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!

Covering:

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

http://www.bmj.com/content/347/bmj.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.

 

Covering:

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.

http://www.ncbi.nlm.nih.gov/pubmed/24756512

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.

 

Covering:

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.

http://www.ncbi.nlm.nih.gov/pubmed/23774337

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!

Covering:

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.

http://www.ncbi.nlm.nih.gov/pubmed/24730399
 

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.

Covering:

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.

http://www.ncbi.nlm.nih.gov/pubmed/24635773

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!

Brian

Brian Doyle, MD FACEM FACEP

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.

Covering:

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.

http://www.ncbi.nlm.nih.gov/pubmed/22921165