More Fluids vs. Vasopressors in the First 24h of Septic Shock (CLOVERS Trial)

Today, we’re going to be reviewing what some might consider to be a landmark study: the CLOVERS trial. The first thing most clinicians do when a patient is hypotensive is provide IV fluids. The surviving sepsis guidelines recommend 30cc/kg in patients who are in septic shock. It often bears reminding that the objective of providing IV fluids is to increase the stroke volume. After all, MAP is equal to cardiac output times stroke volume. To break this down further, cardiac output is heart rate times stroke volume. When patients are septic, patients vasodilate, hence, drop their SVR. It’s worth discussing that these fluids we provide patients does not change the SVR. The SVR is improved by treating the inflammatory process that is sepsis.

One thing that has taken place is that this 30cc/kg recommendation by the surviving sepsis campaign has been adopted by CMS, The center for medicare and medicaid services, as a metric to which hospitalist are scrutinized and reimbursed. I’ve been working on a post for several months now examining where this 30cc/kg of IVF recommendation came from but long story short, it seems like it came out of thin air. That being said, I have always been a proponent of individualized medicine because we treat individual human beings, not metrics and not guidelines.

I was excited to hear about two trials that I incorrectly believed would be potentially pushing back on the 30cc/kg guideline. These two trials were the CLASSIC and now the CLOVERS trial. Unfortunately, the CLASSIC trial still gave patients a significant amount of IV fluids in the ED. It was more of a trial looking at providing fluids in the ICU. Long story short, there were no differences in outcomes.
I am going to read the CLOVERS trial published on January 21st, 2023 and kind of report my findings and thoughts on this study in real-time. I definitely recommend you read this article for yourself and do not trust me as this is my breakdown on the paper.

The purpose of this paper was to sort out if a restrictive fluid strategy for sepsis-related hypotension would lead to lower mortality than a liberal fluid strategy. Right off the bat, I want to know how they define restrictive and liberal fluid strategies as well as when in the course of the resuscitation did enrollment begin. Let me hold my horses. Reading the introduction is always worth ones time as they give a backdrop as to why the authors are conducting the trial.

The next part of the trial are the methods. Here, they specify that this is a multicenter, randomized, unblinded superiority trial. This is also a trial conducted by the PETAL network. They conduct fantastic work with their research so right off the bat I feel that this will be a well-conducted trial.
Next up is the patient population. They enrolled patients over 18 years old. They needed to be septic with either a suspected or confirmed infection. If the SBP was < 100 after a liter of fluid, they were deemed eligible. I kind of wish they would have used a MAP because of the limitations of oscillometric devices. They had some exclusion criteria but one of those tat caught my eye were patients who received more than 3L of IVF including the fluids provided by the EMS teams.

The trial procedures and figure 1 get into the explanation of what the restrictive and liberal fluid protocols looked like. For both groups, however, it is important to note that patients received between one to three liters of fluid. Data from the PROMISE, PROCESS, and ARISE trials between 2015 and 2016 show that patients received a mean of 2.2, 2.8, and 2.5 liters in the first 6 hours respectively. Therefore, the question here isn’t going to answer the 30cc/kg of fluids at all to my disappointment. As I am writing this podcast as I am reading the paper, I just saw that they use a SBP < 100 OR a MAP < 65 to define hypotension. Glad the MAP came out to play as it’s what I use in my practice. Also, both of these protocols took place for 24 hours.

Getting to the restrictive protocols, if a patient received less than 2L of fluids, they received additional fluids to 2 liters. At least that’s how I understand it to be. If the patient is still hypotensive as defined by MAP < 65 or SBP < 90, they were started on NE. If still hypotensive, they received a second vasopressor. 
Patients in the restrictive group received additional fluids if they were severely hypotensive, if their hypotension was refractory to vasopressors, if the lactate was elevated > 4 after 2 hours, if they had sinus tachycardia > 130, or if the echo showed they were dry by looked at the IVC, delta stroke volume, or LVEDI on the echo. In these cases, additional 500cc boluses were given.

Let’s move over to the liberal fluid group. At the beginning of the protocol these patients received 2L in addition to the 1-3 liters they received prior. So we’re starting off with 3-5L in these patients. Patients received additional 500cc boluses if they remained hypotensive, their lactate remained above 4, their UOP was less than 30cc/hr, they were tachycardic above 110, or they were started on vasopressors. I note that they aren’t using any dynamic hemodynamic parameters like stroke volume assessments which they used in the restrictive group. These patients received additional boluses of 500cc. They started vasopressors only if the patients were severely hypotensive, their lactate level was >4 and increasing over 2 hours, if they received more than 5L of fluids total, or if they seemed to be fluid overloaded.
A key point here is that if they received more than 5L, they stopped administering fluids per the protocol. I feel that a practice that takes place at a majority of hospitals is to give more than 5L of fluids at times to avoid placing patients on vasopressors.

Now that we have gone over the protocols, let’s take a look at the results. Over the course of 4 years they enrolled 1563 patients at 60 hospitals. A little over 780 in each group. Spoiler alert: They wanted to enroll more but they stopped the trial early for futility. Some might say right off the bat that there’s no difference and brush the trial off but I’d like to state that there are still several things we can learn from their efforts.

Table one describes the baseline characteristics of the patients. There is nothing outside of the ordinary here in my opinion. On second thought, the fact that the average age was less than 60 makes me think this patient population is rather young. They did a fantastic job of randomizing patience early with a median time of approximately one hour. The medium volume of fluid that the patient received before randomization was approximately 2 L.

Looking at the differences in the fluids that the patient received, it is noted that the restrictive fluid group received a median of 500 mL versus 2.3 L in the liberal fluid group. During the 24 hours after randomization, it was noted that the restrictive fluid group received approximately 1.3 L versus 3.4 L in the liberal fluid group. This is a difference of a little over 2 L. how long would expect, the patience with restrict fluids received far more vasopressors versus the liberal fluid group at 59 verses 37% respectively. The restrictive fluid group also had a longer duration of vasopressors at 9.6 hours versus 5.4 in the liberal fluid group. Some might say that giving fewer fluids leads to a longer time on vasopressors based on the stable however, this is just describing the first 24 hours. We have to read further to see if this carries on during the length of stay.

Amongst the efficacy outcomes, the primary outcome was death before discharge home by the 90. There was no difference here with 14% in the restricted fluid group and 14.9% in the liberal fluid group. What catches my eye about the results here is not that there was a difference, but rather that less than 15% of these patients with sepsis passed away. The reason why this is, impressive is because, generally speaking, mortality from sepsis lingers between 20 to 25% with some data going up to 30%. I hope that this means that we are getting better at taking care of sepsis patients as this trial took place at 60 different centers.

The authors had a long list of secondary outcomes, of which none showed any difference. It was interesting to see that there was no difference in the need for renal replacement therapy, a.k.a. dialysis, between the two groups. There was also no difference in days of vasopressor use in the two groups. It was also interesting to see that the liberal fluid group did not have more ARDS than the restrictive fluid group. There was also no difference in the patients who required intubation and mechanical ventilation. Overall, there was no difference in the severe adverse events which took place in a total of 40 of the over 1500 patients enrolled in the study. None of which were dusky fingers and toes not gut ischemia, by the way. Norepinephrine was the primary vasopressor that was used in the study for these patients, and they had three instances of extravasation, but thankfully all three resolved without any complications nor residual clinical consequences per the authors.

The Authors performed a very thorough subgroup analysis of which nothing was statistically significant between the two groups. There is a marked trend that restrictive fluids should be used in patients with End-stage renal disease, but this is not statistically significant. I am curious if they completed the study then might there have been an appropriately powered sub group to find a benefit towards restrict fluids in patients with end stage renal disease. One of the key points that were mentioned in the discussion is that they did not enroll patients who were already volume overloaded, or had significant volume depletion at the time of possible enrollment. 
The authors did some thing else in this trial to benefit our practice in the ICU and in the emergency department. This was the fact that they started 500 patients on peripheral vasopressors. Amongst those 500 patients, they only had three extra positions of which none of them had complications.

In the discussion, the authors acknowledge the fact that they did not use non-invasive, hemodynamic devices, IVC assessments, or echocardiography to assess for fluid responsiveness. This is the way that I practice in my ICU. When it comes to the trial, the authors state that there are a number of populations that we cannot apply these data for. They did a great job of listing all the limitations that are a byproduct of creating such a study. After all, conducting clinical trials is a challenge. 

Where do we go from here? It’s easy for me to ask people to conduct certain trials without doing it myself. This does not give us the answer to the 30cc/kg question which is what I really wanted. This does not answer the question of dynamic resuscitation from time zero versus the typical practice that takes place at most institutions today which includes giving patients 3-4 liters of fluid and then calling the ICU. I guess that’s not a wrong thing to do given that the mortality of these groups were less than 15%. Let me take a second and look at the SOFA scores for the enrolled patients. Okay, the mean SOFA score in both groups at the time of enrollment was 3.4 The mean SOFA score of the PROMISE trial back in 2015 was 4.2 to 4.2 and they had almost 30% mortality between those two groups looking at resuscitation strategies. Is that enough to account for that mortality difference? I can’t say I know. I had an attending who said that maybe the best we’re going to be able to do regarding sepsis mortality is somewhere between the 15-25% range. I’d like to think we can do better but he’s a far more intelligent man that I will ever be. 

I guess you can keep doing what you’re doing as you do your best to manage septic shock patients because these data certainly do not incline me to change my practice in one way or another. Perhaps I can be less judgmental on those who give 3-4 liters of fluids to patients before starting vasopressors. I wonder if these authors can conduct a subgroup analysis to replicate the findings from the CENSER trial that was published in 2019. In that trial, they found that septic shock patients in whom norepinephrine was started earlier in resuscitation ended up having their hemodynamic endpoints met faster with fewer complications.

Citation for the CLOVERS Trial

National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network; Shapiro NI, Douglas IS, Brower RG, Brown SM, Exline MC, Ginde AA, Gong MN, Grissom CK, Hayden D, Hough CL, Huang W, Iwashyna TJ, Jones AE, Khan A, Lai P, Liu KD, Miller CD, Oldmixon K, Park PK, Rice TW, Ringwood N, Semler MW, Steingrub JS, Talmor D, Thompson BT, Yealy DM, Self WH. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Jan 21. doi: 10.1056/NEJMoa2212663. Epub ahead of print. PMID: 36688507.
Link to (NOT FREE) Article

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