In 10 minutes, I'm going to give a four-hour lecture about which type of fluid we should administer. And so, you'll understand that from the perspective of parsimony alone, I give you my thoughts at the beginning. I'll extrapolate on two of them and really try to see if we can move from just the theoretical to something that we might add to and implement in our bedsides. I'm going to argue today that we should get over which type of fluid but much more consistently establish effective circulating volume regardless of fluid type, because I think that continues to outweigh the net negative impacts of any specific fluid. I continue to believe that there are theoretical benefits of balanced solutions of isotonic saline, but they continue to have insubstantial justification based on very large randomized controlled trials. And I urge you to consider that there are subgroups including non-TBI ICU patients and diabetic ketoacidosis patients, where I think that we do have compelling reasons to select one type of fluid over another. I've now used up a minute and a half of my time. I haven't said the word colloid. I didn't say several other things. And so, please do accept that there are areas beyond my comments today that really warrant further exploration. The premise for using balanced solutions, and I'll show you what those are in a moment, is that there is good basic scientific and mechanistic reason to think that chloride stress, normal saline chloride stress, is associated with renal dysfunction, particularly in patients with elevated creatinine at baseline. That's in non-ICU patients. In ICU patients, less to do with where the patients are but more because of the underlying organ severity, there is an association with both worsened renal outcomes and survival. And the evoked potential mechanisms include inflammation, both in a cytokine, eicosanoid, and cellular death pathways, but also amplified hemodynamic instability. Now, normal saline has been termed initially indifferent fluid. This was described in the mid-1800s by Hamburger. Many have said that there's nothing normal about saline or it's an abnormal fluid. And I think that we have to understand the origins of normal saline was that its chemical characteristics, because it has a freezing point similar to human serum and doesn't cause visible erythrocyte lysis, was the reason that we have this historical anchoring in the use of sodium chloride as our primary resuscitation fluid. The phenomena of hyperchloremic acidosis, pro-inflammatory effects, renal vasoconstriction, and reduced GFR are things that have all evolved through time in large studies, both in the animal laboratory and at the bedside. I'll draw your attention to the fact that taking normal saline and administering it into plasma reduces strong iron difference, which is the acidifying mechanism by which normal saline, as it's called, has that effect. But I'd ask you to look at the constituents of both normal saline and two forms of balanced solutions, lactated ringers and crystalloid, and appreciate there is marked differences in the chloride content per liter or in millimoles between these fluids. So there is reasonable concern at a theoretical level to not use sodium chloride if really using physiologic balance would be the priority. There's also some thoughts that the distribution of balanced crystalloids achieves a much closer dissociation between the extravascular interstitial space, plasma, and intracellular space when administered into an otherwise normal, non-leaky human being, 42 liters of extravascular volume. And there is some discussion about whether the higher potassium content of medications like lactated ringers can cause dangerous hyperkalemia, and both at a theoretical level, the math of which is shown here, but more importantly at the clinical level, that really doesn't seem to hold out an important risk, particularly people with normal renal function. So there's been a very important aggregation of evidence in well-performed, generally well-devised clinical trials starting in 2012. They've really had high impact effect through the SPLIT trial, the SMART pragmatic trials, the BASICS trials that you've heard about in Brazil, the PLUS trial from the ANZICS groups, and a very important and impactful meta-analysis just last year have really added to the discussion. My intention today is to point you in the direction of these primary literature but draw some key points from them. The SALT-ED and SMART trials, two pragmatic trials from the Vanderbilt group, drew important different conclusions about the group sequential randomization of patients to either a saline solution or a balanced solution, predominantly plasmolyte, which indicated or strongly suggested that there may be some benefit in terms of renal failure outcomes. I'll show you those in aggregate but point to you that the difference in the composite of new-onset kidney injury at 30 days was strikingly lower in patients who received the balanced solution rather than normal saline, with smaller net aggregate differences in mortality rates in a subgroup of patients with sepsis. And so one does draw from this that there may well be both clinical and biologic subphenotypes that may, in fact, accrue benefit from a balanced fluid rather than saline. In the BASICS RCT, you'll remember this very large trial in not very sick patients administered modest amounts of fluid, but either a saline solution or a balanced solution. And there was a lot of challenge of the study because of crossover. Patients who, in the pre-randomization period, received solution A but during the randomization received solution B, meaning that when there was no determined difference, adjusted hazard ratio for 90-day mortality crossing unity with a point estimate of 0.97, it was uncertain for sure that this rejected the null. And this important study, which has been well-cited and certainly was well-conducted, raises the important challenge in conducting critical care studies about controlling for pre-exposure treatments. And a similar phenomenon in the ANZIC study, the PLUS study, which drew a similar kind of conclusion, no difference in 90-day mortality and no significant difference in newly initiated renal replacement, had similar challenges between arms with unspecified crossover. When you put all of the four large clinical trials, both pragmatic and randomized trials together, and look at renal outcomes as the composites, the SMART trial is the trial that is most informative for a potential improvement. And even then, it's at the level of subgroup study in patients with sepsis. But let's be clear. Small changes in outcomes may be very, very important. If you look at the patients, for example, in BASICS who did not receive saline but were randomized to a balanced solution, there was a quite significant probability that there was a mortality reduction, particularly in the subgroup of patients with sepsis. For those in whom there had been crossover pre-exposure to saline, that difference was perhaps negated, suggesting that there really may well be a signal there. And in aggregate, of course, meta-analysis is either great studies in, great studies out, giga. The alternative is garbage in, garbage out. It gives you a point estimate of small reduction in mortality to small increase. We've learned, however, that our prevailing biases or expectations or probabilities for change inform the way we look at data. And using a non-frequentist or Bayesian secondary analysis to evaluate the aggregate effect of a balanced solution versus a crystalloid solution, here in these large aggregated fluid studies, would suggest that if you have a semi-informative prior, you've got enough information to suggest that there may be benefit, resulting in a posterior probability using non-frequentist approaches of as high as 85 percent likelihood of benefit for a balanced approach versus saline. Now, lastly, in the last minute, you'd heard about the primary outcome of the Clovis trial, which showed no net difference in 90-day survival using a fluid-liberal, fluid-restrictive approach. There was a large separation between the arms over the course of the conduct of the study in the total amount of fluid administered. But when we break down, and this is data from the appendix of that manuscript, about half the patients over the course of the study received almost exclusively saline, and half received almost exclusively lactate or ringers. At one center, the balanced solution was used as plasmolyte. But I think that what we have a sense of is that the usual care practice spectrum is very diverse. What's really striking to me is this panel here. It looks at all the fluid administered from pre-randomization through the intervention period of 24 hours. And if you look at the volume of fluid between the restrictive and the liberal arm, it's really interesting that patients that get balanced solution rather than crystalloid to achieve the hemodynamic end point end up getting significantly more volume of fluid, more volume of fluid than the saline group. Now, whether this is confounded, of course, is entirely possible, and this warrants further analysis. But it raises the hypothesis that there is something about osmotic stress that's important. And so finally, I want to raise the possibility that maybe it's got less to do with the chloride than whether we really understand the net pharmacologic effects of the treatments we give. And just to draw your attention to the fact that there's really compelling evidence that using hypertonic solutions in small volume have a counteractive effect on inflammation and vascular integrity while not improving survival. And one wonders at what the inflection point is between chloride stress and membrane stabilization with high plasma, high oncotic pressure solutions that we're trading off when we simply look at one solution and the other. So let me go back to my observations. I think that while the impact of balanced solutions are probably there, their effects are small, let's really focus on the bottom line. There are theoretical benefits that may have potential implications at a public health level, 200,000 preventable deaths if we use balanced solution, but we need to squeeze that out. There are subgroups that may benefit, and I think that at the end of the day in your own institution, your responsibility is to establish a usual care practice, stick to it, reduce variability, and if you decide to use a solution that isn't your usual care solution, you really need to document why it is that you've made that discussion. My thanks to the organizers. Sorry about being just a minute over.

fluid type

medical settings

circulating volume

balanced solutions

renal function