The ProCESS Trial

This trial is kind of big news. Big news in the way TTM was. Be sure to get the paper (which is free for now) and the supplement that goes with it.

There has already been some great discussion online so be sure and check it out.

So there’s no shortage of great editorialising already out there.

That being said, I wrote most of this on the plane on the way home from SMACC so figured I may at least get it out there.


Sepsis is big and sexy in critical care. It covers a huge range of patients and has turned individual conditions into one clinical syndrome. This in itself is controversial. Why should we treat pneumonia and gall bladder sepsis with the same bundle. While sepsis evangelism has undoubtedly raised awareness and probably improved care are we dumbing it down? Anyhow, that’s a little bit off topic.

For now the big focus in ED sepsis research is on working out which parts of a bundle of care that includes very different interventions actually makes a difference. Do we need central venous oxygen saturations or is it as simple as antibiotics and fluids? (Never mind the question of which and how much fluid…)

One of three trials (ARISE and PROMISE still to come) looking at early sepsis management, this is the US led version.


  • multi centre RCT, non blinded (as expected, it’s difficult to blind an Edwards catheter)(though as is good practice, the investigators were blinded when doing the analysis)
  • note that these were big academic centres and a requirement to get your centre into the study was use of lactate to screen for cryptogenic sepsis and adherence to the SSC guidelines. The SSC guidelines are not endorsed by Australasia as far I’m aware so this in itself might be a marked difference in practice. What do you think?
  • to get into the trial you had to be early in your sepsis course and have had a decent bolus of fluids
  • three groups:
    1. a protocol based on rivers EGDT model
    2. a protocol  based on international opinion
    3. usual care which would be whatever the doc would normally do.
  • These protocols are as always in a supplementary appendix which you have to search for separately. This is an real personal bug bear of mine –  everyone is reading this electronically and keeping the appendix separate for space saving reasons seem poor form
  • Lead investigators could enrol and manage patients in both protocol based groups but not in the usual care group. I understand why but being looked after by a leading researcher in sepsis is an intervention in itself. [See EMCrits discussion of this on the podcast]
  • primary outcome was in hospital death.
  • they powered the study on the assumption that they’d have a 30-45% mortality (as was the case in the Rivers trial), as happens in a lot of trials this overestimated how sick their patients would be.


  • 31 centres screening 12000 pts and got 1300.
  • no difference in primary outcome (60 day in hospital mortality) 21% v 18.2% v 18.9% for EGDT, protocol, usual care respectively.
  • they report a significant difference in fluid administration but I don’t think the difference is clinically significant. [EMCrit agrees even though the lead author sees a big difference in the three groups] We’re talking a litre difference between the most and the least with the other group half way between. If one group was 6l and one was 2l then that would seem to me a clinically significant difference. Note that the paper reports the numbers as 2.3, 3.3 and 2.8. These figures don’t include the mandatory fluid bolus that was pawrt of the inclusion criteria. So in reality it was more like 4-5 l in each group (HT EMcrit and WessexICS for pointing this out top me.
  • there was a bump in renal failure in the protocol based group but this may well be just noise
  • the only other big difference that caught my eye was differences in transfusion with 10% in the EGDT group and minimal in the other.
  • there was slightly more use of vasopressors in the two protocol used groups but not much.
  • there was an understandably big difference in central line usage. The EDGT protocol mandated a central line whereas the other two left it up to the doc essentially.


  • one big issue here is that it might be difficult to find clear water between the groups. If group 2 was developed following international consensus then it will draw on the principles of group 1 Group 3 will likely be the same as group 2 (a doc doing usual care will hopefully be practising in a manner consistent with international standards) This failure to have a major difference between all 3 groups will make it difficult to find an outcome difference between the three.
  • as a result I didn’t expect a big difference in outcomes as I don’t really think they were treated that differently.
  • maybe if the population had been sicker you might be able to draw out a difference.
  • when i deal with a septic patient I use a number of factors to guide my resus. This includes what happens to the lactate and even an ScvO2 if the line is in. Most docs who manage sepsis have some goal in mind that they’re targeting. Maybe all the goals are roughly equal, or if not equal then at least ‘good enough’ to get these outcomes

PK Talk for SMACC 2014

Here’s my PK talk for SMACC for 2014. The PK talks for those who can’t remember are short, snappy focused presentations on anything – the SMACC ones are of course focused on critical care.

I presented the same material at our  joint ICU/ED meeting a few days ago so I figured I may as well share it as a PK.

Genuinely intersted as to whether people are aiming for the higher MAPs in SCI. Was news to me and no one in our department was that impressed by it. The studies aren’t wonderful after all.

For those interested here’s last years PK too.

See you at SMACC Gold people!

Low yield from cardiac stress testing for ED patients

Title says it all. And it’s all been said before. David Newman is unsurprisingly involved in this paper and the SMART EM on this is well worth your time.

What they did:

  • prospective data on their chest pain unit with some chart review (with good but not fully described methods)
  • their routine was a 6 hour rule out then EST if possible or nuclear testing (which we don’t seem to do much of over here)

What they found:

  • mainly young patients (50) and mainly female and lots of hypertensives
  • about 80% were considered intermediate risk. Which is interesting in itself seeing as so many ended up discharged with negative tests
  • of the 4000 with stress tests ,470 had positive tests
  • ultimately about 130 got angios and only half of them had obstructive disease
  • only 28 got appropriate intervention as defined by cardiology guidelines. Lots of other people got stents but probably shouldn’t have.

Their discussion includes this phrase

While AHA guidelines suggest that provocative testing risk stratifies patients to a potentially near-zero short-term adverse event rate, there is increasing recognition that a negative result on serial bio-marker evaluation (typically a prerequisite for provocative testing) may also achieve this goal, making further risk stratification attempts redundant or inherently difficult.


Hermann, Luke K, David H Newman, W Andrew Pleasant, Dhanadol Rojanasarntikul, Daniel Lakoff, Scott A Goldberg, W Lane Duvall, and Milena J Henzlova. “Yield of Routine Provocative Cardiac Testing Among Patients in an Emergency Department-Based Chest Pain Unit: Yield of Stress Testing in Emergency Department Observation Units..” JAMA Internal Medicine (May 20, 2013): 1–6. PMID 23689690

Long term follow up on IST-3

I read this a few months back and forgot to post something on it. It’s not headline data the way IST 3 was but it’s worth knowing it’s out there. This is the long term (by which they mean 18 month) follow up on IST 3. The original trial has been written about and discussed fairly extensively on the FOAMed sites.

What they found:

  • they got around 2000 or so because only certain countries did follow up.
  • for those available they managed to follow up on the vast majority
  • the follow up was mainly phone and postal so not that great.
  • 30% knew which drug they got which they try to play down but given that the supposed benefit is so small then any recall may cause the difference
  • they do find about a 3.6% difference in alive and independent at 18 months favouring tPA (as pointed out by Brandon in the comments)
  • there’s a great Kaplan Meier curve showing early harm from TPA and then completely flat with placebo from then on. It’s behind the pay wall unfortunately but worth looking at
  • there was no difference in alive and independent at 18 months

“the unadjusted absolute difference in the number of patients alive and independent at 18 months was not significant”

So just to summarise that. A third of the patients knew which group they were in (nothing versus the fancy new drug) and ultimately there was no difference at 18 months.


“Effect of Thrombolysis with Alteplase Within 6 H of Acute Ischaemic Stroke on Long-Term Outcomes (the Third International Stroke Trial [IST-3]): 18-Month Follow-Up of a Randomised Controlled Trial.” The Lancet Neurology (June 2013). PMID 23791822

The 3MG Trial

Didn’t even know this trial was being done till Simon Carley posted on it. It came just too late to be added to be talk on the Crashing Asthmatic but there you go.

Here’s my two cents on the trial

Goodacre, Steve, Judith Cohen, Mike Bradburn, Alasdair Gray, Jonathan Benger, and Timothy Coats. “Intravenous or Nebulised Magnesium Sulphate Versus Standard Therapy for Severe Acute Asthma (3Mg Trial): a Double-Blind, Randomised Controlled Trial.” The Lancet Respiratory Medicine 1, no. 4 (June 2013): 293–300. doi:10.1016/S2213-2600(13)70070-5.


  • UK publicly funded
  • 34 EDs involved in the UK
  • acute severe asthma (remember it’s not that hard to get into that category)
  • specifically excluded those with life threatening features
  • centrally randomised and reasonable description of blinding
  • each pack had nebs and an infusion
  • IV Mag (2g) v 3 Mg Nebs v placebo
  • all dummys so it looked like everyone gets the same
  • treated as per SIGN and BTS guidelines, though I didn’t see details of how many salbutamol nebs they got etc…
  • two primary outcomes
    • hospital admission either at the time or within 7 days or
    • a change in breathlessness on a VAS


  • Big trial – 1000 folk, average age 35 or so. This is important as a trial this size is unlikely to be equaled.
  • about 75% admitted, no one died in the ED. 2 died overall (not sure why)
  • powered to detect a 10% difference in admission rates and there was only about an 6% difference favouring IV Mag. This didn’t reach stat significance of course.
  • Neb Mag didn’t seem to do much of anything
  • 7 of 1000 needed intubation emphasising how “severe” acute severe asthma is
  • Standard treatment with beta agonists and steroids was awesome as you can see in the placebo group.


  • to be honest this is hardly surprising. I’ve rarely, if ever, seen magnesium work like a magic drug. I’ve always given it cause it’s benign (which this trial reinforces) and there was some support for its use. That was enough for me. It’s hardly surprising that the trial was negative but I suspect the small improvement that is there is real but is just that – small. 
  • having never used nebulised Mag, I’m now not about to start.


I had some correspondence from the author of this paper [free full text] regarding the ‘atrial calming’ effect of magnesium. I certainly gave lots of IV magnesium for patients in fast AF. Usually not for the ‘lone AF’ patients, but the sickies with pneumonias and deranged electrolytes. I’d never considered that the supposed rate control effect of magnesium might be useful in the asthmatic to help control the slightly ridiculous tachycardia you get if you’re doing it right.

As mentioned, the paper is free and well worth a read.