Open to Interpretation: Do Not ______

The Gist:  DNR (Do Not Resuscitate) orders are subject to variable interpretation by providers and patients whereas Physician Orders for Life Sustaining Treatments (POLST) are becoming increasingly common and have more specific, meaningful directives. As critical care providers, we should understand the meanings behind each of these documents, as well as the limitations.  The Annals of Emergency Medicine August 2014 podcast has a fantastic Free Open Access Medical education (FOAM) discussion of DNRs and POLSTs as they pertain to the physician in the Emergency Department (ED).  Despite these helpful aids, nothing replaces discussions with patients and their family members or health care proxies about treatment that is clinically appropriate and congruent with the patient's goals.

The Case:  A 82 y/o male presents to Janus General in respiratory distress, 72% on 4L of oxygen via nasal cannula up to 92% on 15L non-rebreather from the rehab facility where he is recuperating from a fractured tibia.  Previously in excellent health, he has been febrile and confused for the past two days with radiographic and clinical diagnosis of pneumonia and therapy with azithromycin and ceftriaxone at the facility.  Patient has a signed DNR order and an advance directive stating that for an irreversible/terminal condition the patient would not want artificial support.  The health care proxy is unavailable by phone and the patient lacks a clear sensorium but is in respiratory distress, appears septic, and has a chest x-ray with clear infiltrate and interstitial pattern that may indicate early ALI/ARDS.
  • What should happen?  BiPAP?  Morphine? Intubation?  What's this patient's disposition?  At Janus General, the providers in the ED and the inpatient team disagreed about what the patient's course should be, whether or not the condition was "reversible," and what the patient would want in this situation.  
In a recent post I shared a talk on tips for palliative care in the ED setting.  Despite our best efforts in the ED, uncovering documents such as DNRs and advance care directives may obscure the picture more than provide clarity.  I discovered on rotations through critical care units that the presence of a DNR seemed to bias both myself and my colleagues regarding the care of patients that was unrelated to the performance of cardiopulmonary resuscitation.  I believe we acted based on what we felt was clinically appropriate in the patient's situation but upon closer inspection, I think we were occasionally subject to a touch of another form of bias - The DNR bias.

The Do Not Resuscitate (DNR):  A medical order that specifies one not initiate cardiopulmonary resuscitation (CPR) in a patient who has died (pulseless/apneic) [1].
  • Technically, applies to a dead patient.
  • Does not indicate a patient's general wishes for medical care, only their preference regarding initiation of CPR. 
The Problem With The DNR
DNR orders, which technically only speak to a patient's wishes to receive CPR, have variable interpretations amongst healthcare professionals and, likely, patients [2-4].  The issue lies in the word "resuscitate," which may be used to include fluids, antibiotics, vasopressors, advanced means of ventilation or, at the extreme, CPR.
  • The TRIAD II-IV studies surveyed EMS personnel, physicians, and medical students respectively and provided the participants with an advance care directive as well as case scenarios.  The participants then indicated whether a patient was a DNR or full code and the appropriate action.  Both physicians and EMS providers performed poorly and variably, indicating that the directives were not clear [2,4].
DNR orders may mean that patients receive care that differs from their wishes or standard medical practice.  This demonstrates that the DNR bias may exist, even if it's partially a reflection of a patient's general clinical situation.
  • Aspirin is a non-intensive and relatively safe standard intervention in patients with acute myocardial infarction (AMI) (NNT=42, NNH=167). In patients with an AMI, the Worcester Heart Attack study demonstrated a negative association between aspirin administration and those patients with a DNR [5].  Of note, the individuals in this study with a DNR were "sicker," meaning they had comorbidities or other poor prognostic signs such as shock.  Other markers of more aggressive care such as PCI, thrombolytics, and cardiac catheterization, were also reduced in the DNR cohort.  Therefore, it is possible that this association may represent the belief that these patients were not candidates for these interventions independent of their DNR status.
  • The Worcester Heart Failure study also demonstrated that patients with a DNR were less likely to receive any quality assurance intervention than those with no DNR (HR 0.52, adjusted HR 0.63- 0.4-0.99) [7].  This may have been appropriate given the clinical situation of the patients.
But, it's not all about the co-morbidities:
  • Residents in Missouri nursing homes with a DNR were less likely to be hospitalized following a LRTI (OR 0.69; 0.49-0.97).  Compared with the Worcester Heart Attack study, patients with comorbidities were more likely to receive aggressive treatment (hospitalization) than those without a DNR (excluded patients with a Do Not Hospitalize order) [7].  
The Physician Order for Life Sustaining Treatment (POLST)Physician orders, on a standardized form, that are designed to transfer amongst settings, following an individual from home to hospital and nursing home/rehabilitation facilities.  Most states have POLST programs or are in the process of developing them these programs (map of programs) and some have online registries for providers, mitigating issues with located print copies.  Jesus et al give a good rundown of POLSTs in the ED in Annals of Emergency Medicine, August 2014 [8].

These may be more meaningful in the critical setting of the ED as they may indicate a patient's preference for a broad array of clinical conditions encountered.  For example, in Massachusetts, the back portion of the MOLST resembles a sushi menu where individuals can opt to specify whether they would accept non-invasive ventilation, dialysis, artificial hydration or nutrition and, if yes, whether temporarily or permanently.

Issues with POLSTs:
  • Require a physician signature and require either medical literacy or a good deal of physician explanation.  
  • It is possible that only the sickest patients or those with terminal illnesses may be prompted to have a POLST.
  • Components are still open to interpretation by providers as the reversibility or predicted length of therapy are often difficult to determine upon initiation.  
  • The FOAM blog, GeriPal, has an interesting discussion on the semantics prevalent in the POLST.  For example, the connotation of the word "only" following Comfort Measures is not necessary and undermines the intensive work often required for end of life comfort.  The blog offers some suggestions that may surface as POLSTs become increasingly adopted.
References:
1. Dugdale DC. .Do Not Resuscitate Orders."  MedlinePlus Medical Encyclopedia.  
2.  Mirarchi FL, Kalantzis S, Hunter D, McCracken E, Kisiel T. TRIAD II: do living wills have an impact on pre-hospital lifesaving care? J Emerg Med. 2009;36(2):105–15. doi:10.1016/j.jemermed.2008.10.003.
3. Mirarchi FL, Costello E, Puller J, Cooney T, Kottkamp N. TRIAD III: nationwide assessment of living wills and do not resuscitate orders. J Emerg Med. 2012;42(5):511–20. doi:10.1016/j.jemermed.2011.07.015.
4.Mirarchi FL, Ray M, Cooney T.  TRIAD IV: Nationwide Survey of Medical Students' Understanding of Living Wills and DNR OrdersJ Patient Saf. 2014 Feb 27. 
5. Gurwitz JH, Lessard DM, Bedell SE, Gore JM. Do-Not-Resuscitate Orders in Patients Hospitalized With Acute Myocardial Infarction. 2014;164.
6. Chen JLT, Sosnov J, Lessard D, Goldberg RJ. Impact of do-not-resuscitation orders on quality of care performance measures in patients hospitalized with acute heart failure. Am Heart J. 2008;156(1):78–84. doi: 10.1016/j.ahj.2008.01.030.4. 10.1002/jhm.2234
7. Zweig SC, Kruse RL, Binder EF, Szafara KL, Mehr DR. Effect of do-not-resuscitate orders on hospitalization of nursing home residents evaluated for lower respiratory infections. J Am Geriatr Soc. 2004;52(1):51–8. 
8. Jesus JE, Geiderman JM, Venkat A, et al. Physician Orders for Life-Sustaining Treatment and Emergency Medicine: Ethical Considerations, Legal Issues, and Emerging Trends. Ann Emerg Med. 2014;64(2):140–144. doi:10.1016/j.annemergmed.2014.03.014.

Seduction, Hype, and the Tradition – FOAM as Effective Learning

I had the phenomenal opportunity to present at SMACC in Australia and it's now out there on the SMACC podcast or here
 So, here are some of the references/resources I promised.  This fantastic conference will be held in Chicago, June 2015 - book your leave!

The Gist - Whether Free Open Access Medical Education (FOAM) represents gizmo idolatry or effective learning depends - not on the resource, but on the user.  Consider treating FOAM like a parachute, for which there are also no human randomized controlled trials - perform safety checks, examining FOAM closely for holes and actively identify and repair these before they become unsafe, start with “tandem jumps," guided through FOAM, directed by teachers, a curator, or role model and teach others the necessary critical thinking and skills needed for successful solo jumps.  Like any educational resource, FOAM can be gizmo idolatry or powerfully effective learning, so let's use FOAM effectively.

Gizmo Idolatry 
Gizmo idolatry, coined by Leff and Finucane, is our intrinsic preference for a technologically advanced approach than one that is less technological.  We're seduced by new technologies/innovations because we like to be on the cutting edge and because they "make sense," are sexy and full of hype.  Often this occurs before the evidence is in, which may show that these interventions don't pan out.  Recent clinical examples revolve around robotic surgery and coronary CT.  Some argue that, as a "new" and popular educational intervention without significant evidentiary basis, FOAM can be gizmo idolatry for the following reasons:
  • Superficial learning/absorption of information (See post: "But I heard it on a podcast..")
  • Over reliance on multi-tasking, which is not as effective as we like to believe [1]
  • Lack of focus on core content and over-emphasis on the fun parts of medicine like airway and memes  (Note: This was one motivation behind co-founding FOAMcast)
  • Sometimes FOAM can even be wrong, as evidenced by one of my own experiences in which I placed part of an algorithm from a peer reviewed journal in this blog post, only to be corrected within hours in post-publication peer review (the individual caught the error in the peer-reviewed journal as well).
Note: it's important to realize that superficial learning, inaccurate information, idolatry, and enjoyment of the fun parts of medicine are not unique to FOAM, rather part of human nature and can be present in classrooms, conferences, peer-reviewed literature, etc.

Effective Learning

While the evidence for the efficacy of FOAM is currently lacking, there is an evidentiary underpinning behind some ways in which we can use FOAM.  Used smartly, FOAM can naturally harness some of the most evidence based learning modalities, spaced repetition and practice testing, and encourage learners to engage in learning and critical thinking[2].  

Spaced Repetition - We learn better in small aliquots over time because we tend to forget things over time, but when we're reminded repeatedly, or "beaten over the head" with a fact, we retain the information better [2].  This learning theory, which has been born out in medical education RCTs, happens naturally in FOAM, as contributors cover the same topic repeatedly, particularly when information is pushed to the learner (RSS feeds, Twitter).  See this post:  "Drinking From the Firehose - One Sip of FOAM at a Time"
Practice Testing - One of the most highly effective learning interventions as it provides learners with immediate feedback in an often non-threatening way [4-5].  FOAM examples include the repository at Life in the Fast Lane and the Detroit Receiving EM blog.

The Pause Principle - Pausing during lectures can allow learners to think and assess what they're learning as it can allow time for clarification and collaboration during an otherwise passive absorption of content [6,7].  This is one appeal of podcasts.

Highlighting the Things We Don't Know that We Don't Know- We often overestimate our abilities or knowledge, especially as novices.  When pushed to us in RSS feeds, podcasts, or tweets, FOAM can expose us things that we would otherwise never seek out, particularly things we think we're good at or know well. This is detailed in this blog post "We Don't Know What We Don't Know, which highlights the

Slides:

References:
1.Kirschner P a., van Merriënboer JJG. Do Learners Really Know Best? Urban Legends in Education. Educ Psychol. 2013;48(3):169–183.  
2.  Dunlosky J, Rawson K, Marsh EJ, Nathan MJ, Willingham DT. Improving Students’ Learning With Effective Learning Techniques: Promising Directions From Cognitive and Educational Psychology. Psychol Sci Public Interes. 2013;14(1):4–58. 
3  Larsen DP, Butler AC, Roediger HL. Comparative effects of test-enhanced learning and self-explanation on long-term retention. Med Educ. 2013;47(7):674–82. 
4.  Chan JC, McDermott KB, Roediger HL. Retrieval-induced facilitation: initially nontested material can benefit from prior testing of related material.  J Exp Psychol Gen. 2006 Nov;135(4):553-71.
5.Larsen DP1, Butler AC, Roediger HL.  Repeated testing improves long-term retention relative to repeated study: a randomised controlled trial. Med Educ. 2009 Dec;43(12):1174-81.
6. Ruhl KL, Hughes C a., Schloss PJ. Using the Pause Procedure to Enhance Lecture Recall. Teach Educ Spec Educ J Teach Educ Div Counc Except Child. 1987;10(1):14–18. 
7.  Di Vesta FJ, Smith D a. The pausing principle: Increasing the efficiency of memory for ongoing events. Contemp Educ Psychol. 1979;4(3):288–296. 

CRITICAL Care – End of Life in the ED

The Gist: Palliative care is an emerging field in Emergency Medicine and most of us are inadequately equipped to discuss end of life issues, death and dying, which are all quite common in the Emergency Department (ED) [1].  We often feel uncomfortable in these situations as our instinct remains - resuscitate first, ask questions later. In a community that values cutting edge, critical care medicine, I was stunned when I realized that Free Open Access Medical education (FOAM) has engendered me to think twice about a procedure and take the time to ascertain what a patient actually wants.

These FOAM resources changed my course as a budding Emergency Physician and made me realize how ill equipped I was to handle dying patients, despite the frequency with which I encounter them.  As such, I felt compelled to use my slot at our residency conference dedicated to critical care to discuss end of life issues with my colleagues.  Here it is as FOAM, since I hassle others to share their talks.


The FOAM
SMACC GOLD (iTunes)
EMCrit with Dr. Ashley Shreves "Critical Care Palliation"
The Geripal Blog - The Importance of Language

The Take Home
Run these ABCD's in tandem with our typical ABCs (Airway, Breathing, Circulation) because the trajectory that we launch patients on matters - whether it's to the ICU with an endotracheal tube, to dialysis with a line, or a palliative care consult [1, 6-9,15].

Advance Care Directives (does the patient have one?), Ask the patient/caregivers what they want.
  • Identify if a patient has a health care proxy or physician order for life sustaining treatment (POLST).  
  • Use appropriate language, avoid jargon.  The phrase, "Do Not Resuscitate (DNR)," is falling out of favor and major societies are now using the language "Allow Natural Death"[3]. Try replacing DNR with "It sounds like she would want a natural death."  
  • Dying patients, even those with DNR orders, Comfort Measure Only orders, or those with Do Not Hospitalize directives come to the hospital because dying is hard, uncomfortable, and stressful.  Figure out what they want and need, it's not always a tube or a line.
Better - Make the patient feel better
  • Turn off monitors or beeping pumps (especially if they're beeping), generously dole out opioids for dyspnea/pain, offer various means of respiratory relief (non-rebreather, nasal cannula, non-invasive ventilation).
Caregivers - identify the patient's caregivers and Communicate with all parties in appropriate language
  • As above, use appropriate language, avoid jargon.  My favorite phrase, effective on nearly all patients, "What is most important right now?"
Decisions - offer medically appropriate decisions in ways patients and caregivers can understand.  Aggressive resuscitation and cardiopulmonary resuscitation (CPR) are appropriate in many situations, but not all.  Think about the downstream consequences, positive and negative, of various courses of action.
  • The publics perception of CPR is largely misinformed and studies show that most people overestimate the success of CPR to hospital discharge.  One study of patients over 70 years of age found over half believed survival after CPR was >50% and 23% believed survival to discharge was >90% after CPR [2].  Furthermore, people may not understand that CPR does reverse the underlying process and a patient is typically sicker after CPR than they were before.  Let patients know the implications of these decisions.  For example, once someone dies, CPR involves chest compressions which often result in broken ribs but sometimes restart the heart.  There's no guarantee that if we restart the heart that we will get his/her brain function back.
  • If appropriate, offer more than one option and recognize the power and responsibility that comes with the entrusted title of physician.  People do listen to provider recommendations [5].  For example, some patients may want aggressive testing and treatment for etiologies of dyspnea, some may want oral antibiotics for a pneumonia if it may improve their shortness of breath, and some may opt solely for opioids. 
References:
1. Members of the Emergency Medicine Practice Committee.  Emergency Department Palliative Care Information Paper June 2012.   ACEP 
2. Adams DH, Snedden DP. How misconceptions among elderly patients regarding survival outcomes of inpatient cardiopulmonary resuscitation affect do-not-resuscitate orders. J Am Osteopath Assoc. 2006;106(7):402–4. 
3. Breault JL. DNR, DNAR, or AND? Is Language Important? Ochsner J. 2011;11(4):302–6. 
4. Cassel JB, Kerr K, Pantilat S, Smith TJ. Palliative care consultation and hospital length of stay. J Palliat Med. 2010;13(6):761–7. doi:10.1089/jpm.2009.0379.
5. Cook D, Rocker G. Dying with Dignity in the Intensive Care Unit. N Engl J Med. 2014;370(26):2506–2514. doi:10.1056/NEJMra1208795.
6. DeVader TE, Albrecht R, Reiter M. Initiating palliative care in the emergency department. J Emerg Med. 2012;43(5):803–10. doi:10.1016/j.jemermed.2010.11.035.
7. DeVader TE, Jeanmonod R. The effect of education in hospice and palliative care on emergency medicine residents’ knowledge and referral patterns. J Palliat Med. 2012;15(5):510–5. doi:10.1089/jpm.2011.0381.
8. Lamba S, Mosenthal AC. Hospice and palliative medicine: a novel subspecialty of emergency medicine. J Emerg Med. 2012;43(5):849–53. doi:10.1016/j.jemermed.2010.04.010.
9. Lamba S, Quest TE. Hospice care and the emergency department: rules, regulations, and referrals. Ann Emerg Med. 2011;57(3):282–90. doi:10.1016/j.annemergmed.2010.06.569.
10. Schmidt TA, Zive D, Fromme EK, Cook JNB, Tolle SW. Physician orders for life-sustaining treatment (POLST): lessons learned from analysis of the Oregon POLST Registry. Resuscitation. 2014;85(4):480–5. doi:10.1016/j.resuscitation.2013.11.027.
11. Wright A a, Keating NL, Balboni T a, Matulonis U a, Block SD, Prigerson HG. Place of death: correlations with quality of life of patients with cancer and predictors of bereaved caregivers’ mental health. J Clin Oncol. 2010;28(29):4457–64. doi:10.1200/JCO.2009.26.3863.
12. Wu FM, Newman JM, Lasher A, Brody A a. Effects of initiating palliative care consultation in the emergency department on inpatient length of stay. J Palliat Med. 2013;16(11):1362–7. doi:10.1089/jpm.2012.0352.

Dip the Tap? – Diagnosis of Spontaneous Bacterial Peritonitis at the Bedside

The Gist:  Study results of urine reagent strips for the bedside diagnosis of spontaneous bacterial peritonitis (SBP) are highly variable with sensitivities from 45-100%.  Some suggest that certain dipsticks, if at least Grade 3 positive, have a great positive predictive value and positive likelihood ratio; thus, initiating treatment for SBP is likely a good idea.  A negative result, however, cannot rule out SBP, and this test is subject to limitations such as which reagent strip one has, what qualifies as "positive," and the prevalence of SBP at that location.  Suspect SBP or sick patient? Give antibiotics.

Why the enthusiasm in the Emergency Department (ED)?
A bedside test for diagnosis of SBP is neat and could potentially help identify an infective source earlier than standard laboratory tests (ascitic fluid cell count of >1000 WBCs or >250 polymorphonuclear neutrophils (PMNs) [1].  This laboratory endeavor takes time and reagent test strips commonly referred to as "urine dipsticks" have surfaced as a candidate.  Some studies cite a time "savings" of 2-3 hours using these strips as one may start targeted antibiotics after the bedside test [6].  In an era of source control and "time to antibiotics" measures in sepsis, early diagnosis of SBP has potential benefit.
Photo: Nottingham Vet School
Typical reagent strips, like the one above, demonstrate different grades of positivity, indicated by the color of the individual block.  Here, the leukocytes are indicated by the box on the far left of the image in which presence of leukocytes is quantified by reaction via leukocyte esterase.  These are read at the bedside after a certain period of time elapses (often 1-2 minutes), either by a person or machine. The pictured stick has a negative (off white), Grade 1 (slightly less off white), Grade 2 (lavender), Grade 3 (darker lavender/purple).

One important lesson that Free Open Access Medical education (FOAM) has hammered home, however, is the importance of understanding how to use a test prior to adoption.  On a recent episode of FOAMcast, we discovered that the core text, Rosen's Emergency Medicine references the positive correlation between SBP and a "positive" dipstick [1].  Unfortunately, the text doesn't go into how specifically to use the test or limitations, which could potentially lead to misapplication.  As an excited resident, I might opt to test this trick of the trade out without investigating exactly how it could or should change my practice. Furthermore, major societies currently recommend against the use of these test strips [2,3].

The Early Literature Hype
The initial studies were promising and cited sensitivity, specificity, Positive Predictive Value (PPV), and Negative Predictive Values (NPV) of 100% [4].  These studies also had relatively small numbers (n=31-257) and were conducted in a variety of settings with limited ED patients [4].  A positive test, in the majority of studies, was any result other than negative.  Some authors, including Gaya et al, called for the ability to rule out SBP based on a negative dipstick (Multistix 10SG) [5].

The Shifting Tide:  The many studies that subsequently followed had varied results and few were conducted in the Emergency Department (ED).  These studies used a variety of strips (Multistix - most commonly tested, Nephur, Combur, Uriscan, Aution Combina, and Choiceline) and demonstrated widely variable predictive scores with sensitivities of approximately 65% in nearly half of the studies and one study with a sensitivity of merely ~45%.  The specificity in these studies, however, remained quite high at >90% [4].  This literature is summarized nicely in a meta-analysis by Nguyen-Khac et al.
  • Multistix (n=12 studies): Sensitivities ranged from 45.3-100%, with higher sensitivities when a lower grade was used as "positive" (64.7-100%) [4].
A more recent study that was not included in this analysis posed a head-to-head ED based comparison between Uri-Quick Clini 10SG and MultistixSG10 in a population with a relative high incidence of SBP - 21.9% (49/223 samples).  Both strips had comparable specificities in the ~98% range.  This study more accurately depicts the way in which one might use reagent test strips, the importance of understanding which strip one has access to and its test characteristics, and the authors emphasize that the test does not rule out or replace the cell count [7].
  • Uri-Quick Clini 10SG Sensitivity 79.6% (64-87); + LR 33.7 (13-90); - LR 0.22 (0.13-0.38)
  • MultistixSG10: Sensitivity 77.5% (64-88%); + LR 33.6 (12.66-89.91); -LR 0.23 (0.14-0.39)
Why the variation?
  • Strips calibrated for urine so they don't match up to the PMN threshold for SBP.  As a result, what qualifies as a "positive" test varies - some studies used any level of positivity as "positive" and some specified a particular "Grade." 
  • Reading times of reagent strips varies and may impact results.
  • Different types of strips - the matrix and enzymes in strips varies based on manufacturer which may affect performance.  The strips used (ex: Aution sticks with high sensitivity) are not universally available [4,7].
  • Subjective interpretation of strips - This is a potential problem; however, the interrater reliability (kappa) was 0.8-0.94 (excellent!) in the studies in which it was calculated [6,7].  This is also dependent on whether the stick is read by a human or a machine (spectrophotometry).  
  • Varying prevalence of SBP in studied population (7-20%) [4,6].
What Now?
  • A 2012 study out of Mexico by Uribe et al demonstrates the utility of reagent strip testing as a rapid rule in diagnosis for SBP in low resource settings, with the caution that it is not a "rule out" test [7].  
  • SBP is associated with great mortality indicative of a very sick population, with an estimated survival after a patient's first episode of 68.1% at 1 month and 30.8% at 6 months [8].  As a result, it's probably best to suspect SBP in any sick cirrhotic, understand the limitations of the clinical exam, and administer antibiotics early in these patients.  Even if these patients get a non-targeted dose of piperacillin-tazobactam, this antibiotic still covers most SBP (although agents of choice are typically cefotaxime 2 grams IV Q4-8 hours or ceftriaxone 2 grams IV Q24 hours) [8].
  • Look for use of reagent strips at the bedside in the future for SBP but, like any test, understand the variability, the limitations, and the ways that the test is usable in one's own ED. 
References
1.  Oyama L.  Chapter 90:  Disorders of the Liver and Biliary Tract.  Rosen's Emergency Medicine, 8e (2014).  pp 1186-1204.
2.  European Association for the Study of the Liver.  EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397-417.
3.  Runyon BA.  Management of Adult Patients with Ascites  Due to Cirrhosis: Update 2012.  (2013) doi: 10.1002/hep.00000
4.  Nguyen-Khac E1, Cadranel JF, Thevenot T, Nousbaum JB. Review article: the utility of reagent strips in the diagnosis of infected ascites in cirrhotic patients. Aliment Pharmacol Ther. 2008 Aug 1;28(3):282-8.
5. Gaya Dr, Lyon DB, Clarke J et al. Bedside leucocyte esterase reagent strips with spectrophotometric analysis to rapidly exclude spontaneous bacterial peritonitis: a pilot study. Eur J Gastroenterol Hepatol. 2007 Apr;19(4):289-95.
6.  Nousbaum JB, Cadranel JF, Nahon P, et al. Diagnostic accuracy of the Multistix? 8 SG reagent strip in diagnosis of spontaneous bacterial peritonitis. Hepatology 2007; 45: 1275–81.
7.  Uribe M, Vargas-vorackova F. Rapid diagnosis of spontaneous bacterial peritonitis using leukocyte esterase reagent strips in Emergency. 2012;11(5):696–699.
8.  O’Mara SR, Gebreyes K.  Chapter 83. Hpeatic Disorders, Jaundice, and Hepatic Failure. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: McGraw-Hill; 2011. p 566-574

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."