fifoot et al excluded this group (Westley score <2) and still found that 0.15mg/kg was as efficacious as larger doses.  The ToPDog study is pending in Australia to demonstrate the effective dose on a larger scale.

    Asthma - Glucocorticoids, given within the first hour of presentation to the ED, may reduce need for hospitalization with a NNT of 8 to prevent one hospital admission and, in pediatrics, the length of stay [8].  The literature demonstrates that IV steroids have no superiority over the oral route and the American Thoracic Society recommends oral steroids [8,9].  In fact, Rosen's strongly emphasizes the preference of the oral route, unless the patient is vomiting, in extremis, or has gastrointestinal malabsorption [7].  Prednisone can be swallowed quickly between/during albuterol treatments.
    • Pediatrics: Prednisone 1-2 mg/kg PO
      • Dexamethasone phosphate 0.6 mg/kg PO 
    • Adults:  Prednisone 40-80 mg/day PO
      • Unable to take PO? Methylprednisolone is weight based, at 1mg/kg, not the standard 125 mg given routinely in the ED, which is equivalent to approximately 156 mg of prednisone.  
    COPD - no effect on hospitalizaiton rate, but steroids decrease return visits [2]. 
    • Prednisone orally, No benefit to doses higher than 60 mg[2]. 
    • 5 days equivalent to longer courses [10].  
    Anaphylaxis - The treatment for anaphylaxis is intramuscular epinephrine [2,7,11].  While glucocorticoids have become part of the standard treatment in anaphylaxis, it's crucial to remember that this therapy is classified as an "adjunct," and is not a treatment for acute anaphylaxis.  Steroids may play a role in resolving the cutaneous manifestations of urticaria and may prevent biphasic or refractory anaphylaxis; however, this is not a proven treatment modality and this intervention takes hours to work.  Furthermore, we historically do not give epinephrine readily enough in anaphylaxis and emphasis on second and third-line agents may detract from actually treating anaphylaxis.

    The core emergency medicine texts, Rosen's and Tintinalli's, both recommend IV methylprednisolone in anaphylaxis, followed by a short burst of prednisone for 3-5 days but these recommendations do not come with supporting citations [2,7].  A Cochrane Review turned up no evidence on this therapeutic endeavor [12].  The pathophysiologic argument for IV steroids exists in the notion that patients may have impaired absorption secondary to shunting of blood away from the GI tract.  So, what's the answer?
    • Shock/sick patients - intravenous steroids such as hydrocortisone or methylprednisolone are likely the right answer.
    • The rest of the anaphylaxis patients that are able to swallow  - oral prednisone 40-60 mg/day for 3-5 days.   
    Are there downsides to giving IV medications in anaphylaxis?  Medication errors abound in anaphylaxis and an IV may create an accidental error in route of administration (although this would be needed for resuscitation, should the patient be sick) [13].

    References:
    1.  Russell KF, Liang Y, O’Gorman K, Johnson DW, Klassen TP. Glucocorticoids for croup. Cochrane database Syst. Rev. 2011;(1):CD001955.
    2. Tintinalli's Emergency Medicine: A Comprehensive Study Guide.  7th ed, 2011.  p509, 515, 789-790, 805
    3. Geelhoed GC, Macdonald WB SOPediatr  Oral dexamethasone in the treatment of croup: 0.15 mg/kg versus 0.3 mg/kg versus 0.6 mg/kg.  Pulmonol. 1995;20(6):362.
    4.  Dobrovoljac M, Geelhoed GC. 27 Years of Croup: an Update Highlighting the Effectiveness of 0.15 Mg/Kg of Dexamethasone. Emerg. Med. Australas. 2009;21(4):309–14.
    7.  Rosen's Emergency Medicine.  7th ed, 2009.  p 897.
    8. Bh R, Spooner C, Ducharme F, Bretzlaff J, Bota G. Corticosteroids for preventing relapse following acute exacerbations of asthma ( Review ). 2008;(4).
    9.   Schatz M, Kazzi A, et al.  Joint Task Force Report: Supplemental Recommendations for the Management and Follow-up of Asthma Exacerbations.  Proc Am Thorac Soc Vol 6. pp 353–356, 2009
    10.  Leuppi JD, Schuetz P, Bingisser R, Bodmer M,et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial.  JAMA. 2013 Jun 5;309(21):2223-31. 
    11.  Gaeta TJ, Clark S, Pelletier AJ, Camargo CA. National study of US emergency department visits for acute allergic reactions, 1993 to 2004.Ann Allergy Asthma Immunol. 2007 Apr;98(4):360-5.
    12.  Kjl C, Fer S, Sheikh A. Glucocorticoids for the treatment of anaphylaxis ( Review ). 2012;(8).
    13.  Benkelfat R, Gouin S, Larose G, Bailey B. Medication errors in the management of anaphylaxis in a pediatric emergency department. J Emerg Med. 2013 Sep;45(3):419-25.