Fluids and Vasopressors in Sepsis, Wechter et al, CCM Journal: Anything Useful? #FOAMed, #FOAMcc

A couple of articles on fluid resuscitation worth mentioning. Not necessarily for their quality, but because they will be quoted and used, and critical appraisal of the content and conclusion is, without a doubt, necessary to us soldiers in the trenches.

The first one, Interaction between fluids and vasoactive agents on mortality in septic shock: a multi-center, observational study, from the october issue of the CCM Journal (2014) by Wechter et al, for the Cooperative Antimicrobial Therapy of Septic Shock Database Research Group, is a large scale effort do shed some light on one of the finer points of resuscitation, which is when to initiate vasopressors in relation to fluids in the face of ongoing shock/hypotension.

So they reviewed 2,849 patients in septic shock between 1989 and 2007, trying to note the patterns of fluid and vasopressor therapy which were associated with the best survival.  They found that survival was best when combining an early fluid loading, with pressors started somewhere in the 1-6 hour range.  I do invite you to read it for yourself, it is quite a complex analysis with a lot of permutations.

So…is it a good study?  Insofar as a retrospective study on a highly heterogeneous bunch of patients, I think so. But can I take the conclusion and generalize it to the patient I have in front of me with septic shock? I don’t think so. In all fairness, in the full text conclusion the authors concede that this study, rather than a clinical game-changer, is more of a hypothesis generator and should prompt further study. That, I think, is the fair conclusion.

In the abstract, however, the conclusion is that aggressive fluid therapy should be done, withholding vasopressors until after the first hour.  This is somewhat of a concern to me, since it isn’t uncommon for some to just read that part…

So why is this not generalizable?  First of all, I think that the very concept of generalizing is flawed.  We do not treat a hundred or a thousand patients at a time, and should not be seeking a therapeutic approach that works best for most, but for the one patient we are treating. Unfortunately, this is the inherent weakness of any large RCT and even more so in meta-analyses, unless the right subgroups have been drawn up in the study design.

Let me explain.

Patient A shows up with his septic peritonitis from his perforated cholecystitis. He’s a tough guy, been sick for days, obviously poor intake and finally crawls in. If you were to examine him properly, you’d have a hard time finding his tiny IVC, his heart would be hyperdynamic, his lungs would have clear A profiles, except maybe for a few B lines at the right base. You’d give him your version of EGDT, and he’d do pretty well. A lot better than if you loaded him with vasopressors early and worsened his perfusion. Score one for the guideline therapy.

Patient B shows up with his septic pneumonia, also a tough guy, but happens to be a diabetic with a past MI. He comes is pretty quick cuz he’s short of breath.  If you examine him properly, he has a big IVC, small pleural effusions, right basal consolidation and B lines in good quantity. He gets “EGDT” with an aggressive volume load and progressively goes into respiratory failure, which is ascribed to his severe pneumonia/ARDS, but more likely represents volume overload, as he was perhaps a little volume responsive, but not volume tolerant. An example of Paul Marik’s “salt water drowning.” (http://wp.me/p1avUV-aD) Additionally he goes into acute renal failure, ascribed to severe sepsis, but certainly not helped by the venous congestion (http://wp.me/p1avUV-2J). If he doesn’t make it, the thought process will likely be that he was just so sick, but that he got “gold standard” care. Or did he?

It may very well be that the studied group may include more Patient A types, and less B types, whose worse outcome will be hidden by the “saves” of the As. If you have a therapy that saves 15/100 but kills 5/100 you still come out 10/100 ahead… Great for those 15, not so much for the 5 outliers.

We, however, as physicians, need to apply the N=1 principle as we do not treat a hundred or a thousand patients at a time. I would not hesitate to be much more conservative in fluid resuscitating a B-type patient, regardless of the evidence.

Unfortunately, until trials include a huge number of important variables (an accurate measure of volume status, cardiac function, capillary leak, extravascular lung water, etc), it will be impossible to extrapolate results  to an individual patient.  These trials will, I suppose, eventually be done, but will be huge undertakings, and I do look forward to those results.

So, bottom line?

It’s as good a study of this type as could be done, but the inherent limitations make it of little clinical use, unless your current practice is really extreme on fluids or pressors. What it will hopefully be, however, is an onus to do the highly complex and integrative trials that need to be done to determine the right way to treat each patient we face.







Lawrence Lynn says:

Excellent post. This thoughtful quote should be read and understood by every sepsis trialists!!

“We do not treat a hundred or a thousand patients at a time, and should not be seeking a therapeutic approach that works best for most, but for the one patient we are treating.”

This single quote exposes the delay in progress caused by the ubiquitous oversimplification which defines present sepsis clinical trials. Bacteria (and viruses) generate “extended phenotypes” which are manifested in the host. These phenotypes combine with the phenotypic host response to produce the range of “dynamic relational hybrid phenotypes of bacterial and viral infection”. These hybrid phenotypes are also affected by the innoculum and/or the site of infection (vis-à-vis, your example of peritonitis).

Certainly Wechter et al and the Cooperative Antimicrobial Therapy of Septic Shock Database Research Group should be commended for beginning the process of moving toward the study of the dynamic relational patterns of complex rapidly evolving disease and treatment.

We are excited to see the beginning of the move of trialists toward the study of dynamic state of disease and treatment. However, before they can help us with meaningful results, trialists will need to study and define the range of “the dynamic relational phenotypes of severe infection” and then study the treatment actual phenotypes. This will not be easy as these organisms have had hundreds of thousands of years of evolution writing the complex genotypes which code for the extended of human infection. Sepsis trailists need to be encouraged by clinicians to rise to the task.

The clinicians must actively teach the trialists, (as you have in your post) that we expect trails which help to identity the therapeutic approach that works best in response to the dynamic hybrid phenotype “we are treating”.

The two linked articles below explain the present oversimplified state of the science of sepsis trails and why we clinicians must teach the trailists not to oversimplify and assure that they move quickly toward the study of the actual dynamic phenotypes of severe infection.



This is a paradigm shift so we, as clincians, must act to teach trailists this move is necessary. Otherwise we will continue to be left with hypotheses, which, while nice, are not useful at the bedside.

Lawrence Lynn



The Clinical Revolution of Bedside Ultrasound: Not Bloodless! #FOAMed, #FOAMus, #FOAMcc

Thanks to @icerman_ex’s sharp eye, just finished reading @EMNerd’s awesome post on bedside ultrasound (http://t.co/y1B5G9RBIv).   I think it casts the right light on bedside ultrasound, and as usual in spectacular prose that is the only #FOAM I know that discusses science so artfully.

There are a couple of things I’d like to add, for those who may be interested.  And, as a disclaimer, I am heavily, heavily biased towards the widespread use of bedside ultrasound. It is a revolution in medicine, undoubtedly the biggest one of the last decades, but, as with any revolution, blood will be shed, and it’s only when the dust settles that our science will be better.

First of all, everyone should understand that due to bedside ultrasound coming into its own in the era of evidence-based medicine, it is being asked to jump through hoops like no other tool has been. Try looking for a randomized trial on the use of the stethoscope… So it is important to keep this in mind as the fine tuning takes place, rather than try to blindly adopt it or toss it out with every new study that comes out.

As Rory points out, the issue isn’t one of accuracy per se, rather than the clinical interpretation of that accuracy – that is, the clinician being able to tune out the noise, just like one would parts of the history or physical that are irrelevant or misleading. The failure to do so will lead to unnecessary interventions or testing.

Another point is that the second generation of bedside sonographers are not inherently the same as the first, who took up the probes to answer clinical questions and created the protocols and algorithms – as always, much kudos to Daniel Lichtenstein, “le premier des pioneers” – whereas the second generation will be a very mixed bag, many of which will carry bedside ultrasound and push it farther, but also many others who will apply what they have learnt without necessarily the same framework.  If you look at the history of medical developments, initial wonders often have subsequent setbacks, until training and practice are fine tuned – take the history of laparoscopic surgery, for instance.

The key point in all this is that proper clinical integration is necessary, and that trainees have to be well mentored by those who do use the tool in a daily fashion, and finally – as always – some good studies in a number of clinical scenarios, so as not to have (only) a pixelated view of the patient.






Jon-Emile says…

Wonderful post:

You know my position on inspiratory IVC collapse [http://pulmccm.org/main/2014/critical-care-review/inspiratory-collapse-inferior-vena-cava-telling-us/]

My problem with the Kenji trial is that is certainly does not [and cannot] tell us if seeing IVC collapse means that a patient will augment their cardiac output in response to a fluid bolus. What their trial tells us is that using less fluids and more pressors in shocked patients probably improves outcomes … but i think few of us doubt that currently [especially in light of the PROCESS trial last spring]. Instead [and i say this facetiously of course] they could have used a random number generator that was weighted to giving less fluids and more pressors instead of bedside ultrasound … and they probably would have received similar results.

It is hard for me to imagine a physiological scenario whereby a patient has a fixed and dilated IVC on ultrasound with respiration [spontaneous, triggered, or passive] but could still be fluid responsive. So when I see a fixed, dilated IVC, I feel fairly confident that fluids should stop [again this does not tell me about the patient’s volume status, as a patient could have a very plump IVC and be volume deplete].

But this physiology is not new and was published by Magder in the early 90s [invariant right atrial pressures with respiration predicted fluid non-responsiveness very well] and also by Pinsky in the early 90s when he found that in post surgical patients that right atrial distending pressure is dissociated from right ventricular end-diastolic volume. Which means that when you see right heart congestion, you have probably already reached cor pulmonale.

The true challenge is IVC collapse … it is affected by many conflicting variables [as you know]; there is probably a good portion of patients who have IVC collapse [especially those on PEEP, triggering the ventilator] who are actually fluid non-responders, yet we push them closer and closer to cor pulmonale needlessly … so until someone finds a better non-invasive physiological solution …

as EM Nerd, so aptly puts it …

“In medicine we frequently propagate half-truths and unsubstantiated certainties.”

Thanks for the post space,


Excellent points!