Wednesday 12 November 2014

The bias of systematic reviews and the neuraminidase inhibitors

6.9 billion dollars were spent around the world in 2009 stockpiling oseltamivir to combat pandemic influeza. So this drug must have magical powers. There’s little doubt it was magic for Roche. But does it actually benefit patients? Maybe we should look for the answer in systematic reviews of the neuraminidase inhibitors. These reviews and meta-analysis are meant to be about the highest form of evidence we have. But could they be subject to substantial bias? Could authors have financial conflict of interest that might sway their conclusions? Unfortunately the answer is an emphatic yes.

The author from the University of NSW Sydney found 26 systematic reviews about the neuraminidase inhibitors. Of these 13 examined prophylaxis and 24 examined treatment accounting for 37 distinct assessments. Two blinded reviewers looked at each of these to determine if the review was positive or negative. They then looked to see if there was a financial conflict of interest.

I think we can all predict the results but I was genuinely surprised at the extent of the results. Of the 8 reviews determined to have a conflict of interest, 7 (88%) were determined to be favourable. Of those without conflict of interest only 5 out of 29 (17%) were in favour. In addition, those without conflicts were much more likely to mention problems with publication bias, the quality of the studies and missing data.

So there is little doubt that systematic reviews can have substantial bias. Many assumptions go in to the selection of included studies, the grading of the evidence and all of this can be easily corrupted. Perhaps it is time we ditch the notion of systematic reviews being high quality evidence- especially if there are any conflicts of interest. Maybe we should bury them under the pile of 6.9 billion dollars worth of oseltamivir rotting in the ground.

Dunn AG, Arachi D, Hudgins J, et al. Financial Conflicts of Interest and Conclusions About Neuraminidase Inhibitors for Influenza. Ann Intern Med. 2014;161:513-518.

Tuesday 11 November 2014

The wonderful ARISE trial

Journal club in 2014 would certainly not be complete without a mention of the fantastic ARISE trial. I think most practicing emergency doctors now are well aware of this study and how it concluded no benefit of early goal directed therapy (EGDT) vs. usual care in early septic shock. Therefore I will only focus on a few key points.

This was a huge undertaking involving 51 centres mostly in Australia and New Zealand and enrolled 1600 patients. The authors are to be absolutely congratulated for such great effort. However, I’ll bet they are kicking themselves for not being the first cab off the rank of the new large RCT’s. ProCESS just beat them by six months. The last of these trials is the ProMISe trial coming out of the UK. Therefore we will be seeing lots more data and meta-analysis coming in the future.

In the ARISE trial, both groups had a mortality just shy of 20%. This seems to be the new norm regarding mortality rates in studies of sepsis now days. Much has been made about the gradual reduction in mortality over the years but I would imagine that much of this is probably due to early recognition of milder sepsis and the creation of a lower risk cohort rather than any major breakthrough. (Although some might consider this a breakthrough.)

Both arms in the ARISE trial got just about the same amount of fluids. Two and a half litres were given before enrollment and almost two more litres in the six hours after. (To be fair, there actually was a statistical difference with a p value containing lots of pretty zeros but this most certainly was clinically meaningless). More patients in the EGDT group got red-cell transfusions, central lines, vasopressors, dobutamine and went to ICU. So many more resources were used to no benefit. Could this be thought of harm of EGDT? I think so.

So once again the original study of EGDT which claimed a 15% absolute mortality reduction has been debunked. ARISE has taught us again to be skeptical of small studies showing large treatment effect. Where else have we seen this recently? Think hypothermia after cardiac arrest? Could NINDS be next?

The basic summary for the early care of septic shock in the ED? Early recognition, aggressive fluids, and early antibiotics. Who would have figured?


Peake SL, Delaney A, Bailey M, et al. Goal-Directed Resuscitation for Patients with Early Septic Shock. N Engl J Med 2014 Oct 16;371(16):1496-506.

Monday 10 November 2014

Should traumatic pneumothorax get a gentle pigtail or a massive painful chest tube?

Okay, so I think you have already figured out the answer so I’ll keep this brief.

There is quite a philosophic difference in how many clinicians manage spontaneous versus traumatic pneumothorax. Spontaneous usually gets nothing or a simple aspiration whereas traumatic often are managed with chest tubes. I have been teaching ATLS (EMST) for years and the current 9th edition still advocates a massive chest tube. Why such discord?

To be honest, the following paper is rather bad but at least addresses this important issue. So please ignore the small sample size, absolutely crazy power calculation (that must have been done in retrospect), lack of blinding and confounding factors.

40 adult patients with traumatic pneumothorax were randomized to either a pigtail catheter or a 28 French chest tube. They excluded anyone with haemothorax and those who needed emergent tubes.

The primary outcome was looking at pain on a numerical rating scale (NRS) at the insertion site of either the chest tube or pigtail. Secondary outcomes included success rate and complications.

The results confirmed the obvious. Pigtails hurt a lot less. Yes, a lot less. This was statistically significant even with such a small sample size. The duration of tube insertion and success rate were all similar. Safety can never be adequately addressed with the size of this study but one would imagine it should be fine.

Will this change what we do? The quality of this evidence shouldn't change anything. But it has caused me to look at recent studies (that I must have overlooked) advocating a smaller solution to uncomplicated traumatic pneumothorax. It may not sound kosher, but I’m going the pigtail from now on.


Kulvatunyuou N, Erickson L, Vijayasekaran, A, et al. Randomized clinical trial of pigtail catheter versus chest tube in injured patients with uncomplicated traumatic pneumothorax. Br J Surg 2014;101:17-22.

Do an ultrasound first for suspected kidney stones… if you’ve got the skills

You are seeing a patient in the ED with suspected renal colic. Should you do a point-of-care ultrasound first, a radiology ultrasound or just go straight to CT

Why not just CT everyone? After all, it is the gold standard test. Yes, but the authors correctly point out the radiation issues, cost and get kudos for mentioning morbidity from over-diagnosis and incidental findings. All of this coming from the lead author who is a San Francisco radiologist! (I wonder if she has had her keys to the radiology tea room revoked.)

Inclusion criteria were patients between 18-76 years old where the ER doctor decided to order imaging to establish or rule out a primary diagnosis of kidney stones.

Excluded patients included obesity, pregnancy, those at “high risk” for serious alternative diagnosis such as cholecystitis, appendicitis, AAA, bowel disorders and a few other things.

Patients were randomized in a 1 to 1 to 1 fashion to the first study being a point-of-care ultrasound, radiology ultrasound, or CT. After this was done, the ER doctor could do order whatever tests they felt appropriate.

There were three primary outcomes that all seem relevant but somewhat hard to measure.

The first was did the initial treatment strategy cause any harms? This was defined as high risk diagnosis with complications that could be related to a missed or delay in diagnosis. Three separate non-blinded reviewers determined this outcome and came to a consensus.

The other two outcomes were total radiation exposure and cost.

Results? 2759 patients were enrolled across 15 different ED’s. Most of these ED’s had a very active ultrasound program.40% of the patients had a prior diagnosis of kidney stones. Of the total, only 11 patients (0.4%) had a high risk diagnosis with complications in the first 30 days. There were no differences between the groups.

Of note, 60% of patients randomized to the point-of-care ultrasound never got a CT in the ED.

Not wanting to paraphrase an issue of such importance, the authors state the following:

“Our results do not suggest that patients should undergo only ultrasound imaging, but rather that ultrasonography should be used as the initial diagnostic imaging test…”

The obvious limitation to this study is external validity. I always seem to chuckle a little when I see a study of ultrasound that quotes test performance to three decimal points. The fact is that the sensitivity and specificity of the test will change each and every time a different person picks up the probe. This study clearly used doctors experienced in ultrasound. In addition remember they were also very good at excluding high risk patients on clinical grounds. Therefore caution is in order.

Will this change practice? As usual, the answer is it depends. It really matters who is holding the probe and making the clinical decisions. Nevertheless, this study gives strong support to those who might perform a point-of-care ultrasound without having to resort to CT if it was not felt to be indicated.

All of this from a radiologist…it must be a cold day in hell.


Smith-Bindman R, Aubin C, Bailitz J, et al. Ultrasound versus Computed Tomography for Suspected Nephrolithiasis. N Engl J Med 2014;371:1100-10.

Friday 7 November 2014

Can ethanol be neuroprotective?

Should we load head injured patients with a neuroprotective bolus of ethanol? Oh please let this be true!

Honestly, some papers are so good for journal club simply because they are so incredibly bad. The following is a great example. One might wonder if the peer reviewers were the head injured participants of this study.

These authors performed an un-blinded chart review with no methods to determine the physiologic values and outcomes of a cohort of 184 severely injured patients as defined by an ISS of >17. (Why 17 you might ask?)  Within this “matched” cohort, they compared those who had a blood alcohol level (BAL) greater than 0.05 g/dl (n=34) to those that were lower or had measurable alcohol (n=150).

Both groups had similar ISS. Those in the higher alcohol group had lower GCS scores (9.64 vs. 12) upon arrival. There was a trend towards higher values in the abbreviated injury score (AIS) for the head (3.29 vs. 2.81). But after two hours of admission the GCS scores “leveled out.”

Their conclusions are so great that I dare not paraphrase. “Severely injured patients with a raised BAL have higher incidence of severe traumatic brain injury...However the survival rate and in-hospital stay is not influenced. This supports the theory of a neuroprotective role of alcohol.”

Before you start hitting the bottle, please consider the following.

If someone is drunk, might they look to have a worse head injury? Yes you say? Then they would likely score higher on the head component of the AIS. Without getting too nerdy, this value is squared to become part of the ISS. Therefore almost half of the ISS in the drunk cohort came from their over appreciated “head injury.”

I think it is quite obvious that the drunk cohort was ultimately less injured but had the same outcomes. This would suggest a harmful effect of alcohol rather than a protective effect.

In the end, this is really a small and sloppy study that can’t tell us much of anything important. But its ultimate value may be for teaching critical appraisal of the literature. Cheers... and have one for me so long as I am not a trauma patient!

Covering: Scheyerer MJ, Dutschler J, Billeter A, et al. Effect of elevated serum alcohol level on the outcome of severely injured patients. Emerg Med J 2014;31:813-817

Friday 19 September 2014

Are antiemetics efficacious in the Emergency Department?

Giving antiemetics in the Emergency Department is a very common ritual that we perform without much thought. But it might be surprising to know that there is very little evidence as to their efficacy. Most studies looking at antiemetics have been performed in patients who are post-operative or in those undergoing chemotherapy.

Ironically, conducting a well-designed trial should be a reasonably simple and feasible undertaking. Nausea is a near ubiquitous complaint in the ED and intuitively it should be easy to create a double blind randomized controlled trial with adequate power to make reasonable conclusions.

These authors sought to compare ondansetron 4mg, metoclopramide 20mg and placebo in adult patients in whom the treating doctor thought they needed an antiemetic. There were lots of sensible exclusion criteria. The primary outcome was a reduction of 30mm on a VAS recorded half an hour after drug administration. There were lots of secondary outcomes investigated.

They ended up with 258 patients for analysis. Mean decrease in VAS score was 27mm for ondansetron, 28mm for metoclopramide, and 23 for placebo. This was not statistically significant. The authors state that this study adds weight to the recommendation that drug use not be routine for nausea and to focus on other specific treatments or supportive care.

However, I am not so sure we can make any conclusions that suggest we throw away our antiemetics. This study was powered to find a 30mm reduction in VAS from baseline. Trends clearly favoured the antiemetics over placebo; therefore a larger study with more statistical power could very likely demonstrate a difference.

The authors seemed to down play the importance of the administration of rescue medications as meaningful outcome measure. In reality, this may actually be the most objective outcome measure as it does not rely on self-reporting of nausea. Many less people in the metoclopramide group required rescue medication.

The limitations section rightfully point out that one could easily argue over the doses of drugs chosen in this study. Why not 8mg of ondansetron and 10mg of metoclopramide?

One important aspect not mentioned in the limitations is the effect of placebo. As I have mentioned before, remember that placebo is not “nothing.” It can have substantial physiologic and psychological effect especially when it comes to pain and nausea. It would have been interesting if they had a “nothing” arm.

Is this study practice changing? Definitely not. But it does raise some interesting questions. A study of many more patients would be necessary to make any meaningful conclusions. I won’t throw away my antiemetics quite yet. But perhaps I am kidding myself.


Egerton-Warburton D, Meek R, Mee MJ, et al. Antiemetic Use for Nausea in Adult Emergency Department Patients: Randomized Controlled Trial Comparing Ondansetron, Metoclopramide, and Placebo. Ann Emerg Med. 2014;?:1-7 [article in press]

Wednesday 17 September 2014

Oseltamivir (Tamiflu) for Influenza... A Crushing Cochrane Review

Billions of dollars has been spent around the world stockpiling neuraminidase inhibitors to be used in case of pandemic influenza. The presumption is that they are effective, have little side effects, prevent transmission, complications and will save the planet. Was this money well spent?

The 2014 Cochrane review to describe the benefits and harms of oseltamivir was truly a gargantuan and unprecedented undertaking. The authors recognized there was the substantial risk of reporting bias as all of the RCT’s investigating oseltamivir were industry sponsored. Would a drug company that stands to make billions of dollars suppress or hide information that may be damning to their cause? I’ll let you decide.

In order to get around reporting bias, the authors conducted a four year campaign to obtain full clinical study reports of the oseltamivir trial programs. This has never been done before. Full study reports are not simply the papers that get published or rejected from peer review journals. No, they are the raw data and a lot more. In the case of oseltamivir, clinical study reports were of a mean length of approximately 1300 pages each.  In the end, the authors succeeded in accessing the reports and relevant regulatory comments totalling approximately 150,000 pages! How anyone could go through all of this information is beyond me. Heck, I struggled to read their 18 page Cochrane review in the BMJ.

To get right to the point, let’s look at the conclusions.

How well does oseltamivir work? It reduces the time to first alleviation of symptoms by about 16 hours. This represents a reduction in time from having the flu for a full 7 days to about 6.3 days in the treatment group.  This of course likely represents best case scenario as all of the study designs were industry supported.  

Does it reduce admissions to hospital? No.

Could conclusions be drawn on the ability of oseltamivir to interrupt viral transmission? No and nor could the FDA. This leads one to question why this drug has been stockpiled.

What about potential harms of oseltamivir? It increased the risk of nausea (NNTH 28), and vomiting (NNTH 22). In addition it increases the risk of headaches and renal & psychiatric syndromes. One interesting fact to come out of all of this was the “placebo” used in the trials contained dehydrocholic acid and dibasic calcium phosphate dehydrate. Both can cause GI symptoms which may have been a source of bias in favour of minimizing the potential harms of oseltamivir.

The conclusions as stated by the authors strike me as very cautious and measured. It made me wonder if they were concerned about the legal power of a wealthy pharmaceutical company. The last sentence of their abstract simply states, “The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.” It took them 4 years of struggle, expending so much time, effort, and energy to come up with this wimpy conclusion? My guess is the authors would have a different opinion over a glass of beer.

At least the authors did leave a little sting at the end of their manuscript buried on page 9 of 18. They conclude by stating:

Given that oseltamivir is now recommended as an essential medicine for the treatment of seriously ill patients or those in higher risk groups with pandemic influenza, the issues of mode of action, lack of sizeable benefits, and toxicity are of concern. This is made worse by the record and stated intentions of governments to distribute oseltamivir to healthy people to prevent complications and interrupt transmission on the basis of a published evidence base that has been affected by reporting bias, ghost authorship, and poor methods.

We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the WHO list of essential drugs, and its use in clinical practice as an anti-influenza drug.


Jefferson T, Jones M, Doshi P, et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545

Wednesday 10 September 2014

Can We Rule-out MI in Two Hours?

I love any study that provides evidence that allows us to use less time or resources in the Emergency Department. Can I use a high-sensitive troponin (hsTnT) assay to rule-out MI in two hours rather than the traditional six? Yes, but with some cautions and caveats.

The authors of this paper looked to validate an accelerated hsTnT assay measured at 0 and 2 hours for diagnosing acute myocardial infarction in the Emergency Department.

This was a prospective observational cohort study conducted on consecutive eligible patients at the Royal Brisbane and Women’s Hospital in Australia. Inclusion criteria specified adults whereby the treating doctor thought they should perform serial troponin measurements to rule-out MI. In addition to the hsTnT assay they also got all of the usual work-up for potential ACS including ECG’s, “old school” troponin I at 0 & 6 hours and other follow up.

As with all studies investigating a new “better” test, the gold standard is always a little troublesome. To what do you compare your new test against when yours is presumably the best? This study used the usual adjudicated diagnosis by a non-blinded cardiologist based on all of the clinical data available. I do not believe they were blinded to the hsTnT as this was not 100% clear in the text.

What were the results? 764 patients were enrolled. There was a 7.3% (56 patients) rule in MI rate which is rather low compared to usual Australian standards but probably high compared to those in North America. The hsTnT measured at 0 & 2 hours was 96% sensitive and had a negative predictive value of 99%. Only two patients out of 56 were missed with this strategy. Sounds great! But some caution is in order.

The median time from symptom onset to presentation was FIVE hours. Therefore be very careful in patients who present early after chest pain onset. Other studies (Reichlin or Keller NEJM August 27, 2009) have shown that the hsTn assays generally become positive within about three hours. So it is not surprising that the early hsTnT worked well in this study. In fact the sensitivity of the first troponin was 93%. The addition of the two hour troponin only picked up two more patients and increased the sensitivity to 96%.

Don’t get overly excited about the 99% negative predictive value as this of course is a reflection of the low prevalence of disease in this cohort. Remember they started out with a negative predictive value of 93% before any test was performed. This is bound to be worse in a higher risk cohort.

The authors go on to state that time saved by this approach could have a major impact on health service delivery. Not so fast. I agree that two hours is better than six. But the high sensitive troponin assays have already added to our work load with its drop in specificity. More and more patients are “positive” creating a big headache. In the end, I have no doubt they increase further diagnostic testing and admission rates. So I doubt we can consider the high sensitive troponin assays as time or resource saver.

What do I take home from this? If my goal is to rule-out MI, I can probably do this with adequate sensitivity with a 0 and 2 hour  high-sensitive troponin in a patient with reasonably low pre-test clinical suspicion. But not in a patient who is high risk or presents early after chest pain onset. In the end, I am very happy that there is now some more evidence that can support an accelerated rule-out MI strategy in suitable patients.  


Parsonage WA, Greenslade JH, Hammett CJ, et al. Validation of an accelerated high-sensitive troponin T assay protocol in an Australian cohort with chest pain. Med J Aust 2014;200(3) 161-165.

Sunday 7 September 2014

Paracetamol (Acetaminophen) Does Not Work For Low Back Pain?

This is the message I heard being touted recently by a study author while listening to the Australian ABC news radio. Could this be? Have we been prescribing this medication inappropriately for all these years?

As it turns out, the devil is in the details. It all depends upon which question you are asking.

Enter a large multicentre RCT across 235 primary care centres in Sydney, Australia. 1652 patients with new low back pain were randomized in a 1:1:1 ratio to receive up to 4 weeks of regular paracetamol, as-needed paracetamol or placebo. Patients with suspected serious spinal pathology were excluded from the study. The methods were quite good and the double-dummy blinding was quite clever.

Patients were followed up at 1 week and participants recorded pain scores in to a daily pain and drug diary until recovery or 4 weeks.

The primary outcome was time to recovery in days. Recovery was defined as the first day of 0 or 1 pain intensity, measured on a 0-10 point scale, maintained for 7 consecutive days.

Did I read this correctly? The study authors were trying to determine if paracetamol could cure low back pain? I had no idea that there were those who thought paracetamol could cure low back pain. I was always under the impression that it might take the edge off of the pain a little bit for a brief period of time. But a cure, no.

The authors justified this primary outcome as below.

We chose this outcome on the basis of previous findings of fast recovery in a cohort receiving regular paracetamol. As such, we postulated that regular paracetamol would improve recovery by decreasing pain intensity and allowing people with acute low back pain to remain active and resume normal movement as soon as possible.

The results showed a median time to recovery of 17 days with no statistical difference between the groups. So, paracetamol does not cure low back pain. Big surprise.

To be fair, the study did look at secondary outcomes of pain intensity, disability, function, global rating of symptoms change, sleep quality and quality of life and found no differences. But one could reasonably question the validity of the measuring tools. In addition, one should always be a bit more skeptical when looking at multiple secondary outcomes.

One should also remember that "placebo" is not an inactive treatment arm. To put another way, placebo is not nothing. It can have substantial physiologic and psychological effects in some people especially when it comes to pain. This may have watered down the results of the primary outcome. It would have been interesting if the study had a "nothing" arm. 

In the end, this study truly emphasizes the need for clinicians to be vigilant and emphasizes the value of taking a critical look at the medical literature. If one was not aware of the study’s primary outcome, one might be convinced there is no role for paracetamol for low back pain. This is far from the truth. Nevertheless, I don’t think anyone is deluded that paracetamol does very much. But at least it is cheap, has a low side effect profile and might help for a little bit for a brief period of time.

What’s the take home message? Paracetamol is still fine for low back pain and beware what you hear on the radio.


Williams CM, Maher CG, Latimer J, et al. Efficacy of paracetamol for acute low back pain: a double-blind, randomised controlled trial. Lancet 24, 2014;  [Epub ahead of print]


Williams CM, Latimer J, Maher CG, et al. PACE--the first placebo controlled trial of paracetamol for acute low back pain: design of a randomised controlled trial. BMC Musculoskelet Disord 2010;11:169

Thursday 14 August 2014

Half of all IV’s in an ED are Unused? Could this be true?

A recent paper published in Annals of Emergency Medicine makes the claim that half of all peripheral IV’s placed in an Australian ED were unused. Could this be true? Well, maybe... and maybe not. Either way, this paper got a lot of attention and is certainly worth a closer look.

In the paper’s introduction, the authors point out the harms of peripheral IV line placement such as time to insert, discomfort, phlebitis and sepsis. This is technically correct but is probably overstated.

To determined how often IV’s went unused, two trained abstractors did a structured electronic medical record review over a one month period. Their EMR has a mandatory field for recording of IV’s inserted in the ED. Unused IV’s were defined as “those that were not used for delivering fluids or drugs, including intravenous contrast, until discharge from the ED.”

How many went unused? Fifty percent! Yes, I can hear the gasps.

But there is a catch. Although not meeting the studies definition of “used”, 92% of patients had bloods drawn at the time of cannulation. In addition, the authors were very correct in emphasizing that this study did not address the difference between unused and unnecessary peripheral IV cannulas.

Yes, we probably overdo IV’s in the ED. But I think this emphasis is a bit of a storm in a tea-cup. There are much bigger issues of waste for us to focus our attention. I would love to see a study that tells us something more important and what we already know (although this would be a very difficult study to define and conduct); half of all blood tests and other investigations in an ED are unnecessary and a waste of time & money. Good luck with this one.


Limm EI, Fang X, Dendle C, et al. Half of All Peripheral Intravenous Lines in an Australian Tertiary Emergency Department Are Unused: Pain With No Gain? Ann Emerg Med 2013;62:521-525.

Tuesday 12 August 2014

Sub-Dissociative Ketamine for pain in the ED? The Enthusiasm Exceeds the Science.

All emergency physicians love ketamine. Under the right circumstances, it is a fabulous agent for procedural sedation and as an induction agent for RSI or DSI.

Recently there has been a lot of enthusiasm to use sub-dissociative doses of ketamine for pain. Everybody seems to be talking up the greatness of ketamine. But this study was a bit different and looked at the intra-nasal administration of ketamine as a primary analgesic agent for adults with moderate to severe pain. Crazy you say? Well, yes probably so.

This was a prospective observational study. To be clear, this was not a trial and did not compare any different analgesic agents. Adult patients with a VAS of >6 were included. There were lots of reasonable exclusion criteria including administration of opiates in the previous 4 hours. Patients were given an initial dose of 0.7mg/kg (this was increased to 1mg/kg after 6 months) with a secondary dose of 0.5mg/kg after 15 minutes if pain did not improve.

The primary outcome was the change in VAS at 30 minutes and the percentage of patients reporting what they called clinically significant reduction in the VAS of >20mm. (This cut-off could certainly be debated.)

A total of 72 patients were included in the data analysis. Unfortunately there was quite a lot of heterogeneity in the painful conditions treated and this may have made the response to therapy different. There were 4 patients with renal colic and I would question the ethics of their inclusion.

The bottom line? It didn’t work very well and there were lots of side effects.

The median reduction in VAS rating at 30 minutes was 24mm. 56% reported a VAS reduction of >20mm. Therefore it failed about half the time (if you take their primary outcome at face value.) I wonder if placebo would have had a similar response.

The satisfaction rate at 30 minutes was 60% which is absolutely abysmal. In general, most people report very high levels of satisfaction in studies regardless of the eventual outcome. This is why it is always a challenge to use changes in satisfaction as a study outcome measure.

About 80% of the subjects reported some adverse events. These were reported to be relatively minor such as dizziness and “spaced out.” But in trauma patients and those with undifferentiated conditions, this might make evaluation quite difficult.

Overall this study definitely provides us with some useful information and the medical student lead author is to be congratulated. Nevertheless, there were a few issues with the methods of statistical analysis (but this is probably irrelevant anyway.) A power calculation was probably not necessary as this was not a trial.

It is a bit difficult to understand the key conclusions as stated in the paper since they are a bit contradictory when comparing the abstract, text and key findings. But I think the data speaks for itself. Sub-dissociative doses of ketamine as the primary agent of analgesia does not work that well and causes lots of side effects. Although not studied here, ketamine may have a role as an adjunct to opiates or in individuals who are chronically habituated.

If the intranasal (IN) route of administration you want, then fentanyl is your drug! Despite the text of the paper, fentanyl is available in Australia in a concentrated vial of 600mcg/2ml and therefore suitable in adults as well as children. I am unaware of any published head-to-head comparison of IN ketamine vs. fentanyl but given previous experience I think this would be an absolute waste of time.

In the end, I don’t understand why we are trying to fix something that is not broken. In general we know that opiates are great drugs as the primary agent for acute painful conditions. There are those that proclaim we need to “spare opiates.” But what is so wrong with opiates? They are a known entity, generally safe, reversible and work in the vast majority of patients when dosed appropriately. Opiates are certainly better when compared to the side effect profile and the lack of efficacy of sub-dissociative ketamine. How about we save our enthusiasm for what we know works.


Yeaman, F, Meek, R, Egerton-Warburton D, et al. Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients. Emerg Med Aust. 2014; 26:237-242.

Thursday 22 May 2014

Being right or being happy: pilot study

I have put the link below to an absolutely brilliant & funny piece published in the last Christmas edition of the BMJ.

I could never do it justice by trying to summarize this two page paper, so please read for yourself!


Arroll B, Goodyear-Smith F, Moyes S, et al. Being right or being happy: pilot study. BMJ 2013;347:f7398

Prehospital Stroke Thrombolysis... OMG!

What do you get when you put a mobile CT scanner, neurologist, radiology tech, paramedic, point-of-care lab, and a telemedicine unit in the back of an ambulance? At best a whole lot of wasted resources for marginal benefit.

The PHANTOM-S trial was conducted in Berlin, Germany and published in JAMA. It was designed to study the use of ambulance based thrombolysis (within 4.5 hours) for stroke as compared to conventional hospital based thrombolysis. The primary outcome was alarm-to-thrombolysis time. (This is obviously not a patient oriented outcome.) Secondary outcomes included overall thrombolysis rate, ICH rate after treatment, and 7 day mortality. Despite the title reporting to be a “randomized” trial it most certainly wasn’t. Not to be pedantic but the JAMA reviewers should know better.

The consent process is interesting to imagine. Think of the conversation and information provided by a neurologist who arrives on your doorstep with a mobile CT scanner and ready with tPA? In addition, they assumed consent in patients unable to communicate. Implied consent is fine if the therapy is of reasonable proven benefit without significant chance of harm. Many would argue that tPA for stroke does not fit this mould.

Results? It is absolutely no surprise that they were able to thrombolyse strokes quicker when it was done in the back of a million dollar ambulance. The mean alarm to treatment time was shortened by 25 minutes as compared to hospital based thrombolysis.

A close look at the data shows that this special ambulance with a stroke team was generally busy. On average they were dispatched 6 times in a (16 hour) day. Thrombolysis was performed in an amazing one third of strokes or about every other day. But in the quest for fast and faster treatment it is certain that they must have been treating a good number of stroke mimics.

The big question one must ask is what happens to the vast majority of patients who get thrombolysis of stroke? Answer...  absolutely nothing. No harm or benefit. If we consider a reasonable number needed to treat of 8 (this number is clearly arguable one way or another) then this fancy ambulance with mobile stroke team perhaps helped one patient about every two weeks. How many of these were actually helped by getting it 25 minutes faster? Regardless if you believe in the efficacy of stroke thrombolysis, it is absolutely clear that this is not an effective use of resources.



Ebinger M, Winger B, Wendt M, et al. Effect of the Use of Ambulance-Based Thrombolysis on Time to Thrombolysis in Acute Ischemic Stroke. A Randomized Clinical Trial. JAMA 2014;311(16):1622-1631.

Measuring CVP? A plea for some common sense.

There was an updated meta-analysis recently published looking at the utility of CVP measurement to predict fluid responsiveness. You can probably guess the answer. If the CVP is low then give them some fluid and they get better... right? Not so fast.

These authors from Virginia and Kentucky performed a typical but good quality systematic review. They were looking for clinical trials that reported the correlation coefficient or area under the curve (AUC), between CVP and change in cardiac performance following an intervention that altered cardiac preload. 43 studies were eventually selected for data abstraction. The vast majority were small studies conducted in an ICU or operating room and none were done in an emergency department. Most patients got a small bolus of colloid. Cardiac output was measured using various means.

Results? 57% of patients were fluid responders. The summary AUC was 0.56. This is as good as flipping a coin. The summary correlation coefficient was a terrible 0.18. (1.0 would be considered perfect and 0 is no correlation.)

The authors conclude that there is no data to support the widespread practice of using CVP to guide fluid therapy and it should be abandoned.

This looks to be quite definitive. The Achilles heel of a meta-analysis is negative reporting bias. One should be quite cautions of “positive” meta-analysis, but one that tells you something doesn’t work is believable.

 I would most certainly not place a central line for the sole purpose of CVP measurement. Many would argue that they only real reason for placing one would be for administration of noradrenalin (norepinephrine).

With the widespread uptake of point-of-care ultrasound I can’t imagine relying on a CVP measurement to guide therapy. One only needs to non-invasively take a quick look at the IVC (and probably the lungs and heart while you are there) to get an idea of fluid status. Sure, this is far from perfect. But it probably works well at the extremes (when it’s important) and will certainly avoid the morbidity of central line placement.



Marik PE, Cavallazzi R. Does the Central Venous Pressure Predict Fluid Responsiveness? An Updated Mea-Analysis and a Plea for Some Common Sense. Crit Care Med 2013;41:1774-1778.

Wednesday 21 May 2014

Corneal abrasion? Yes you can take that topical anesthetic home!

For over twenty years I have heard that you can’t let patients go home with topical anaesthetic drops for treatment of their corneal abrasions. The fear is that this would somehow delay wound healing and their eyeballs would spontaneously combust and melt away.

Therefore I was more than pleased to see this double-blind randomized clinical trial conducted in an actual Emergency Department. Is undiluted topical tetracaine safe for the treatment of pain caused by corneal abrasions?

The lead author Dr Neil Waldman FACEM is to be absolutely congratulated for this undertaking. This trial was conducted in shiver-me-bones Invercargill, New Zealand. Anybody who is up on their geography knows this smaller regional community is located closer to Antarctica than anywhere else.  Conducting high quality research outside of a major tertiary centre is always challenging. It is quite clear that a lot of personal time, energy and effort went in to pulling this off.

The hypothesis of the study was that undiluted topical tetracaine would be safe for patients with corneal abrasions to use for 24 hours. Inclusion criteria were corneal abrasions, ultraviolet keratitis, and post foreign body removal (i.e. rust rings). Patients were randomised to tetracaine or saline and all got topical chloramphenicol ointment. The primary outcome measure was “safety” as measured by persistent fluorescein uptake of the abrasion at 48 hours and the occurrence rates of any prespecified complications. Secondary outcomes looked a reduced pain on a self reported VAS and an overall effectiveness score.

The results? 116 patients were included in the study. The conclusion was that topical tetracaine used for 24 hours is safe; the VAS pain score showed no difference but patient surveys on overall effectiveness showed patients happier with the tetracaine.

There is no such thing as a perfect study and to be honest, this one was a little sloppy. One would need to recruit many more patients than 116 in order to make any claims about safety. In fact, it is usually not feasible to conduct an RCT with a primary outcome of safety in mind. RCT’s usually focus on efficacy whereas large cohort studies have the statistical power to make claims about safety. So it is not surprising to see a confidence interval of up to 6.1% for this primary outcome.

There were a few other issues. The power calculation was backwards and not really followed anyway. The blinding was not that good, patients were lost to follow up, rust rings were a confounder, the self reported VAS was probably not an accurate measuring tool and the title is a bit misleading.

Despite off of this, I really like this paper. The literature search included in the discussion could not find any good quality evidence of harm in previous studies.  I like the conclusion of this paper and it will very likely change my practice. I am happily going to send patients home with corneal abrasions and some drops of topical anaesthetic.  It goes to show that important & meaningful clinical research can be conducted in smaller centres without much support. Well done!


Waldman N, Denise IK, Herbison, P. Topical Tetracaine Used for 24 Hours is Safe and Rated Highly Effective by Patients for the Treatment of Pain Caused by Corneal Abrasions: A Double-blind, Randomized Clinical Trial. Acad Emerg Med 2014;21:374-382.

The ProCESS Trial and the official burial of EGDT

Not quite ten years ago I conducted a multidisciplinary journal club looking at the original Rivers study on Early Goal Directed Therapy for sepsis. Despite the EM community embracing this new concept, my critical care colleagues were certainly less impressed. Well to be fair, they absolutely lambasted the study and could not believe that any reasonable person would change their practice based on one small study conducted in a single institution showing an unbelievably large treatment effect. After all, they had been conducting their own studies of ICU goal directed therapy for years to no avail.

It has taken over a decade for another more definitive RCT looking at EGDT in the form of the much publicised ProCESS trial. The authors are to be congratulated for their efforts. In a nutshell, they conducted a large multicenter RCT at 31 emergency departments in the USA. Patients with septic shock were randomly assigned to one of three treatment arms; the Rivers EGDT, protocol based standard care (without mandates for central lines, pressors or blood transfusions), or usual care (whatever the doctor wanted to do). The primary outcome was in-hospital mortality at 60 days. I think we all know the results showed no difference with mortality around 20% in all three groups. More patients in the EGDT went to the ICU, got transfusions and dobutamine. EGDT is officially dead.

To be fair, EGDT has been dying a death of a thousand cuts since it was originally published in 2001. There has been a mammoth amount of research and emphasis on sepsis care since its release and modifications of the original protocol have been ongoing. There still are two more large RCT’s yet to come from the UK and Australia so perhaps we still have more to learn.

I have always concerned about the resource implications of EGDT. In particular the harms it might create especially in smaller ED’s by diverting attention away to perform far from proven tasks. In the end it looks like early recognition, aggressive fluids and early antibiotics are still the mainstay of care- surprise, surprise.

There is no doubt this study will change the guidelines as put out by the Surviving Sepsis Campaign. But I don’t think there is any reason to wait for their formal recommendations. After all this “campaign” was originally created and funded by a public relations firm hired by Eli Lily in order to promote their now defunct drug Xigris. Shame on us...

What is the take home message? Please, please, please be sceptical of small studies showing large treatment effects especially when they show the unbelievable. Now scoop some dirt on the coffin of EGDT... too good to be true.


Yealy, DM, Kellum JA, Huang DT, et al. A Randomized Trial of Protocol-Based Care for Early Septic Shock. N Engl J Med 2014;370(18):1683-1693.

Friday 18 April 2014

Welcome to EmergencyMedJC

The following posts are short and pertinent summaries of interesting articles discussed at our multi-disciplinary journal clubs in our area. We are a small Emergency Department located in regional Tasmania and as such we have the fortune of combining our meetings with other departments throughout the hospital. The different perspectives are worth their weight in gold and provide insight beyond the typical dedicated EM journal club. I thank my colleagues for their support and input. Much of what I post are the highlights from the discussion and certainly I cannot claim all of it as my own.

I endeavour to keep each post short and hit the key points. In order to maintain interest, I purposely do not mention every last detail of the methodology, statistics & results. Rather I have tried to filter out the best parts and hope readers find this educational and practical.  

I very much appreciate any feedback or suggestions. Enjoy!



Which blood test is the best at identifying serious bacterial infection (SBI) in febrile children without a source?

In the new era of widespread childhood immunization the rates of SBI in children has been plummeting. Hib and PCV7 vaccine have made our lives almost boring in the ED. When was the last time you saw a good case of pediatric epiglotitis? Have you even heard of buccal cellulitis? Well, at least vaccination has been good for kids.

But widespread immunization has also created a diagnostic problem for us. The prevalence of serious bacterial illness is now so low it is a kin to finding a needle in a haystack. Imperfect clinical acumen will certainly find more false positives than true positives. Or perhaps we will just get complacent and call everyone negative until it’s too late. We really don’t want to be missing something serious. I wish there was a blood test to help us.

Along comes a well done systematic review and meta-analysis published in the Annals of Emergency Medicine looking at the old favourites WBC, CRP and the new kid on the block procalcitonin. Which one is best at picking up SBI?

After a good systematic review, 8 studies were included for a total of 1,883 patients comparing the three blood tests. The primary outcome was the ability to detect SBI in children with fever without a source.

Right off the bat there is a problem with the definition of SBI. Included are some rare but serious conditions such as meningitis and sepsis. But also included are UTI, gastroenteritis, pneumonia and occult bacteremia. Cynics might proclaim, “If the bacteremia is so occult, then why should I care?” Do I really need a blood test to help me identify pneumonia, gastroenteritis or UTI’s? Shouldn’t I have picked up on this by other means? How many of the UTI’s were really false positive? As is the case in many of the studies of SBI, the majority had UTI as their “serious” illness.

In the end procalcitonin was the best of the worst. Its point estimate of sensitivity was 0.83 and specificity 0.69. Despite getting bigger numbers to crunch in this meta-analysis the confidence interval for sensitivity was as low at 0.70. CRP was hardly better. WBC was as good as flipping a coin. One might reasonably ask if this is good enough.

Another concern is these studies are performed in a heterogeneous population. These tests likely perform better at the more extreme spectrum of disease. I am not looking for a blood test to help me when it is quite clear one way or another if a child is sick. I want to know if it can help me when I’m on the fence. Therefore these tests may perform worse in the exact situation when I want to use them the most.

So what’s the take home point? At best these tests are a piece of the puzzle when evaluating the child without a source of fever. We should never use them in isolation or be overly reliant upon their ability to change our medical decision making. It is unusual for them sway my cognitive process in the ED. Believe it or not, I actually have the patient in front of me. Sometimes I can admit them or observe them for a period of time... crazy.


Yo Hc, Hsieh PS, Lee SH, et al. Comparison of the Test Characteristics of Procalcitonin to C-Reactive Protein and Leukocytosis for the Detection of Serious Bacterial Infections in Children Presenting With Fever Without a Source: A Systematic Review and Meta-analysis. Ann Emerg Med 2012;60:591-600.

Thursday 17 April 2014

Single dose dexamethasone for asthma?

In the chaos of the Emergency Department, I love to keep things simple. Nothing makes me happier than to be able to give a single dose of a drug to cure a particular condition. No need for a prescription and no need to worry about medication non-compliance. Acute exacerbations of asthma are such a ubiquitous presentation that I have longed hoped that a single dose of dexamethasone would be sufficient to effect a cure in suitable outpatients. I have been looking for data to support my “hypothesis” for some time now. Perhaps we have found it in the form of a recent systematic review and meta-analysis published in the journal Pediatrics.

Six randomized trials were identified after an explicitly defined search of Medline looking at dexamethasone vs. prednisone/prednisolone for the outpatient treatment of asthma. The primary outcome was return visits or hospital readmissions. As is the potential weakness of meta-analysis, there was some heterogeneity in the studies identified. Dexamethasone was given as a single IM dose in 3 studies, as a single oral dose in 1 study and as multiple oral doses in 2 studies. Therefore combining them may be problematic.

Nevertheless, there were no differences in relative risk in the primary outcome and the conclusion was “practitioners should consider single or 2-dose regimens of dexamethasone as a viable alternative to 5 days of prednisolone/prednisone.”

The whole point of a meta-analysis is to combine similar smaller studies in order to have greater statistical power to detect differences between groups. In addition, this greater number gives you better point estimates, narrow confidence intervals and allows you to look at subgroups that may have been impossible had the studies not been combined. Unfortunately this meta-analysis only included ONE small study with 117 patients that gave a single dose of oral dexamethasone (0.6mg/kg up to 18mg). Perhaps the jury is still out.

Whats the bottom line? I like the conclusion. I like the fact that it is printed in pretty font in a high impact journal. This may provide me with greater confidence (perhaps bravado) when prescribing a single dose of dexamethasone for outpatient asthma. But the monkey on my back has me worried that there still is a lack of high quality evidence to support this practice. A single large good quality RCT will trump a meta-analysis any day. Can someone please chuck a banana to the monkey and conduct a large RCT?


Keeney, GE, Gray MP, Morrison AK, et al. Dexamethasone for Acute Asthma Exacerbations in Children: A Meta-analyisis. Pediatrics 2014;133:493-499

Tympanostomy tube and otorrhea. Which treatment is best?

This well done open label randomized published in the NEJM comes to us from the Netherlands. Parts of Europe and Scandinavia have long had a more enlightened & conservative approach to acute otitis media. But this condition is a little different. I think we have all had the young child with tubes (grommets) in their ears who now has fluid (or pus) discharging from the ear. Should we put them on oral antibiotics, topical drops or adopt a wait and watch approach? This is a useful question to answer.

This study randomized children in a 1:1:1 fashion to hydrocortisone-bacitracin-colistin ear drops, or augmentin (think diarrhea) or initial observation. The primary outcome measure was the presence of otorrhea at 2 weeks as determined by otoscopy by a study investigator.

There were 230 patients enrolled. The results showed a fantastic treatment effect of the topical drops. At 2 weeks only 5% of the children randomized to drops had otorrhea as compared to 44% in the Augmentin group and 55% in initial observation.

There are perhaps a few issues of external validity when interpreting this paper. The specific ear drops studied are only available in the Netherlands and France. Nevertheless, there likely are similar drops around the world that do not contain ototoxic aminoglycosides. The study protocol involved quite a lot of home visits which may have provided extra insensitive for medication compliance.

The primary outcome is interesting and of dubious importance. The reason for placement of typmanostomy tubes is to allow for the drainage of the middle ear. Therefore drainage could be considered a normal and perhaps desirable process in the setting of otitis media. Of course one might be concerned about prolonged otorrhea and inflammation. But it is hard to know if this is a meaningful outcome.

I think the biggest issue of concern is the general caution that should come when looking at small studies showing dramatic treatment effects. These are almost always shown to be less impressive on subsequent study.

What are the take home points? Despite some of the above concerns, this is a compelling study. I doubt that the drops really work as well as this small study suggests. But now I find myself searching for the appropriate drops the next time I see that kid with tympanostomy tubes and pus flowing from ear.


M.A. va Dongen T, J.M.G. van der Heijden G, Vanekamp RP, et al. A Trial of Treatment for Acute Otorrhea in Children with Tympanostomy Tubes. N Eng J Med 2014;270:723-33.


Cough and Cold? Getting a better nights sleep with Vick's Vapo Rub?

It is great to see the eye’s of science peer down on a consumer product as old and ubiquitous as Vicks Vapo Rub. A recent randomized trial in the journal Pediatrics looked at the effect of vapor rub, petrolatum (petroleum jelly), or no treatment for children with nocturnal cough symptoms. As the parent of small children who currently have colds, I want to know the answer. Which works best?

Surveys (6 questions on a 7 point Likert scale) were administered to parents on 2 consecutive days. The first was done on the day of presentation to a pediatric clinic before medication was given. Children were randomised to get one of the above treatments. Then the next survey was completed the following day by the parent self report who hopefully had a better night’s sleep

I already know what you are thinking? How did they blind Vapo Rub? Believe it or not, the study design cleverly asked parents to place Vapo Rub below their nose before opening the study packet which contained the randomised medication. (I wonder how many actually performed this requested step!? ) In addition, they asked the children not to disclose to their parents whether the treatment had an odor. Despite these efforts, the parents were able to accurately identify the actual treatment arm 90% of the time.

The results? 138 children completed the trial. Vicks Vapo Rub consistently scored the best and no treatment was the worst.

Unfortunately it is hard to really get a sense of how much the Vapo Rub actually works given the nature of the complex Likert scale utilized as the outcome measure.

Obviously there could have been some bias introduced due to lack of blinding. Do smelly placebos work better? Once again, this was a self completed survey by the parent.

In addition, this study was industry funded! It was supported by an unrestricted grant from Procter & Gamble and the lead author has been a paid consultant for company. Is nothing else sacred in this world?

This study is far from definitive. I would be disappointed but not overly surprised if I saw direct to consumer advertisements for Vapor Rub stating it is “clinically proven” to decrease nocturnal cough and cold symptoms in children.

What will I do with my kids? I’m busting out the Vapo Rub! Yes the science isn’t perfect but if the parents said they all slept better than what am I to do. If my evidenced based sceptical head is sleeping on a pillow made of placebo, then so be it.


Paul IM, Beiler JS, King TS et al. Vapor Rub, Petrolatum, and No Treatment for Children With Nocturnal Cough and Cold Symptoms. Pediatrics 2010;126;1092-1099.

How much IV fluids should we be giving children in DKA in order to avoid cerebral oedema (CE)?

The pathogenesis of CE in children with DKA is controversial. There are those who propose that it is caused by excessive administration of IV fluids and cerebral osmotic shifts. Alternatively it might be caused by cerebral hypoperfusion and reperfusion during DKA treatment. Should we be giving more fluid or less fluid… Who knows?

In an ideal world, we would answer this question by conducting a large randomized control trial in the sickest subset of children. These are the kids who develop CE. We would randomize two groups. One gets lots of fluids and the other not so much. The primary outcome would be death as this is usually caused by cerebral oedema. Unfortunately such a study would be near impossible to conduct given the rarity of clinical apparent CE in children with DKA.

The authors of this paper perhaps tried the next best thing. They conducted an RCT using 2 different rehydration protocols (but some would argue were not that different). In the end, one group got 60ml/kg and the other 40ml/kg in the first 8 hours. They used the “apparent diffusion coefficient” on serial MRI’s as a surrogate marker to look for cerebral oedema.  All of kids recovered well.

The conclusion of the paper? Cerebral oedema does not appear to be substantially affected by the rate of IV fluid administration.

But hold on a minute… There were only 18 children included in this study. Clearly there would have only been enough statistical power to find very large differences in the study arms. In addition, one might question the validity of the surrogate marker looking for subclinical CE. The conclusion as written in the paper clearly overstates any reasonable interpretation of this study.

In the end, this paper raises more questions than it answers. It certainly would raise the hypothesis (again) calling for a large RCT which will probably never happen.

Before we get too critical, we should remember that the lead author, Dr Nicole Glaser, a professor of pediatric endocrinology at UC Davis has done some fantastic work well over the past decade looking at this subject. (Remember NEJM 2001;344(4):264-269?) This is a very challenging niche of research and we see look forward to see more of her work.



Glaser NS, Wootton-Gorges SL, Buonocore MH et al. Subclinical Cerebral Edema in Children With Diabetic Ketoacidosis Randomized to 2 Different Rehydration Protocols. Pediatrics 2013;131;e73-e80.