Thrombolytics for stroke: The evidence

A summary of the evidence for (or against) thrombolytics for stroke

Thrombolytics for stroke: undoubtedly the biggest controversy in emergency medicine. Also, the topic of this week’s Emergency Medicine Cases Journal Jam podcast. Rory Spiegel, Anton Helman, and I take a deep dive into the evidence. Why would we do this? No, it isn’t just that we have too much time on our hands. The journal jam podcast exists because we truly believe it is important to understand why we do what we do, both to ensure we are always providing the best care for our patients, but also so that we can explain that care to our patients. The evidence for (or against) thrombolytics is important precisely because the topic is so controversial. You will hear arguments on both sides. So will your patients. It is only through a familiarity with the studies, their strengths, and their weaknesses, that you will be able to decide for yourself what the evidence really shows and guide your patients to the best decision for their circumstances.

What follows are the notes I made while preparing for the podcast. First, I review the major randomized controlled trials looking at thrombolytics for stroke. That is followed by a discussion of the things I think are important to consider when trying to interpret this data. (Many folks might want to skip straight to this discussion section.) Continue reading “Thrombolytics for stroke: The evidence”

Articles of the month (May 2016)

My monthly summary of the best reads from the emergency medicine literature

Welcome to the May 2016 edition of my favourite reads from the medical literature. This will probably be the last post on First10EM for a little while, as I plan to take a summer vacation as well as a prolonged Ireland stay for SMACC.

Gastro game changer

Freedman SB, Willan AR, Boutis K, Schuh S. Effect of Dilute Apple Juice and Preferred Fluids vs Electrolyte Maintenance Solution on Treatment Failure Among Children With Mild Gastroenteritis: A Randomized Clinical Trial. JAMA. 315(18):1966-74. 2016. PMID: 27131100

Kids just want to drink juice, but I’ve been told that if I let kids with gastro drink juice they will die (or something like that). This is a randomized, controlled non-inferiority trial out of the Hospital for Sick Children that compared an electrolyte solution to a combination of half strength apple juice in the ED and the child’s preferred fluid (juice or milk) at home. 647 children aged 6 to 60 months with acute (less than 96 hours) diarrhea or vomiting with mild dehydration were included. For the primary outcome, which unfortunately was a composite of a number of things including IV use, hospitalization, health care contact, and prolonged symptoms, the juice group had a ‘treatment failure’ rate of 16.7% as compared to 25.0% with the electrolyte solution (difference 8.3%; 97.5% CI 2% – infinity). Converting from a non-inferiority analysis to a superiority analysis resulted in a p value of 0.006. In other words, the juice group was statistically better than the electrolyte group. The biggest caveat is that these kids were not sick, so the results could be different in kids with even moderate dehydration.

Bottom line: I am no longer forcing kids to drink something they hate. Whatever their preferred liquid is, it will keep them hydrated.

This is another paper that will be featured on EMCases Journal Jam. If you have questions you want the author to answer, let me know.

I’m not so ENCHANTED

Anderson CS, Robinson T, Lindley RI. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. The New England journal of medicine. 2016. PMID: 27161018 [free full text]

I am honestly surprised that I managed to read an entire article that started with the statement: “Thrombolytic therapy with intravenous alteplase (recombinant tissue-type plasminogen activator) at a dose of 0.9 mg per kilogram of body weight is an effective treatment for acute ischemic stroke, despite increasing the risk of intracerebral hemorrhage.” (This is a good reminder that when reading articles, it is often best to just skip the introduction. This section is just a non-systematic review of the topic, aka a statement of the author’s biases and opinions.) Moving beyond that, this was a multi-center, prospective, randomized, open-label, non-inferiority trial comparing usual dose tPA (0.9mg/kg) to low dose tPA (0.6mg/kg) in 3310 patient with acute ischemic stroke within 4.5 hours of onset. (As a reminder of how rarely we use this intervention, they screened 69305 patients to enroll those 3310.) The primary outcome was a composite of disability and death, defined as a modified rankin score of 2 or more. There was no statistically significant difference between the two groups (53.2% low dose and 51.1% usual dose, p=0.51). However, the 95% confidence intervals around this result go beyond a pre-specified definition, therefore they were unable to demonstrate non-inferiority. For the primary harm outcome, there was less intracranial bleeding in the low dose group  (1.0% vs 2.1% (p=0.01) by SITS-MOST criteria or 5.9% vs 8.0% (p=0.02) by NINDS criteria). Death at 7 days was lower in the low dose group, but death at 90 days was unchanged. There are a number of problems with this study. I am not going to delve too deeply into the issues of comparing different doses of placebo. (A dose response relationship is generally something we look for in efficacious therapies.) There is really no reason to make a study like this open-label and unfortunately that introduces a number of potential biases. Almost all the follow up was done by phone and the modified Rankin score is notoriously unreliable. Finally, like almost all of this research, the authors have significant conflicts.

Bottom line: High dose, low dose, no dose? I like this line of research. Maybe we can just keep lowering the tPA dose until is diluted by a factor of 10300 and hand care of acute stroke patients over to the homeopaths.

Read more: Rebel EM, The Bottom Line, EM Nerd

Neuropathic analgesia?

Therapeutics Initiative. Benefits and harms of drugs for “neuropathic” pain. Therapeutics Letter. 2016; 96:1-2. [free full text]

We see a lot of chronic pain. More than a lot. Since I started practicing, the number of people on gabapentin or lyrica for their neuropathic pain has skyrocketed. But just how good are these medications? This therapeutics letter looks at the evidence summarized in 11 different Cochrane reviews, and the best evidence on the topic is:

    • The evidence is weak (surprise anyone?) and the available RCTs have a high risk of bias
    • At best, about 1/10 patients will achieve any meaningful reduction in pain
    • Almost everyone has some side effects from these drugs
    • If there is going to be a benefit, you will see in within about 1 week
    • There does not seem to be any benefit in higher doses. (I think this is the most important takeaway, as I often see people on crazy escalating doses)

Bottom line: It might be reasonable to try these medicines, but start at a low dose, and recheck at 1 week if benefits outweigh side effects. If they don’t, stop the drug.

Black box on fluoroquinolones

FDA Drug Safety Communication: FDA advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together [available here]

So this isn’t research – it’s a notice of a new black box warning from the FDA. I am often skeptical of these warnings, as in some cases I think they have clearly done more harm than good (droperidol), but I think this one is worth knowing about. They say that “the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with sinusitis, bronchitis, and uncomplicated urinary tract infections who have other treatment options. For patients with these conditions, fluoroquinolone should be reserved for those who do not have alternative treatment options.” I would say this is pretty obvious, as there is no benefit of antibiotics in sinusitis and bronchitis. If a patient has a bad outcome and you are giving them a drug that has no chance of helping them, I would find that hard to defend.

Bottom line: Don’t use fluoroquinolones first in uncomplicated UTIs. Don’t use antibiotics at all in sinusitis or bronchitis.

But can we change our bad antibiotics habits?

Meeker D, Linder JA, Fox CR. Effect of Behavioral Interventions on Inappropriate Antibiotic Prescribing Among Primary Care Practices: A Randomized Clinical Trial. JAMA. 315(6):562-70. 2016. PMID: 26864410

We know that antibiotics don’t help for the vast majority of acute respiratory tract infections, but for some reason people just can’t help themselves. Every patient I see in the ED with a cough for 3 days is already on azithromycin or amoxicillin. They come to the ED because they can’t understand why they aren’t getting better on antibiotics. They think they need something stronger. This is a randomized controlled trial trying to get doctors to smarten up. In a total of 243 different clinicians, they tried three different interventions: 1) automated reminders that antibiotics are inappropriate and alternate treatment suggestions 2) the requirement of an ‘antibiotic justification note’ as part of the permanent record, and 3) intermittent e-mails comparing the performance of various doctors. Each clinician was exposed to anywhere from 0 to 3 of the interventions. The control group (no intervention) decreased their prescribing rate by 11% – a good demonstration of the Hawthorne effect. The reminders did nothing. Requiring a justification and being compared to peers decreased inappropriate antibiotic use.

Bottom line: Sadly, simply giving physicians information is not enough to change their practice. We need to be shamed into change. Maybe I should stop writing about the evidence and instead walk around personally shaming people?

Again – we don’t listen to good advice

Rosenberg A, Agiro A, Gottlieb M. Early Trends Among Seven Recommendations From the Choosing Wisely Campaign. JAMA internal medicine. 175(12):1913-20. 2015. PMID: 26457643

I love the choosing wisely campaign – except that we know doctors love to ignore good advice. This is a retrospective look at a billing database (so not necessarily the most reliable data, although the conclusions are believable.) They looked at 7 items that were listed by choosing wisely as being of minimal or no benefit (such as pre-op chest x-ray in the absence of concerning history, or imaging of low back pain without red flags) and looked to see if the number billed for changed over a 3 year period after the recommendations. They didn’t. (OK, imaging for headache went down from 14.9% to 13.4% – not exactly a clinically important change). Horrendously, the use of antibiotics for sinusitis remained at 84%!

Bottom line: Physicians just don’t change their practice when presented with good evidence or advice. It does makes me wonder if I should stop sending these e-mails – as they are probably not accomplishing anything.

Police officer: “Sir, How high are you?” Pothead: “No officer, its ‘Hi, how are you’”

Tefft BC et al.  Prevalence of Marijuana Involvement in Fatal Crashes: Washington, 2010 – 2014. May 2016. Washington, DC: AAA Foundation for Traffic Safety. [free full text]

This is a report by the AAA Foundation for traffic safety. It retrospectively looked at a database from the Washington State Traffic Safety Commission. In Washington State, as many will know, marijuana became legal in December of 2012. This study looked at all motor vehicle collisions that resulted in death and the proportion who had THC (delta-9-tetrahydrocannabinol) in their blood on autopsy. They compared collisions in the 2 years before the new law to the 2 years after the law. Out of the total of 3031 fatal MVCs over 4 years, 303 (10%) involved drivers testing positive for THC. The percentage rose from 8.9% in 2013 (before the law) to 17% in 2014. Of the individuals with positive tests for THC, 39% also had alcohol on board, 16% had other drugs, and 10% had alcohol and other drugs (leaving 34% with only THC detected). There are some problems with this data, the biggest probably being that we don’t know what levels of THC correlate with being impaired. THC wasn’t measured in every case, and sometimes measurement was delayed. Also, the total number of fatalities didn’t increase, just the number with THC on board, so the marijuana could be a bystander rather than a cause of the collisions. However, the issue of impaired driving, and our lack of science to guide us, remains a huge issue as this popular legalization movement continues forward.

Bottom line: Don’t smoke and drive

Would you be surprised if this patient died?

George N, Phillips E, Zaurova M, Song C, Lamba S, Grudzen C. Palliative Care Screening and Assessment in the Emergency Department: A Systematic Review. Journal of pain and symptom management. 51(1):108-19.e2. 2016. PMID: 26335763

I really hate adding work for our overly taxed triage nurses, who end up doing a lot of our screening. However, we are awful at recognizing patients with palliative care needs. This is a review, and I don’t think it is strong enough to completely overhaul triage systems, so I won’t go into the details, but they do conclude that palliative care screening is feasible. My favorite screening question is “would you be surprised if this patient died during this visit or in the coming month?” If no, they should probably have palliative care involved. Of course, the harder part of this equation is actually having adequate palliative resources for all the patients who need them.

Bottom line: Emergency medicine is all about dying patients. Palliative care should be an essential part of our mindset. You can have a much bigger impact by starting palliative care than you ever will handing out antibiotics for sore throats.

Epinephrine is safe in fingers – is that old news by now?

Ilicki J. Safety of Epinephrine in Digital Nerve Blocks: A Literature Review. The Journal of emergency medicine. 49(5):799-809. 2015. PMID: 26254284

This is a systematic review looking at the use of epinephrine in digital blocks. It should be stated up front that the conclusions are only good as the original studies – and they aren’t great. In a total of 30 studies, they identify 2797 blocks performed with epinephrine without any complications. They conclude that epinephrine is safe to use in digital nerve blocks in healthy patients. (Although, to be fair, it probably doesn’t help most of the time.)

Bottom line: This is probably another classic myth, although the data isn’t actually strong enough to definitely conclude safety.

CT first for the scaphoid?

Yin ZG, Zhang JB, Gong KT. Cost-Effectiveness of Diagnostic Strategies for Suspected Scaphoid Fractures. Journal of orthopaedic trauma. 29(8):e245-52. 2015. PMID: 25756914

I hate cost-effectiveness studies. The results hinge on a huge number of assumptions that really can’t be confirmed. However, sometimes they provide some insight that can be interesting. In this study they compared the cost of working up scaphoid fractures using a number of different strategies, such as immediate CT, immediate MRI, MRI on day 3, bone scan on day 3, and x-ray at 2 weeks. Maybe counterintuitively, the immediate CT was the most cost effective approach followed by the immediate MRI. I am not sure that you can take these results to the bank, but it is a good reminder that there a number of costs that we often forget about. Although immediate CT seems expensive, to come to a follow-up visit the patient must miss work, pay for parking, and see another physician. Additionally, being in an unnecessary cast for 2 weeks could result in 2 weeks unnecessarily off work. It’s not time to change yet, but I wouldn’t be surprised if immediate definitive testing for the scaphoid became the standard in the future.

Bottom line: CT first for scaphoid fracture might actually be cheaper than standard practice.

Compassion and the good Samaritan study

Darley JM, Batson CD. “From Jerusalem to Jericho”: A study of situational and dispositional variables in helping behavior. Journal of Personality and Social Psychology. 27(1):100-108. 1973. [article]

This is a classic study from the psychology literature. It is a study of seminary students. Half were told they had to give a talk on the parable of the good Samaritan. The other half were told they had to give a talk on routine seminary jobs. Some students were told they were late for the talk and had to hurry, whereas others were told that they were on time. There was a plant on the way to the lecture hall: a man slumped in a doorway who moaned twice as the students walked by. Whether or not they had been thinking about the parable of the good Samaritan made no difference in whether or not they stopped. The only thing that influenced their decision to help was how hurried they felt. I see a clear connection to emergency medicine. Our job requires an incredible amount of compassion. However, simply thinking about compassion doesn’t seem to help. If we are rushed, we are less likely to be compassionate, whereas if we have time, we will use it. Unfortunately – how many people feel like they have a lot of free time in the emergency department? Managing our departments so physicians are not constantly run off their feet is probably a really good idea. (Of course, that is quite a reach from this research scientifically speaking – but it makes a lot of sense to me.)

Bottom line: Ensuring that physicians aren’t rushed might be crucial in increasing our ability to be compassionate on the job.

Cheesy Joke of the Month

I was sitting in a bar the other night when the waitress yelled out “does anyone know CPR?!”

I yelled back, “yeah, and I know the rest of the alphabet too.”

Everyone laughed. Well, except one guy.

#FOAMed of the month

How is it that one develops mastery? Cliff Reid provides some insight into deliberate practice in the context of getting his ass kicked.


Articles of the month (January 2016)

Welcome to another edition of the First1oEM articles of the month – a collection of my favorite reads from the emergency medicine literature.

Location, location, location

Drennan IR, Strum RP, Byers A et al. Out-of-hospital cardiac arrest in high-rise buildings: delays to patient care and effect on survival. Canadian Medical Association Journal. 2016. [article]

This was a retrospective study looking at a cardiac arrest registry. They decided to look at the floor that you lived on to see if it impacted your survival from cardiac arrest (with the primary analysis looking above or below the 3rd floor). They found that living on higher floors was associated with an increased likelihood of death. In the raw numbers, 4.2% of patients living below the 3rd floor survived, compared to only 2.6% of those living on or above the 3rd floor (p=0.002). Survival above floor 16 was only 0.9%, and no one living above the 25th floor survived. The theory is that higher floors mean longer delays to EMS arrival, and therefore the ever important chest compression and defibrillation.

Bottom line: Choose your home wisely

 What’s the best antibiotic to bring on your trip to Las Vegas?

Geisler WM, Uniyal A, Lee JY. Azithromycin versus Doxycycline for Urogenital Chlamydia trachomatis Infection. The New England journal of medicine. 373(26):2512-21. 2015. PMID: 26699167

This is a randomized, controlled non-inferiority trial comparing azithromycin (1 gram PO once) to doxycycline (100mg PO BID for 7 days) in 587 adolescents with chlamydia infections. For the primary outcome of treatment failure at 28 days, there were no treatment failures in the doxycycline group as compared to 5 (3.2% 95%CI 0.4-7.4%) in the azithromycin group. Based on their assumptions, they could not establish the noninferiority of azithromycin in this group, although I imagine the result will vary greatly depending on local resistance patterns.

Bottom line: I will continue using doxycycline as my first line agent

 The Quixotic quest for the chest pain decision rule

Greenslade JH, Parsonage W, Than M. A Clinical Decision Rule to Identify Emergency Department Patients at Low Risk for Acute Coronary Syndrome Who Do Not Need Objective Coronary Artery Disease Testing: The No Objective Testing Rule. Annals of emergency medicine. 2015. PMID: 26363570

We would all love a good rule to use to send chest pain patients home. This is a secondary analysis of 2 prior prospective ED trials including a total of 2396 chest pain patients. They derive 3 different rules that are supposed to tell you which patients don’t need further testing after biomarkers and ECGs. (Of course, if you have listened to me in the past, you will know that stress testing is not helpful in our low risk chest pain patients.) I am not going to go into the rules themselves, because I think the study is too flawed to be helpful. Incorporation bias is the major downfall of this study. Classic cardiac risk factors are a large component of these rules, but previous research has consistently shown that having classic cardiac risk factors does not help predict whether a patient’s chest pain is ACS in the emergency department. So how could those risk factors possibly help in a decision rule? It’s because the definition of ACS included unstable angina and revascularization, both of which are subjective outcomes determined by the cardiologist, and the cardiologists had access to the risk factor information. A patient with 5 risk factors is more likely to be cathed, but that doesn’t mean the cath was necessary. Similarly, a patient with more risk factors is more likely to be given the diagnosis of unstable angina. The risk factors didn’t predict the diagnosis of ACS, they were the cause of it.

Bottom line: It is unlikely that we will find easy decision tools for chest pain patients, but for the time being we should be happy that most patients are so low risk that they should be sent home without stress testing.

 How prepared are you to run a neonatal resuscitation?

Yamada NK, Yaeger KA, Halamek LP. Analysis and classification of errors made by teams during neonatal resuscitation. Resuscitation. 96:109-13. 2015. [pubmed]

I like the idea here: these authors videotaped a total of 250 real neonatal resuscitations and reviewed the tape to determine how well the neonatal resuscitation algorithm was followed. Continuous quality improvement in our most stressful resuscitations makes sense. These authors report that 23% of the actions observed were errors as compared to the published algorithm. However, I don’t think the errors were truly important errors. The most common error was failure to have a cap to place on the child’s head – is that really essential in the first minutes of resuscitation of an apneic neonate? There were some important errors reported, though, with half of the 12 intubation attempts lasting longer than 30 seconds. Although I don’t think this study really demonstrates it, neonatal resuscitations are stressful and rapid paced, making errors probable. Mental practice and simulation are great tools to help prevent these errors, in my very biased opinion.

Bottom line: Quality improvement in your most stressful resuscitations is a good idea. 

If you want to review the newest NRP guidelines, you can see my post here.

Best treatment for pediatric gastro? Prevention

Soares-Weiser K, Maclehose H, Bergman H. Vaccines for preventing rotavirus diarrhoea: vaccines in use. The Cochrane database of systematic reviews. 11:CD008521. 2012. PMID: 23152260

This is a Cochrane systematic review of two different vaccines (monovalent versus pentavalent) for rotavirus. They identified 29 RCTs covering 101,671 infants for the monovalent vaccine and 12 RCTs covering 84,592 infants for the pentavalent vaccine. Unfortunately, most studies use the relatively non-sensical “rotavirus specific diarrhea” as an endpoint, but it definitely seems to be decreased (RR 0.33 95% CI 0.21-0.50 for the monovalent). All cause diarrhea was also decreased in the trials that looked at it, with an NNT of about 40 for any diarrhea and 100 to prevent a hospitalization. There was no change in mortality. They did not document an increase in adverse reactions, but efficacy studies often under report harms.

Bottom line: The rotavirus vaccine prevents serious diarrhea – maybe that’s an easier sell than the measles?

 Overtreatment and anticoagulation for atrial fibrillation

Hsu JC, Chan PS, Tang F, Maddox TM, Marcus GM. Oral Anticoagulant Prescription in Patients With Atrial Fibrillation and a Low Risk of Thromboembolism: Insights From the NCDR PINNACLE Registry. JAMA internal medicine. 175(6):1062-5. 2015. PMID: 25867280

With the rise of the new, expensive anticoagulants, we are beginning to see a push to get these agents started for atrial fibrillation patients in the emergency department, ignoring the tiny daily risk of stroke and the importance for long term monitoring that we cannot provide. This is a registry based study. Out of a total of about 360,000 atrial fibrillation patients in the study, 11,000 had a score of 0 on two major stroke scales. However, 25% of this extremely low risk population was on blood thinner contrary to current guidelines.

Bottom line: We over treat patients. For everything. Remember that studies are generally the best possible scenario for medications, and that results in the real world will be worse as we expand treatment to patients who would not have been included in the studies. (If you want to watch this happen in real time, just watch interventional treatment for stroke over the next few years.)


Fauci AS, Morens DM. Zika Virus in the Americas – Yet Another Arbovirus Threat. The New England journal of medicine. 2016. PMID: 26761185 [free full text]

This is a basic review of the Zika virus that is currently causing a significant pandemic through Central and South America, and has potentially been linked to a significant number of birth defects (microcephaly) in Brazil. Zika is another mosquito borne virus without a specific treatment (like Dengue or Chikungunya). The symptoms are described as a milder version of Dengue fever, with fever, myalgias, eye pain, and maculopapular rash. Treatment is supportive.

Bottom line: Another emerging illness to be aware of in the returned traveller.

The CDC has issued a travel advisory advising pregnant women to postpone travel to areas in which Zika transmission is occurring.

Can you really multitask?

Skaugset LM, Farrell S, Carney M. Can You Multitask? Evidence and Limitations of Task Switching and Multitasking in Emergency Medicine. Annals of emergency medicine. 2015. PMID: 26585046

Emergency physicians are masters of multitasking – or so we think. This review explains that most of what we think of as multitasking is really rapidly switching between tasks, and even if you are good at it, this task switching slows you down and results in error. Unfortunately, the solution promoted in most other fields – limiting interruptions – just isn’t feasible in emergency medicine. Some suggestions this review makes to help: prioritize tasks according to acuity, recognize when interruptions can be delayed or redirected, practice skills so they become automatic (and don’t add to cognitive load), and use mental frameworks or external brains to limit cognitive work. Of course, optimizing your departmental workflow to limit interruptions, especially at critical times, is also important.

Bottom line: There is no such thing as multitasking, just rapid task-switching.

 Should we add TXA to the water supply?

Fox H, Hunter F. BET 1: Intravenous tranexamic acid in the treatment of acute epistaxis. Emergency medicine journal : EMJ. 32(12):969-70. 2015. PMID: 26598634

This is another one of those situations that we have to make decisions in the absence of any real evidence. The authors of this review were unable to find any studies to answer their specific question about the use of IV TXA in acute epistaxis. However, they do note that there are a few studies that show benefit of oral TXA in epistaxis as well as the study of topical TXA that I have previously discussed in this newsletter. Furthermore, the use of intravenous TXA in elective sinus surgery seems to limit blood loss, and we all know about the evidence for IV TXA in trauma. So there is no direct evidence, but plenty of reasons we might guess it could help.

Bottom line: I have never used IV TXA for epistaxis, but use it topically all the time. You can bet if I have a patient with severe epistaxis, I will give it a shot.

 Much like TXA, I love skin glue

Bugden S, Shean K, Scott M. Skin Glue Reduces the Failure Rate of Emergency Department-Inserted Peripheral Intravenous Catheters: A Randomized Controlled Trial. Annals of emergency medicine. 2015. PMID: 26747220

Tape and tegaderm has always seemed like a rather ineloquent method of securing IVs to me. In this non-blinded RCT of 380 peripheral IVs, they compared standard tegaderm and tape to skin glue (1 drop at the skin insertion site and one under the hub – this can be seen in this video.) For the primary outcome of IV failure (infection, phlebitis, occlusion, or dislodgement) at 48 hours, the skin glue was better (17% failure vs 27%, absolute difference 10% 95%CI 2-18%). The study was underpowered to assess the components of the composite outcome, but most of the failures were dislodgement. I don’t follow people for 48 hours – but a 27% failure rate with usual care seems high to me. Also, skin glue is likely more expensive. However, an NNT of 10 to avoid another IV stick would probably be attractive to many patients.

Bottom line: Skin glue is an option for securing PIVs – maybe difficult ones you really care about?

 I love ultrasound for looking at things, but for breaking up clots?

Piazza G, Hohlfelder B, Jaff MR. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC. Cardiovascular interventions. 8(10):1382-92. 2015. PMID: 26315743

This is a large prospective study, but I won’t get too much into the details because their primary outcomes were a bunch of surrogate markers rather than patient important outcomes. Why included it then? They used a novel device that uses ultrasound to try to break up the PE, and then gave tPA at the very slow rate of 1mg/hr. So far the lytics for submassive PE trials have shown some promise, but aren’t convincing. Alternate methods (non-bolus) of giving the medication might be the thing that tip the balance in favour of lytics. But mostly I wanted to include this article to bring up two excellent blog posts written by Josh Farkas about ultrasound guided thrombolysis and controlled thrombolysis of submassive PE.

Bottom line: My guess is that we will find that lytics are beneficial in submassive PE over the coming years, once we find the correct subset of patients and the best dose. (This is a big departure for me, because I am much more used to saying that things won’t work. That is almost always the safer bet.)

 Ondansetron and the dreaded QT

Moffett PM, Cartwright L, Grossart EA, O’Keefe D, Kang CS. Intravenous Ondansetron and the QT Interval in Adult Emergency Department Patients: An Observational Study. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 23(1):102-5. 2016. [pubmed]

Droperidol, possibly the most useful medication I have never had the opportunity to use, was taken away because of what it could do to the QT interval, right around the time when ondansetron was coming to market. Then, as ondansetron was coming off patent, we found out that it prolonged the QT just like droperidol did. OK, I will take off my tin foil hat to write the rest of this. This is a prospective observational trial of 22 adult patients receiving ondansetron at a single hospital. They did ECGs at baseline and every 2 minutes for 20 minutes. The QT did lengthen by 20 msec (95% CI 12-26 msec), but this is almost certainly clinically insignificant. There were no adverse events.

Bottom line: Yes, ondansetron will prolong the QT. No, it won’t be a problem. (Maybe avoid it if the patient overdosed on methadone, lithium, and haldol and tells you he has a family history of congenital long QT syndrome.)

 But little Johnny just aint right

Nishijima DK, Holmes JF, Dayan PS, Kuppermann N. Association of a Guardian’s Report of a Child Acting Abnormally With Traumatic Brain Injury After Minor Blunt Head Trauma. JAMA pediatrics. 169(12):1141-7. 2015. PMID: 26502172

I’ve included papers on the low risk of significant head injuries in children with isolated vomiting and isolated loss of consciousness before. This time we will look at whether parental concern that their child is acting abnormally, in isolation, is indicative of blood in the brain. This is another secondary analysis of the PECARN database. Out of 43,399 children in the original study, only 1297 were reported as acting abnormally. Of those, 411 (32%) had abnormal behaviour as their only finding. Only 1 child of these 411 had a clinically significant injury (0.2% 95% CI 0-1.3%). Of the smaller subset who had CTs performed, 4 out of 185 (2.2%) had any sign of traumatic brain injury. So injuries were rare, even when the parents report the child is not behaving normally.

Bottom line: Once again, you have to evaluate the entire patient, not just single variables. Observation is probably a better test than CT.

 How good is the ECG for hyperkalemia?

Montague BT, Ouellette JR, Buller GK. Retrospective review of the frequency of ECG changes in hyperkalemia. Clinical journal of the American Society of Nephrology : CJASN. 3(2):324-30. 2008. PMID: 18235147 [free full text]

Remember memorizing the classic progression of ECG changes in hyperkalemia: peaked Ts, prolonged PR, flatted Ps, wide QRS, then the deadly sine wave? Well, forget it. This is a chart review that looks at the ECGs of 90 hyperkalemic patients. (This is actually a reasonable topic for chart review, given that both the potassium level and the ECG are likely to be objective and easily identified on the chart.) Only half of the patients had any ECG signs of hyperkalemia, and only 18% met their strict criteria (which meant peaked Ts that were documented to resolve as the potassium decreased.) Although the ECG was insensitive for hyperkalemia, that might not be the important question. I don’t care as much about the number of the potassium, but whether it is affecting the heart – and the ECG might be a better marker of cardiac outcomes, but we don’t know from this study.

Bottom line: The ECG is not sensitive for hyperkalemia.

 A guideline that say something sensical? I must be dreaming

Kearon C, Akl EA, Ornelas J et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline. Chest. 2016. [free full text]

This is a new guideline from the American College of Chest Physicians covering antithrombotic therapy for VTE. The recommendation to know about: “For subsegmental PE and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C).” That’s right – they are suggesting NOT treating certain PEs! They also recognize the high false positive rate of CTPA, which I have discussed here before. When is a subsegmental PE likely to be a true positive? “We suggest that a diagnosis of subsegmental PE is more likely to be correct (i.e. a true-positive) if: (1) the CT pulmonary angiogram (CTPA) is of high quality with good opacification of the distal pulmonary arteries; (2) there are multiple intraluminal defects; (3) defects involve more proximal sub-segmental arteries (i.e. are larger); (4) defects are seen on more than one image; (5) defects are surrounded by contrast rather than appearing to be adherent to the pulmonary artery; (6) defects are seen on more than one projection; (7) patients are symptomatic, as opposed to PE being an incidental finding; (8) there is a high clinical pre-test probability for PE; and D-Dimer level is elevated, particularly if the increase is marked and otherwise unexplained.” The best way to avoid this dilemma all together is still to avoid ordering CTs in low risk patients.

Bottom line: Not all PEs are really PEs. Not all PEs require treatment.

 Speaking of which

Nielsen HK, Husted SE, Krusell LR. Anticoagulant therapy in deep venous thrombosis. A randomized controlled study. Thrombosis research. 73(3-4):215-26. 1994. PMID: pubmed

I may have included this one before. Its really the only RCT of anticoagulation for VTE that exists as far as I know. This is a prospective, randomized trial of 90 patients with proven, symptomatic DVTs comparing anticoagulation (heparin followed by warfarin) with an NSAID (phenylbutazone). All the patients had VQ studies performed, both initially and for follow up. About half of the patients had PEs (asymptomatically). There was no difference between the groups with regards to regression of DVT, recurrent DVT, or PE up to 60 days. In terms of mortality, there was one death in the anticoagulation group and none in the NSAID group. The only difference was that the anticoagulation group had an 8% rate of bleeding complications while they report no adverse events from the NSAID. Now this is a small and imperfect study – but quite amazingly, it’s the only real study of anticoagulation for VTE, and it’s negative!

Bottom line: In the only RCT of anticoagulation in DVTs (half of whom had PEs), there was no difference between using an anticoagulant or an NSAID. I know which I would prefer.

 You thought diagnostics was difficult? How about pain caused by analgesics?

Tabner A, Johnson G. Codeine: An Under-Recognized and Easily Treated Cause of Acute Abdominal Pain. The American journal of emergency medicine. 33(12):1847.e1-2. 2015. PMID: 25983269

I have no idea what to do with this one. They present 2 case reports of patients with abdominal pain in whom the ultimate diagnosis was sphincter of Oddi spasm secondary to codeine use. Both patients’ pain resolved rapidly with naloxone (400mcg), which is not one of my usual analgesics. But how should we use this information? I imagine that you could do a lot of harm trying to treat abdominal pain with naloxone. This is definitely an interesting diagnosis – and one that I have never seen, or at least recognized.

Bottom line: Maybe one more reason that codeine should not be used

 Back pain? Do we really have to talk about back pain? Ugh

Friedman BW, Dym AA, Davitt M. Naproxen With Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back Pain: A Randomized Clinical Trial. JAMA. 314(15):1572-80. 2015. PMID: 26501533

It’s sort of frustrating that trial after trial comes out telling us nothing really works for low back pain. Obviously we need to do something for our patients. This is a randomized, double-blind, placebo controlled trial comparing naproxen plus placebo to naproxen plus cyclobenzaprine and to naproxen plus oxycodone and acetaminophen in adults with acute non-traumatic lumbar back pain. For the primary outcome of a scale measuring pain and function, there was no difference between the groups. There were more adverse effects in the cyclobenzaprine and oxydodone/acetaminophen groups. The biggest weakness of this study was that there was relatively poor compliance with all treatment regimens, but that makes it more like real life.

Bottom line: Naproxen monotherapy is probably better. Adding cyclobenzaprine or oxycodone/acetaminophen just increases adverse effects.

 Sir, you have a severe antibiotipenia – we need to start an infusion, STAT

The BLISS trial: Abdul-Aziz MH, Sulaiman H, Mat-Nor MB. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive care medicine. 2016. PMID: 26754759

This wasn’t even on my radar: should we be giving antibiotics (specifically beta-lactams) as a continuous infusion? I know, we all heard about time dependent versus dose dependent antibiotics in medical school, but I honestly thought that was useless pharmacological drivel, because the studies I have seen so far have indicated that dosing regimen doesn’t matter much when we are giving antibiotics. (Maybe because we are giving so many antibiotics to people who really don’t need them?) Anyhow, on to the study: this was a prospective, randomized, open-label study of 140 adult ICU patients with severe sepsis being treated with cefepime, meropenem, or piperacillin/tazobactam. They were randomized to either receive their antibiotics as a continuous infusion, or by the usual intermittent dosing. The primary outcome was clinical cure, and was lower in the continuous group (56% vs 34%; absolute difference 22% 95%CI 10-40%, p=0.011). Unfortunately, I’m not sure that is the most important outcome, and the study wasn’t powered for mortality, so there was no significant mortality difference despite the numbers being better in the continuous group.

Bottom line: Continuous administration of beta-lactam antibiotics is interesting, and definitely warrants further study focusing on mortality differences

 Want to see how quickly I can contradict myself?

Dulhunty JM, Roberts JA, Davis JS. A Multicenter Randomized Trial of Continuous versus Intermittent β-Lactam Infusion in Severe Sepsis. American journal of respiratory and critical care medicine. 192(11):1298-305. 2015. PMID: 26200166

Hold your horses. The previous study was open-label, but there is another, larger study that was double-blinded. This is a double-blind, double-dummy multi-center randomized controlled trial of 432 ICU patients with severe sepsis being treated with meropenem, ticarcillin-clavulanate, or piperacillin-tazobactam, again comparing continuous versus intermittent dosing. For the primary outcome, ICU free days alive at day 28, there was no significant difference between the groups (18 vs 20 day, p=0.38). 90 day mortality was also the same, 26% in the continuous group vs 28% with intermittent antibiotics (p=0.67). So was the previous study just an example of the bias that can occur with open-label studies, or might there be a small but real difference that these studies were just under-powered to detect?

Bottom line: This will require a massive trial to answer definitively. For now, intermittent dosing is just so much easier that it should probably remain the preferred method of antibiotic administration.

Cheesy Joke of the Month

Why did the scarecrow get an an award?

He was outstanding in his field


#FOAMed of the month

We vastly overestimate the benefits of many of the medications that we tell our patients are essential. As a result, you can hear many of the elderly coming well before you see them from the rattle of all the pills. A large percentage of emergency department visits are from medication side-effects, but most of these are misdiagnosed. So although this tool was designed more for family physicians, I think it probably has a role in emergency medicine as well


This is a tool developed by some very intelligent Canadian doctors (including the team behind another amazing FOAMed resource: The Best Science Medicine podcast) to help clinicians and patients make decisions about reducing or stopping medications. The thing I miss most about family medicine was the ‘drugectomy’: it was astounding how many patients would feel so much better just because we stopped a few of their less necessary or unnecessary medications.