So this morning a 65yr old man with shock and respiratory failure was admitted to the ICU, hypotensive on levophed and vasopressin, with a lactate over 10.
So, as usual, my first reflex was to reach for the probe to assess hemodynamics. He had been well resuscitated by a colleague, and the IVC was essentially normal, somewhere around 15 mm and still with some respiratory variation. However, scanning thru the liver, my colleague had noted a large hepatic lesion, which on CT scan (non-infused since patient had acute renal failure) the two radiologists argued whether it was solid, vascular or fluid filled.
Having the advantage of dynamic ultrasound, you can tell that there is some fluid motion within the structure, very suggestive of an abcess, especially in the context of severe septic shock:
So the next step was source control:
Pretty nasty. Pardon my french!
We got over 1.5 L of exceedingly foul pus.
Within a couple of hours the lactate dropped to 3 and the levophed was down by more than half.
I think this case illustrates once again, the power of POCUS in the hands of clinicians. While I am certain that the diagnosis would have been made without POCUS, it probably would have taken additional time as the radiologists themselves were debating its nature, and without POCUS, bedside drainage in the ICU would have been out of the question. That liter might still be in there tonight…
For those interested in how to integrate POCUS in their daily rounds, I think I put together a fair bit of clinical know-how and tips in this little handbook.
The only thing I would add to this is a more physiological way to assess the IVC, which I’ve blogged about here. Sadly, I’ve heard a few people stating how they didn’t want to get into the dogma of IVC ultrasound, that it wasn’t reliable, etc. The IVC doesn’t lie. It’s just not a recipe. The IVC findings have to be integrated into the rest of the echo graphic and clinical examination. Trying to use it as a single value is akin to using serum Na+ as a diagnostic test for volume. It works only sometimes.
Please spread among the POCUS non-believers. We’ll convert them, slowly but surely. But the sooner, the better for the patients. Again, there’s no excuse to practice acute care without ultrasound. It’s not right. I’m not saying every probe-toting MD is better than one without, but everyone would up their game by adding POCUS, once past the learning curve!
So today, I had the chance of having a private tutorial with Dr. Thomas Woodcock (@thomaswoodcock) about the glycocalyx and the revised Starling principles. For anyone interested in fluid resuscitation, this is an area you have to delve into. The basic principles we all learned (which are still being taught) are basically the physiological equivalent of the stick man we all started drawing as toddlers: overly simplified and far from an accurate representation of reality.
Now my first disclaimer is that I have been a colloid supporter for many years. My physiological logic for that had been to minimize the crystalloid spillover into inflamed/septic areas, particularly the lungs and abdomen, when those are the septic sources. However, I was likely misled by my education and lack of knowledge about the endothelium.
So I stumbled upon the whole glycocalyx thing a couple years ago, and this prompted me to try more enteral fluids – the only way fluids normally ever enter the vasculature – but little else. Aware that it’s there, but unsure what to do about it.
Now a year and a half ago, Andre Denault, my closest thing to a mentor, casually dropped the line to me about albumin not working. “Don’t use it. It doesn’t act the way we think it does.” But it was a brief chat, and I didn’t get to pick his brain about it. Just a few weeks ago, I discuss with Jon Emile (Kenny), and he’s coming to the same conclusion. Damn. I’m finding it a bit harder to hang on to my albumin use, which is beginning to look a bit dogmatic and religious.
I was really psyched when Jon-Emile mentioned he would like to talk about the glycocalyx. I first blogged about it here, basically when I stumbled on the extensive literature on this huge organ we have been completely ignoring in terms of physiology and therapeutics. It lines our entire endothelium, which is where most of our therapeutic interventions go, and we only heard of it in passing, possibly in histology class as med 1’s. Hmmm. Anyhow, here, Jon-Emile and I talk about it a little, discuss possible clinical implications, but more importantly Jon mentions the relatively new blog of Dr. Thomas Woodcock (@thomaswoodcock), http://www.fluidtherapy.org, who is one of the pioneer clinicians who have studied the glycocalyx, and who is now trying to bridge the bench to the bedside.
I’ve been fortunate enough to get in touch with him and we’re planning to record some discussions soon.
So, in my view, the glycocalyx is a formidable force we have been ignoring, and have been damaging often with our interventions. I’m hoping to see some developments allowing glycocalyx assessment outside of the labs in order to give us the tools to reassess every fluid in terms of the relative damage it does to what is essentially the gatekeeper between the blood and the tissues.
Well, at least this is chosen with good knowledge of its pharmacological properties, right?
Hmmm… 57% peg it as physiological or basic. Only 9% get it right. The pH is 5.6 or so.
So here we have favorite medication used by a lot of people, who use a lot of it, usually in quite ill patients, often acidotic, and who are not aware that the pH is in fact also quite acidotic.
I think it just is an important example on how we need to treat fluids as medications, and not think of them as benign interventions, and by doing so, we’d feel much more obliged to look at what we are giving in terms of composition and quantity, rather than the debonair attitude we have mostly grown up with.
Enteral Fluid Resuscitation in the ER/ICU?For those who did’t come across it, part 1 of this series can be found here: http://wp.me/p1avUV-e8 So back to bringing the basics back to our ultra-tech world… Can I actually use this field technique in my bright and shiny ICU? Can I use oral hydration as a cutting edge therapy in my life-and-death patients? Sounds strange. Sounds like I should be using a precise device which lets me know exactly how much fluid has gone into my vascular space, because that’s where I want it to go, and I want to control exactly the composition of my serum electrolytes, etc, etc. We like to control. But do we really? We actually have absolutely no idea how much of a fluid bolus remains intravascularly, in any one patient. It will depend on his/her pre-existing venous filling, his serum protein levels, the integrity of the glycocalyx, and probably a few more things we don’t even know yet. And as I rapidly distend atria, I release ANP which damages my glycocalyx further. Hmmm… As I mentioned in the last post, the only way fluid enters our vascular space is via the endothelial cells at the level of the GI tract for the most part. All “venous access” is iatrogenic. I do believe that the endothelial cells, by and large, will do a better job – in concert with the kidneys and rest of the blood cells – of controlling the plasma than we will, if given the chance. What logically follows is that, in the presence of a functional gut, I can consider using Enteral Fluid Resuscitation – that is, giving fluid for hemodynamic purposes, not just “maintenance,” by an enteral tube of some sort. So what could I give? What’s in it? The current reduced osmolarity WHO/UNICEF formula contains approximately the following: So, lets take a closer look at the players: 75 mmol/l of sodium, 75 mmol/l glucose, some potassium and the rest basically to balance the electroneutrality. The whole thing hinges on the glucose-sodium cotransporter, which drags sodium and water in along with the “desired” glucose. Optimal water absorption takes place with Na between 40-90 mmol/l, glucose 110-140 mmol/l, and an osmolality around 290. A higher Na may cause some hypernatremia, and a higher osmolality may result in water loss. Here is our friend the enterocyte illustrating just how this kind of solution will allow sodium absorption: Do-it-Yourself Enteral Fluid Resuscitation Solution: So I’ve got a neat DIY option if I don’t want to break out the powder and start mixing in the middle of my unit: 0.45% or 1/2 NS plus 30 ml of of D50 would give us Na 77, Cl 77 and glucose 74, with an osmolality of 228. Pretty close. That’s what I’ve been using. How much? Well, I like the slow and gradual. Some of the rehydration data out there supports some pretty huge amount of fluids, but this has been done mostly in healthy but dehydrated athletes – not the case for most of our patients. I’ve been going with 250ml every 1-2h, as – for now – an adjunct to IV fluid therapy. This is conservative and completely arbitrary, but essentially a glass every hour or two certainly doesn’t seem excessively taxing. Who can I give this to? You do need a functional gut, so for now, my criteria are (1) essentially normal abdominal exam, (2) obviously no recent bowel surgery, (3) a patent and functional gut as far as I know, (4) no ultrasound evidence of ileus or gastric distension. But how can I be sure it’s going in the right place? I can’t. Just like I can’t be sure my IV fluids are staying in the right place. But I do check – IVC ultrasound (gross but better than skin turgor!), urine output, HR, BP, etc. None of those are perfect as they are all multifactorial, but that is the nature of the game. The other thing I check is gastric distension by bedside ultrasound every couple of hours – obviously, if I’m just getting a fluid filled stomach, there’s no point, and eventually harm may ensue. When should I stop? Whenever you clinically decide you don’t need/want any further fluid resuscitation. As far as I am concerned, might as well stop the IV infusions first and have the enteral going after – in the end, you are hoping your patient will go back to drinking and not require a PICC line for discharge, aren’t you? So you stop when the patient does it on his or her own. I’d really like to know if anyone out there is doing something like this. It would be great to compare notes and evolution. Drop a line! cheers, Philippe
So something has been trotting around my head for a few months, and it actually stems from a small and not-so-proud moment I experienced during a conversation with my wife, while she was still a resident.
She was telling me some of the stories of the day, and how one of her supervisors who had a mixed outpatient and ED practice, always pushed them to use PO fluids, get rid of IVs and get the patients home. I kind of scoffed, in a sadly typical acute care physician mode, saying how you had to be a bit more aggressive and give them IV fluids to revert their dehydration a bit faster.
Then I caught myself. Hmmm. What exactly am I saying this (con brio) on the basis of. Knowledge, or belief? I tried to find knowledge but came up woefully short. It seems I’m doing this out of habit, what I’ve seen/learned/believed in the two decades since someone handed me an MD degree. Damn.
So, I do believe in evolution. We have evolved platelets to stop bleeding, fibroblasts and osteoblasts that can fix bones, white cells that go mop up the messes, and all kinds of other good stuff. One thing we do NOT have is small openings in vascular structures that allow unprocessed, man-made fluids directly into the bloodstream. We make these. We insert tubing into normally sterile environment and infuse a vast number of medications directly into this fragile matrix of cells and organic colloid – with the best of intentions.
In our physiology, however, the ONLY way fluid ever enters the vascular spaces is by diffusion from the outside of the endothelial cell into the lumen, molecule by molecule and ion by ion.
So let me seemingly diverge for a bit…
Prior to the 1970’s, restricting oral intake was a “cornerstone” therapy of diarrheal illness, due to the pervasive belief that the GI tract needed time to heal and recover before resuming normal function. This was felt to be crucial. Hence, only IV therapy was used (in developed countries), and in the underdeveloped world, the death toll was appalling – especially among children. In the 40’s, Dr. Darrow of Yale started actually studying the GI tract fluid and electrolyte issue, and advocating oral rehydration with mixed fluids. He was able to bring infant mortality radically down in his practice, but it would take over twenty years before a groups started to formally look at this in the 60’s. Finally, in the late 70’s, the WHO pushed this out into the field, and the childhood worldwide mortality from acute diarrheal illness dropped by over 70%, from over 5 million deaths a year to a bit over 1 million – at that time.
Oral Rehydration Therapy (ORT) is now felt to be one of the most significant advances in modern medicine. Compared to that impact, all the critical care and cardiology trials are about as significant as a drop in a bucket. We’re not talking about composite end points and subgroup odds ratios of 0.85…
For a great review on this check out The History of Oral Rehydration Therapy by Joshua Nalibow Ruxin (google it). A great story of science and humanity, good and bad.
So, back to 2015 ED/ICU’s.
The question now becomes the following: why – in the presence of a functional gut – do I choose to entirely rely on non-physiological IV fluid resuscitation?
I can already hear the roars and the outrage and the cries of heresy. And heresy is certainly what this is (Heresy is any provocative belief or theory that is strongly at variance with established beliefs or customs – Wikipedia). But that doesn’t make it wrong.
So I would ask everyone – particularly the naysayers, to examine their knowledge and see if they actually have any at all that supports the strong conviction that IV fluids are the way to go in ALL cases (my N=1 principle precludes going for the one-size-fits-all therapeutic approach).
Now everyone agrees that, once patients are better, they should be on feeds with little maintenance fluids. I don’t think many will debate that. So that should be the basis to wonder whether, in the presence of a functional gut, a variable proportion of fluid resuscitation in acute illness should be enteral…
So I posted about this a few weeks ago, and the discussion it brought up with Jon-Emile (www.heart-lung.org) turned out to be way better than the original post, and I just wanted to make sure everyone interested got to see it, so here we go (part 1 is here, for those who didn’t come across it:http://wp.me/p1avUV-bJ):
Jon-Emile: This is a great topic for review Philippe!
I have come across this problem, certainly on more than one occasion. I was first introduced to the idea of renal venous pressure and renal hemodynamics as a house-officer at Bellevue Hospital in New York. Dr. Jerome Lowenstein published work on this phenomenon as it pertained to ‘Minimal Change Syndrome.” He used to ‘wedge’ the renal vein and measure renal interstitial pressure in these patients and measured the response to diuresis. It was very enlightening and made me feel more comfortable given more diuretics in such patients. [Am J Med. 1981 Feb;70(2):227-33. Renal failure in minimal change nephrotic syndrome].
I am also glad that you bring up the cranial vault in this discussion, because I have often wondered if the encapsulated kidneys behave in a similar way. That is, as renal interstitial volume increases from edema, if there is some point on their compliance curve [like the cranium] where there is a very marked increase in renal interstitial pressure? I have found a few articles which loosely address this idea, but would be interested if anyone else knew of some. In such a situation, there would be a ‘vascular waterfall’ effect within the kidneys whereby the interstitial pressure supersedes the renal venous pressure [like West Zone II in the lungs]; then, renal blood flow would be driven by a gradient between MAP and renal interstitial pressure [not renal venous pressure]. I know of one paper that addresses this physiology in dogs, and finds the vascular ‘choke point’ to be in the renal venous system and not Bowman’s space.
What’s even more interesting, is that when renal interstitial pressure is elevated is that the kidney behaves in a sodium avid state [i.e. urine electrolytes will appear ‘pre-renal’] and this physiology has been known for at least a century!
Lancet. 1988 May 7;1(8593):1033-5. Raised venous pressure: a direct cause of renal sodium retention in oedema?
There is no good explanation as to why this occurs, but one I read is that the high renal interstitial pressure tends to collapse the afferent arteriole and the decrease in afferent arteriole trans-mural pressure which facilitates renin secretion [just like low blood pressure would]; but that would require a fairly high renal interstitial pressure unless the MAP was concomitantly low.
Again, what I must caution [and I’ve been personally wrong about this] is the reflex to give diuretics when seeing a ‘plump IVC’. When I was treating a woman with mild collagen-vascular-related pulmonary arterial hypertension, community-acquired pneumonia with a parapneumonic effusion and new acute renal failure, I assessed her IVC with ultrasound. It was plump an unvarying. I lobbied the nephrologist to try diruesis based on the aforementioned reasoning, but was very wrong. Her kidneys took a hit with lasix. What got her kidneys better was rehydration. In the end, what happened was her mild PAH raised her venous pressure and the hypoxemic vaso-constrction from her new pnuemonia only made that worse. Her right heart pressures, venous pressure and probably renal venous pressure were undoubtedly high. But I didn’t take into consideration her whole picture. She had a bad infection, had large insensible losses and had not been eating and drinking. She was hypovolemic, no doubt, despite her high right heart pressures. Fortunately, her pneumonia resolved and fluids brought her kidneys back to baseline.
Thanks again for another thought-provoking topic
Me: Great points as usual Jon, and your last one brings up a bit of a concern I have always had. To play devil’s advocate, one could argue that it may have been resolution of the pneumonia and its metabolic sequelae and possibly other treatment that resulted in improvement of her renal failure, rather than the fluid, no? Did her hypoxia resolution decrease PAP back to normal – with IVC dynamics restoring – and relief of renal congestion, and improvement “despite” fluid?
To me, fluid administration must – at least transiently – increase CO to have any effect on the perfusion side. To do so, my understanding is that it has to go from right to left. Because of the pericardium and interdependence, if RAP exceeds LVEDP, we will start to impair LV preload, which sets up the vicious cycle of a shrinking LV and growing RV. If we can’s increase our RT heart output, obviously our LV CO headed to the kidneys can’t increase either. Hence the assumption would have to be that somehow this additional fluid can – by increasing RV preload (without increasing RV size and further impinging LV?) – help overcome elevated PAP and increase right to left flow. To me, hard to believe without a pericardiectomy (on a short time frame, naturally). Hence I struggle with understanding how a really plump IVC with little variation (if significant pleural pressure variation is occurring) can really still need fluid.
I’d really, really like to get your comments on this. I’ve had a number of conversations about this with people – some of them pretty bright – but none satisfying. Am hoping you can point out my flawed thinking.
Jon-Emile: Philippe, you ask very good questions. Your first point is quite valid. I think we have a bias of assigning meaning to a particular intervention because we think that particular intervention will work. For the patient I treated, we administered multiple drugs [oxygen, antibiotics, bronchodilators, we may have even given a dose of steroids] and yet I assign meaning to the fluids given. I think in all patients with complex hemodynamics that there are multiple co-varying interventions that all [hopefully] push the patient in the right direction – making it quite hard to grant significance to one in particular. Yet in the patient I treated, the timing with respect to creatinine change and urine output made it very hard to argue in favor of diuresis. We were checking her creatinine fairly regularly as she was in step-down and we were concerned about the trajectory of her illness. With lasix, her creatinine jumped abruptly on the following chemistry while with fluids, creatinine dropped and her urine output really picked up.
Which brings me to Ulrich’s point. It is well-taken and I hope to have a pulmccm post on this shortly. While the CVP does not have any correlation with volume status or volume responsiveness as you point out, the physiology of the CVP can help explain confusing echocardiographic findings.
All a plump, unvarying IVC with spontaneous inspiration means [if you believe the Guyton, or Magder approach] is that the IVC transmural pressure is remaining on the flat portion of its compliance curve during inspiration.
In other words, the IVC is at such high volume [on the flat portion] that lowering its transmural pressure [lowering the CVP, raising the intra-abdominal pressure or both] does not cause it to shrink in volume.
The question then becomes why is the IVC in this state? And a great analysis to this question is to consider the determinants of great vein volume [which really is a question of great vein/right atrial pressure or the CVP – which is related to volume by compliance].
There are two primary processes which will raise great vein volume and these flow from the Guyton Diagram 1. excessive venous return 2. poor cardiac function or a combination thereof [its really just inflow versus outflow]. Volume status plays one part of venous return, so certainly, if someone is hugely fluid overloaded, their venous return will be enhanced and this will favour a high great vein volume and high great vein pressure, BUT this will be mediated by cardiac function because if the heart can eject the large venous return it is receiving, then the great vein pressure and volume won’t change or may be low. Conversely, if cardiac function is poor, a patient could have a low venous return [e.g. be hypovolemic or euvolemic] and still have a high great vein volume and pressure – simply, because the heart can’t expel from the thorax what little venous return it receives. Importantly, poor cardiac function can mean almost anything [valve dysfunction, tachycardia with arrhythmia, high afterload, poor contractility, etc.].
To me, the above is the true value of thinking about Guyton and the CVP, so when I approach a patient, I try to think about what their venous return curve looks like [by a clinical exam] and I use a TTE to actually see what their heart function looks like [and to me this is the true power of ICU TTE]. The above also explains why CVP simply cannot be a marker of volume status.
In the patient I was treating, her history and physical really suggested poor venous return [she was clearly with a pneumonia, hadn’t been eating and was euvolemic to dry on examination] yet her great vein volume was high on TTE which meant that her cardiac function was most likely poor [on the Guyton Diagram her low venous return curve would be intersecting a very low, flattened cardiac function curve such that shifts with intra-thoracic pressure would not change right heart pressure at all].
But why was her heart function poor? Why could her right heart not eject what little inflow it was receiving? It was probably a combination of things. The pneumonia probably increased right heart afterload which caused some TR, she was tachycardic so wasn’t getting optimal filling time, she was septic with perhaps some underlying cardiomyopathy, perhaps her diastolic blood pressure was lower than normal [she was an elderly lady with likely stiff arteries] and she wasn’t perfusing her right coronary artery well and was suffering from relative ishcemia] it’s certainly is a lot of hand-waving, but all taken together perhaps plausible.
The antibiotics improved her lung function as did the bronchodilators which lowered pulmonary vascular resistance which improved right heart forward flow, maybe the inhaled beta-agonists increased her contractility, maybe the oxygen also lowered her pulmonary vascular resistance, maybe the steroids sensitized her to catechols and this raised her blood pressure and coronary perfusion pressure which improved her right heart function, but also maybe the fluids? Empirically, and in retrospect, venodilating her with lasix probably really lowered her venous return and this crashed what little cardiac reserve she had. It was improving her venous return with fluids that helped.
Sorry if this post is getting too long …
In terms of ventricular interdependence [an excellent, under-appreciated point in the ICU] I think that you have to be very careful extrapolating whether or not this effect is present from an IVC examination. In a classic paper [that caused much consternation at the time] Pinsky found that right atrial pressure was completely uncoupled from right ventricular end-diastolic volume [why the CVP is a poor indicator of volume responsiveness]. Her is a recent review of that paper by Pinsky himself.
The take home is that while right atrial volume and pressure [and by corollary great vein volume and pressure] can be high, this may not translate to a right ventricle near its elastic limit. Pinsky offers no good explanation as to why this is, but postulates that it may have to do with the complex RV geometry and how this changes during diastole. So until there is a widely accepted means of assessing RV filling with TTE [like an Ea ratio] which could pick up a restricted filling pattern, this is really hard to call on echo. As you are aware, you could look for a flattened septum or D sign during diastole, but I’m not sure how well that sign predicts a patient’s response to a fluid challenge – it certainly screams caution.
This Pinsky paper also highlights a potential disconnect between the physiology proximal to the tricuspid valve and the physiology below it which is also part of my general reluctance to use IVC volume change as a marker of fluid responsiveness, just as I have total reluctance to use CVP [or its change with respiration] as a marker of fluid responsiveness.
Unfortunately, a lot of the time it comes down to ‘guess and check’ – give fluids or give lasix and see what happens. This is why I firmly believe that determining volume status and volume responsiveness are the hands-down hardest party of ICU medicine.
If you’re still reading, I hope this helps.
One more point. I don’t think I gave a full explanation to one of your questions. Please bear with me as this is exceptionally hard to explain with words [indeed why I made heart-lung.org].
The venous return and cardiac function curves are essentially inverse of each other [that is lowering right atrial pressure increases venous inflow but decreases cardiac outflow] so they approximate the letter X [venous return is the \ and cardiac function is the / & the point at which the two lines intersect make up the CVP and defines cardiac output].
If you consider the patient I described, If we assume her venous return is low [because she is venodilated from sepsis and hypovolemic from low PO] then the venous return curve [\] is shifted leftwards. If we assume her cardiac function is poor the cardiac function curve slope [/] is shifted down and to the right.
When she takes a breath in, the lowering of intrathoracic pressure pulls the cardiac function curve leftwards [lowers its pressure relative to venous return] while the increase in in abdominal pressure with diaphragm decent tends to temporarily increase venous return by decreasing abdominal venous capacitance. This effect shifts the venous return curve in a rightward manner.
If the patient’s venous return curve initially intersects the ascending portion of the cardiac function curve [i.e. she is truly volume responsive] BUT, the intersection is very near the plateau of the cardiac function curve [i.e. the portion of the cardiac function curve that will render the patient non-volume responsive and also favour unvarying respiratory change in right atrial pressure/volume with inspiration], THEN with inspiration it is possible to see the intersection of the two curves on the flat portion of the cardiac function curve [as the cardiac function curve is pulled leftwards and the venous return curve is pushed rightwards], even though she does have some cardiac preload reserve. This would be an example of impaired specificity of IVC volume change with spontaneous inspiratory effort as a predictor of volume unresponsiveness [i.e. a false positive for a plump IVC predicting the lack of fluid responsiveness].
I address this physiology in chapter 6 parts C and D and chapter 8 part F.
Me: Very, very interesting. I think this discussion, as many, show how medicine is not a “hard science” but remains a “pseudo-science”, inherent to the fact that we are blending physics, chemistry, biology and cannot really apply simple principles of flow and pressures when dealing with elastic, muscular systems lined with microscopic coating whose compliance and resistance change from moment to moment and thru effect of neural and hormonal influence. There are simply too many unmeasurable variables to come up with single guidelines and rules.
I think, as you say, that there remains a need for some degree of trial and error, that we are hopefully narrowing with the appropriate application of technology and proper data integration.
I’ll percolate all this and see how I can tweak my mental model!
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 theCooperative 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.
So if you keep abreast of the fluid literature, you’ll note that more and more logical voices are bringing up very, very valid points against the powerful cultural backdrop of aggressive fluid resuscitation in various pathologies. Paul Marik’s recent publication, a great SMACC 2013 lecture by John Myburgh, not to mention several studies and analyses (VISEP, SOAP) illustrating consequences of overzealous fluid resuscitation. On the other side of the fence, you have the guidelines of various associations proclaiming loudly that fluids are “critically important” that there is a need to be “aggressive” and “generous.” However, scratch a little beneath the surface and find…very little besides opinion and history. Zip. Nothing.
So my aim isn’t to make anyone stop giving fluids, but instead to treat fluids as any other therapy. Carefully given and assessed rather than in hyped-up frenzy.
I invite every physician reading or listening to, for a few minutes, put pre-concieved notions aside and approach the problem from a neutral and educated point of view, and come to your own conclusion, as unbiased as possible.
So here is my little podcast.
ps just as I was uploading, checked my twitter and noted a great addition to the body of analysis by Josh Farkas, check it out: