FOAMcastini – ACEP15 Day 2

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FOAMcast brings you pearls from conferences we attend and presently it’s the American College of Emergency Physicians annual meeting, ACEP15 in Boston. On this episode we cover the following topics:

Extracorporeal Membrane Oxygenation (ECMO) – Dr. Haney Mallemat (@CriticalCareNow)

ECMO is promising in certain devestating disease processes – essentially heart or lung failure. For example, in the CHEER trial, the investigators had a 54% rate of neuro-intact survival after cardiac arrest with ECMO []. Yet, ECMO can be confusing. Dr. Mallemat simplified this for the emergency physician (see this site for more complete explanations)

Screen Shot 2015-10-27 at 5.55.44 PM

Stop the Madness: Diagnostic Imaging in Nephrolithiasis – Workshop with Drs. Eddy Lang, Rebecca Smith-Bindman, Grant Innes, and Lauren Westafer

Debunking Trauma Myths – Billy Mallon

FOAMcastini – ACEP15 Day 1

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FOAMcast brings you pearls from conferences we attend and presently it’s the American College of Emergency Physicians annual meeting, ACEP15 in Boston.

Jeremy Hoffman and Rick Bukata summarize recent, relevant literature each year (recently known as #hofkata).  This year, our top three favorite

A top 5 list for emergency medicine: a pilot project to improve the value of emergency care.  Schuur et al. JAMA Internal Medicine. 2014.

  • Just say NO to:
    • CTs for trauma patients who are negative using the NEXUS and Canadian tools for cervical spine injuries.
    • CT for ruling out PE without some sort of risk stratification.
    • MRI for Low back pain w/o red flags.
    • Head CT in with mild TBI who do not meet criteria using the New Orleans OR Canadian Head CT tools.
    • Routine coagulation profile (unless they have a known coagulopathy or are hemorrhaging)

Emergency Physician Perceptions of Medically http://www.mindanews.com/buy-valtrex/ Unnecessary Advanced Diagnostic Imaging. 

The effect of malpractice reform on emergency department care.  Moskow et al.   N Engl J Med. 2015 Jan 8;372(2):192.

Dr. Jeff Kline (@klinelab) spoke on pulmonary embolism.

  • High Risk PE? Consider lysis (this is controversial, we are simply reporting Dr. Kline’s talk)
    • Size and location. Massive and proximal= bad
    • SBP <90 for more than 15 min OR 40mmHg drop from baseline
    • Signs of RV strain – echocardiography showing RV dilation OR hypokinesis?
    • Elevated troponin or BNP
    • ECG findings suggestive of cardiac strain: sinus tachycardia, incomplete right bundle branch block, complete right bundle branch block, T-wave inversion in leads V1 – V4.
  • Kline also participated in a knowledge translation workshop where he argued that sub-segmental PEs, without DVT on ultrasound, are NOT a real thing.  This is controversial but he also argued that treating these is associated with harm [Carrier et al]

 

FOAMcastini – Core Content Journal Club

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This is an exciting week of primary literature, particularly as many large critical care trials were published in major journals despite being “negative studies.”  We are excited by this as, too often, we see “negative studies” discarded.  Further, these studies examined things some practices we seem to believe in: balanced crystalloids, apneic oxygenation (see Dr. Scott Weingart’s podcast on the FELLOW study), treating fever. We love that the Free Open Access Medical Education (FOAM) community and study authors are examining beloved practice and open to questioning the very things we believe in. Well done.

We cover two core content papers out by Dr. Paul Young (@dogICUma) in JAMA and NEJM this week. His trials are as clever as his Twitter handle.

SPLIT – The FOAM world has sung the praises of balanced fluids given they have more physiologic composition. The thought, as detailed in this post, is that 0.9% NaCl contains an ABnormally large amount of chloride which may cause a hyperchloremic metabolic acidosis. Prior literature suggests an increased incidence of kidney injury with saline compared with balanced solutions. Thus, Dr. Paul Young and colleagues sought to study this with the best trial, to date, on this topic.

  • Multicenter, blinded,  cluster-randomized, double-crossover trial of adult ICU patients receiving crystalloids randomizing patients to 0.9%NaCl or Plasma-lyte (balanced solution).
    • Sites used one fluid for seven weeks and then crossed over to the other fluid (labeled Fluids A and B).
  • Primary outcome: AKI according to the RIFLE criteria  within 90 days – no difference between groups.
    • 9.6% in Plasma-lyte group vs 9.2% in the saline group (absolute difference 0.4% [95% CI, −2.1%-2.9%]; RR, 1.04 [95% CI, 0.80-1.36]; P = .77)
  • Secondary outcomes: No difference in renal replacement therapy, ICU days, mechanical ventilation, or mortality
  • A few things to keep in mind:
    • 70% of patients were admitted to the ICU from the OR (mostly cardiac surgery) and only ~15% from the ED
    • Patients got a median of 2L (1L -3.5L) of the study fluid, that’s it. These were not large volume resuscitations.
    • 90% of patients received fluids prior to enrollment, 60% got balanced crystalloid and only 30% 0.9% NaCl.

HEAT – We can’t help treating fever. We like the numbers euboxic, elevated temp? It must be bad! Doctors, parents, nurses treat fever reflexively.  Yet, there’s a thought that fever may be evolutionary and could potentially be protective. Treating pain or discomfort? That’s one thing, but here the authors sought to determine if there was a clinically important benefit to treating the number in ICU patients.

  • Randomised controlled, double blinded study of n=690 ICU patients with T>38F + suspected infection randomized to receive either 1 g paracetamol (acetaminophen/APAP) or placebo every 6 hours.
  • Primary outcome: median ICU-free days to day 28 – no difference 23 (IQR 13-25) in paracetamol group vs 22 in placebo group (IQR 12-25); P=0.07
  • No difference in secondary outcomes of mortality at 28 and 90 days
  • Limitations: ~30% of patients in both arms received open label APAP after the course of the study drug

Bottom Line Pearls:

  • It appears we may be SPLITting hairs over fluid choices. Giving a couple of liters? Fluid choice may not matter. SPLIT does not provide literature for larger volume resuscitations.
  • Treating fever in ICU patients with suspected infection doesn’t have an effect on ICU free days. Treat discomfort and pain with APAP but don’t expect to save lives or ICU beds by doing so.
  • “Negative studies” are important. So is examining our practice.

FOAMcastini – The “Left Shift”

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The Free Open Access Medical Education (FOAM)

The blog Brown Coat Nation (University of Illinois, Chicago) has a new series entitled “Inconceivable.” The idea is to expose medical terminology that we tend to use incorrectly. The first installment is focused on the misuse of the term “left shift,” and it’s the focus of this FOAMcastini.

The Core Content

The correct use of the term “left shift” refers to the presence of banded (immature) neutrophils in the blood. It does not refer to an elevated white blood cell count with a high percentage of neutrophils. An elevated white blood cell count with an abnormally high percentage of neutrophils should be called “neutrophillic leukocytosis.” Only the presence of immature neutrophils in the periphery (including bands) can accurately be called a “left shift.”

The term “left shift” is derived from the diagrams of the six stages of neutrophil development in the bone marrow. On the far left, you see the most basic precursor: the myeloblast. On the far right of the diagram one finds the mature segmented neutrophil (also known as the “polymorphonuclear leukocyte, or PMN). But just to the left of that is the “banded” neutrophil (the 5th stage of neutrophil development in which the large band of nuclear material has not yet “disbanded” into segments).

When an infection runs rampant, sometimes the bone marrow runs out of mature neutrophils to send to the periphery. So, the marrow panics and releases immature banded neutrophils that normally would not be considered “ready for prime time.”

Here’s some relevant spaced repetition on SIRS: Along with leukocytosis (>12,000) and leukopenia (<4,000), Bandemia >10% is one of the SIRS criteria (Systemic Inflammatory Response Syndrome). Temperature (>38C or <36C), Heart rate >90 (“sirs-ycardia”), tachypnea (RR>20) or PCO2 <32) are the other SIRS criteria. The presence of at least two these categories constitutes “positive SIRS”. In pediatrics, the temperature, heart rate, and respiratory rates should be age-adjusted.
Check out our previous episode on appendicitis for a reminder on whether leukocytosis (with or without neutrophillic predominance) is useful in risk stratification.

Episode 32 – Appendicitis

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The Free Open Access Medical Education (FOAM)

This week we cover a post from Dr. Rory Spiegel, author of EMnerd, on initial nonoperative management of acute appendicitis based on an article by Salminen et al in JAMA 2015.

  • 530 patients with CT confirmed acute, uncomplicated appendicitis were randomized to operative intervention (n=273 receiving open laparotomies) or non-operative intervention (n=257 receiving antibiotics).
  • 27.3% (n=70, CI 22-33.2%) of patients who received medical management (ertapenem x 3 days then 5 days of levofloxacin) had an appendectomy by the 1 year mark
    • 7 patients (2.7%) in medical management group had complicated appendicitis at one year, 0 had abscesses
    • 45 patients (20.5%) in the operative group had surgical complications

This is a non-inferiority study where the intent  is to demonstrate that an experimental treatment (antibiotics alone) is not substantially worse than a control treatment (immediate surgery). The authors set the non-inferiority margin at 24%, which means that a failure rate (appendectomy by 1 year) >24% would render medical management inferior.

Authors Conclusion: “Among patients with CT-proven, uncomplicated appendicitis, antibiotic treatment did not meet the prespecified criterion for noninferiority compared with appendectomy.”

Spiegel’s Conclusion: “there is a great deal to be determined before this non-invasive strategy can be considered mainstream practice…in what was once considered an exclusively surgical disease, the majority of patients can effectively be managed conservatively. Despite not meeting their own high standards for non-inferiority, the authors demonstrated that for most patients with acute appendicitis, when treated conservatively with antibiotics we can avoid surgical intervention without complications of delays to definitive care.”

More FOAM on non-operative treatment of appendicitis: The SGEM

Core Content
Tintinalli (7e) Chapters 84, 124;  Rosen’s Emergency Medicine (8e) Chapter 93

Appendicitis

Diagnosis:

Diagnosing Acute Appendicitis
Diagnosing Acute Appendicitis

Use of contrast enhanced CT scans controversial.  Rosenalli and the American College of radiology concur that oral contrast is probably not needed but does increase the emergency department length of stay [3-5].

Treatment:

  • Surgical consult
  • Antibiotics:
    • Broad spectrum beta-lactams: ampicillin-sulbactam 3g IV (75 mg/kg IV in peds)  piperacillin-tazobactam 4.5g IV, cefoxitin 2g IV (40 mg/kg IV in peds)  OR metronidazole 500 mg IV + ciprofloxacin 400 mg IV

Other things to consider in special populations in right lower quadrant:

Pelvic Inflammatory Disease and Tubo-Ovarian Abscess in women

  • Symptoms: vaginal discharge, adnexal or uterine tenderness, lower abdominal pain, cervical motion tenderness, fever
  • Cause: chlamydia and neisseria gonorrhoea most commonly
  • Treatment: ceftriaxone 250 mg IM + doxycycline 100 mg BID x 14 days

Typhlitis (neutropenic enterocolitis) –

  • Symptoms: crampy abdominal pain (often RLQ), abdominal distension, fever, diarrhea, bloody diarrhea
  • Diagnosis: CT scan
  • Treatment: NPO, IV fluids, broad spectrum antibiotics (piperacillin-tazobactam, meropenem, metronidazole) + surgical consult if needed
  • Complications: perforation, gastrointestinal bleeding, sepsis

Generously Donated Rosh Review Questions 

1. A 22-year-old man presents with abdominal pain followed by vomiting for 1 day. His examination is significant for right lower quadrant tenderness to palpation. He has a negative Rovsing sign. [polldaddy poll=9026936]

2. A 22-year-old woman presents with lower abdominal pain and vaginal discharge. She is sexually active with men with inconsistent barrier protection. Her vitals are normal other than temperature of 101°F. On examination, there is yellow cervical discharge, no cervical motion tenderness, but uterine and left adnexal tenderness. An ultrasound does not show any evidence of tubo-ovarian abscess. [polldaddy poll=9026939]

Answers.

1. B. Sensitivity or the true positive rate measures the proportion of actual positives that are correctly identified as such. It is determined by dividing the number of true positives of the test by the number of true positives + false negatives. Tests with a high sensitivity are good for ruling out disease as the test has very few false negatives. A test with high sensitivity is advantageous as a screening tool as it misses very few people with the disease. The onset of pain before vomiting has been found to be as high as 100% sensitive in diagnosing acute appendicitis.Rovsing’s sign (D) (indirect tenderness) describes pain felt in the right lower quadrant upon palpation of the left lower quadrant. This sign signifies the presence of peritoneal irritation and has a sensitivity of 58%. Right lower quadrant pain (C) has a sensitivity of 81% and fever (A) has a sensitivity of 67%.

2.This patient presents with signs and symptoms consistent with pelvic inflammatory disease (PID) and should be treated with ceftriaxone 250 mg IM and 2 weeks of doxycycline. PID is an ascending infection beginning in the cervix and vagina and ascending to the upper genital tract. Neisseria gonorrhoeae and Chlamydia trachomatis are most commonly implicated. It can present with a myriad of symptoms although lower abdominal pain is the most common. Other symptoms include fever, cervical or vaginal discharge and dyspareunia. Pelvic examination reveals cervical motion tenderness (CMT), adnexal tenderness and vaginal or cervical discharge. Inadequately treated PID can lead to tubo-ovarian abscess, chronic dyspareunia and infertility. Due to the variable presentation and serious sequelae, the CDC recommends empiric treatment of all sexually active women who present with pelvic or abdominal pain and have any one of the following: 1) CMT, 2) adnexal tenderness or 3) uterine tenderness. Treatment should cover the most common organisms and typically consists of a third generation cephalosporin (ceftriaxone) and a prolonged course of doxycycline. Patients with systemic manifestations or difficulty tolerating PO should be admitted for management.Ceftriaxone and azithromycin (A) are used in the treatment of cervicitis or urethritis. Clindamycin (C) and metronidazole (D) are used in the treatment of bacterial vaginosis.
References:

1.Salminen P, Paajanen H, Rautio T, et al. Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis: The APPAC Randomized Clinical Trial. JAMA. 2015;313(23):2340

2. Horst JA, Trehan I, Warner BW et al. Can Children With Uncomplicated Acute Appendicitis Be Treated With Antibiotics Instead of an Appendectomy? Ann Emerg Med. 2015;66:(2)119-22

3.”Acute Appendicitis.” Tintinalli’s Emergency Medicine: A Comprehensive Study Guide.  7th ed. pp 574-581.

4. “Acute Appendicitis” Rosen’s Emergency Medicine. 8th ed. pp. 1225-1232.e2

5. ACR Appropriateness Criteria.  American College of Radiology. 2013.

6. Cohen B, Bowling J, Midulla P, et al. The non-diagnostic ultrasound in appendicitis: is a non-visualized appendix the same as a negative study? J Pediatr Surg. 2015;50:(6)923-7

7. Ashdown HF, D’Souza N, Karim D, Stevens RJ, Huang A, Harnden A. Pain over speed bumps in diagnosis of acute appendicitis: diagnostic accuracy study. BMJ. 2012;345:e8012.

8. Bundy DG, Byerley JS, Liles EA. Does This Child Have Appendicitis? 2009;298(4):438–451.

Episode 31 – Vasopressors

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The Free Open Access Medical Education (FOAM)

This week we cover posts from the Wessex ICS site, The Bottom Line, which is an excellent source for breakdown of recent and important trials. This site is great for reviews of high impact trials in critical care. We cover their post on a systematic review of peripheral pressor complications and then we delve into a recent prospective trial by Cardenas-Garcia and colleagues that came up at SMACC.

The Bottom Line on the Loubani paper

  • Systematic review of the literature 1946-Jan 2014 (does not include most recent trial)
  • Outcome – local tissue injury or extravasation: 325 separate events, 318/325 peripheral pressors
    • Signal that distal lines are not ideal for running pressors: 204 events (local tissue injury) were distal to the antecubital fossa/popliteal fossa (90% of events)
    • Signal that duration of pressors running peripherally may impact likelihood of adverse event. Increasing number of events were reported at the 6-12 hour mark (n=9) then 12-24 hour (n=18) and then almost all >24 hour

The Cardenas-Garcia Paper

  • Single arm consecutive study of ICU patients
  • ICU fellows and attendings determined if peripheral pressors were warranted and then initiated the following protocol:
    • Vein diameter >4 mm measured with ultrasonography and PIV confirmed with US before pressors started
    • Upper extremity only, contralateral to the blood pressure cuff
    • IV size 20 gauge or 18 gauge
    • No hand, wrist, or antecubital fossa PIV access position
    • Blood return from the PIV access prior to VM administration
    • Assessment of PIV access function q 2h as per nursing protocol
    • Immediate alert by nursing staff to the medical team if line extravasation, with prompt initiation of local treatment
    • 72 hours maximum duration of PIV access use
  • N=734 patients
  • 19/783 peripheral vasopressor administrations with infiltration of site (2%) with no events of local tissue injury

The take home: If a patient needs vasopressors, you can start them through a good, proximal peripheral IV.  Sometimes patient or situation factors delay central lines, this doesn’t mean it needs to delay patient’s therapy.  Know what to do in the event of infiltration (see this EMCrit post).

Core Content
Tintinalli (7e) Chapter 24

Screen Shot 2015-07-25 at 11.14.51 AM

Panchal et al – Phenylephrine bolus dosing in peri-intubation period

Central line technique from Dr. Reuben Strayer – Wire through catheter vs wire through needle

Generously Donated Rosh Review Questions 

1.[polldaddy poll=8996471]

Answer. C. Norepinephrine is considered the vasopressor of choice for treatment of septic shock.   Norepinephrine acts primarily as an α-adrenergic agonist, causing vasoconstriction that results in an increase in blood pressure. It also has β-adrenergic properties, which causes an increase in cardiac output and heart rate. The combination of α-adrenergic and β-adrenergic properties benefits patients who have septic shock. Norepinephrine also has a short duration of action, which allows for rapid adjustment of dosing in response to changes in a patient’s hemodynamic status. Dopamine (A) was once widely used in the treatment of septic shock, but studies have shown that it has no advantage over norepinephrine and its use is associated with a higher death rate. Epinephrine (B) has both α-adrenergic and β-adrenergic properties and has a greater affinity for alpha- and beta-receptors than norepinephrine. Its use is associated with a higher rate of cardiac dysrhythmias and a decrease in splanchnic blood flow. Phenylephrine (D) is a pure α-adrenergic agent that causes vasoconstriction and impairment of tissue blood flow throughout the body, most notably in the splanchnic circulation.

FOAMcastini – Dr. Jerome Hoffman on ACEP’s tPA Clinical Policy

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In a prior FOAMcastini, we covered the updated ACEP tPA clinical policy. As residents, we sought perspectives from experts, the FOAMcast brain trust (Drs. Anand Swaminathan, Ken Milne, Ryan Radecki, and David Newman).  We (Jeremy) also interviewed Dr. Jerry Hoffman, faculty at UCLA.

In this interview, Dr. Jerry Hoffman, a public skeptic and author of peer reviewed critiques of tPA provides interesting perspective on more than thrombolysis but on the future of guidelines (referencing this paper) and science in Emergency Medicine.

A few of Dr. Hoffman’s articles on the topic:

Ensuring the integrity of clinical practice guidelines: a tool for protecting patients.

How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST-3).

Thrombolysis for stroke: policy should be based on science, and not on politics, money or fear of malpractice.

Stroke thrombolysis: we need new data, not more reviews.

Against: And just what is the emperor of stroke wearing?

Thrombolytic therapy for acute ischemic stroke – Tissue plasminogen activator for acute ischemic stroke: Is the CAEP Position Statement too negative?

FOAMcastini – ACEP tPA Clinical Policy

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In a prior FOAMcastini, we covered a draft of an ACEP clinical policy on tPA for acute ischemic stroke.  This came in the wake of years of controversy over the aggressive position taken in the 2012 clinical policy.  In June ACEP released the final version of this policy.

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Per the policy within 3 hours:

  • NNT of 8 for excellent functional outcomes; 95% [CI] 4-31
    • Paucity of patients presenting with mild stroke (NIHSS score 0 to 4)
  • NNH of 17 for symptomatic intracerebral hemorrhage; 95% CI 12-34

While FOAMcast is not an interview style podcast, we felt compelled to get some perspective on Emergency Physicians a little more experienced than ourselves.  Here we interview:

Dr. Ryan Radecki (@emlitofnote), Assistant Professor, University of Texas – Houston

  • See his response to the policy on his blog here

Dr. David Newman (#draftnewman), Associate Professor of Emergency Medicine, Mount Sinai Hospital

Dr. Anand Swaminathan (@EMSwami), Assistant Professor of Emergency Medicine, NYU

Dr. Ken Milne (@thesgem), Chief of Staff at South Huron Hospital

FOAMcastini – SMACC Day 3

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We are bringing you pearls from conferences we attend including SMACC (#smaccUS).  This conference was amazing and we enjoyed meeting everyone.  We look forward to seeing y’all at SMACC in Dublin June 13-16, 2016 and hope you check out the Free Open Access Medical education (FOAM) lectures from SMACC, in podcast form, until then.

Things in medicine aren’t always engineered to help us succeed. Engineering the environment smarter may make care safer. – Kevin Fong

  • Medication vials often look quite similar and in a busy, heated moment this may lead to medication errors.  Check out the EZdrugID project.
EZdrugID
Photo: Dr. Nicholas Chrimes

Analgesia, there’s more to it than medicine – Jeremy Faust

  • Distraction is a good thing.  Doing a painful procedure such as injecting local anesthetic? Distract the patient in tactile fashion by lightly scratching the patient proximal to the procedure. Alternative, music and videos can distract children and adults.
  • Calm music may reduce perception of pain.
  • Take advantage of child life, if you have them [AHRQ]!

The Glasgow Coma Scale is a problem – Mark Wilson (see this blog post)

  • The score doesn’t have intrinsic meaning. A GCS score can be associated with mortality ranging from 20-57%, depending on the individual components [Healey]
  • We’re really bad at assigning correct GCS scores to patients, even when we have cheat sheets [Feldman]
  • The interrater reliability of the GCS is abysmal [Bledsoe, Gill]
  • Describe the patient’s exam!

Shift work is disruptive – Haney Mallemat

  • Microsleep is dangerous, yet fairly common in the over tired provider
  • Replacing traditional night shifts with “casino shifts” may help.  These are often comprised of 2 short shifts from 10p-4a and 4a-10a with the notion that each provider would get sleep during the “anchor period” of the Circadian cycle, 2am-6am.  Small studies have shown this feasible, preferred by many, and perhaps perceived [Croskerry, Dukelow]

FOAMcastini – SMACC Day 2

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We are bringing you pearls from conferences we attend including SMACC (#smaccUS).  The plenary, facilitated by the brilliant Dr. Victoria Brazil, focused on the impaired provider. At SMACC we’ve heard time and time again – we are fallible, we make mistakes.

Dying – Dr. Ashley Shreves

  • What often presume what our patients want without asking them.  When dying patients are asked what they want, it comes down to dignity. 1) Being clean 2) Naming a decision maker and then other top priorities essentially come down to healthcare providers listening [Steinhauser et al]
  • We don’t ask patients about their code statuses appropriately. First, we often spend almost no time doing this.  One study of hospitalists found that code status discussions lasted, on average, one minute. Further, that one minute was spent mostly focused on procedures [Anderson et al]
  • Communicate!

Evidence Based Medicine – The consensus of these cage matches was that evidence isn’t all equal; the existence of data doesn’t necessarily mean it’s good data.

  • The Randomized Control Trial (RCT) has problems – Drs. Paul Young and Simon Finfer
    • Beware the Fragility Index – small effects in RCTs
    • Caution with Base Rate Neglect – we jump to inappropriate conclusions.  For example, pretend you have tested positive for a typically fatal disease.  The test is accurate 95% of the time.  Most people would conclude that there was a 95% chance they have the disease – a death sentence. Yet, one would need to know the prevalence of the disease in the general population to determine the actual likelihood that the test was correct.  If the prevalence of the disease is 1 in 1000, the likelihood that you actually have the disease based on this test is <2%.
  • We should read the primary literature, but we can’t read all of it. Use FOAM (judiciously) – Drs. Rory Spiegel and Ken Milne
    • Due to the volume of literature, we have to make some decisions on what to read (Systematic reviews? Meta-analyses? RCTs? Case Reports?)

Impact Apnea

  • Severe traumatic brain injury can cause apnea which leads to a spiral of hypoxia (and thus cell death) and hypercapnea (with cerebral vasodilation causing cerebral edema) which can result in poor neurologic outcome.
  • The key?  Resuscitate these patients as a hypoxic arrest. These are patients that need an airway and need oxygen.