IV fluid choice part 3: The SALT-ED trial

So far, this week’s discussion of IV fluid choice has focused on ICU patients in our discussion of both the SPLIT and SMART trials. I work in the emergency department and really want to know how to manage emergency department patients. To close out IV fluids week, we will look at the SALT-ED trial, which was run by the same group and at the same hospital group as the SMART trial, but focused on patients in the emergency department.

The paper

Self WH, Semler MW, Wanderer JP, et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. The New England journal of medicine. 2018; 378(9):819-828. PMID: 29485926 [free full text]

The Methods

This is a single-center, pragmatic, unblinded, multiple-crossover trial.

Patients: Adult emergency department patients who received at least 500ml of IV isotonic crystalloid and who were subsequently hospitalized outside of an ICU. (The trial was run at the same time as SMART, so the ICU patients were enrolled in that study).

Intervention: Balanced crystalloids (either Ringer’s solution or Plasma-Lyte A)

Comparison: 0.9% saline

Outcome: The primary outcome was hospital free days to day 28

• There were three major secondary outcomes: major adverse kidney events at 30 days, acute kidney injury of stage 2 or higher, and in-hospital death.

The Results

19,949 patients were treated with isotonic crystalloids in the ED. 3689 received less than 500 mL, and so were excluded. 2913 were admitted to the ICU. Therefore, the final sample size was 13,347.

The median amount of fluid given was about 1 L in each group. The mean was about 1.6 L.

For the primary outcome, the was no difference in the number of hospital free days (25 days in both groups, OR 0.98, 95%CI 0.92-1.04, p=0.41).

As a secondary outcome, there was a lower incidence of major adverse kidney events at 30 days in the balanced crystalloid group (4.7% vs 5.6%, OR 0.82, 95% CI 0.7-0.95, p=0.01).

My thoughts

The study population is actually defined retrospectively. They included patients who were admitted to hospital, but weren’t admitted to the ICU. When I start fluid resuscitation in the emergency department, I have no idea whether my patient will fit into that category, and so the results are difficult to apply prospectively.

Clinicians could choose to use an off-protocol fluid if they thought it was warranted, resulting in potential selection bias. There were a relatively large number of protocol violations, with only 88% of patients receiving only the fluid they were supposed to. There was also a differential in the violations, with more violations in the balanced crystalloid group (16% vs 7%). The issue is further complicated by the fact that they are looking at 28 days outcomes, but fluids used in hospital were not controlled and not recorded.

They didn’t have a baseline creatinine for 35% of the cohort, and just assumed that their baseline renal function was normal, which is not a great assumption among hospitalized patients. One of the most talked about outcomes in this trial is the secondary outcome of major adverse kidney events, but I question the accuracy of that result when such a large cohort of patients had unknown baseline creatinines.

The outcome of hospital free days until day 28 is really a composite outcome of death and length of stay. It is problematic when you consider that this outcome counts a 29 day hospital stay as being the same as death. (Not that a 29 day hospital stay would be particularly pleasant).

I try not to make to much to subgroup analyses, but it is reassuring that for the primary outcome the two groups look very similar in all subgroups. Among patients with a baseline elevated creatinine, saline did look worse for the secondary outcome of acute kidney injury, but the other way of looking at that data is that you don’t have to worry about this issue at all if your patient has normal renal function.

Trying to make sense of composite outcomes is difficult. Yesterday, I noted that the positive outcome of SMART was primarily driven by mortality. In SALT-ED, we see the opposite, with no changes in important outcomes, and the statistically significant results limited only to a 200% increase in creatinine. The fact that we are seeing different outcomes driving the results makes me question whether we are seeing a true effect here. If the results were real, I would have expected similar outcomes to drive the results in both groups.

This is a negative trial. Many of the commentaries I have read have been really excited about the secondary outcome of adverse kidney events, but in addition the the usual caveat about it being a secondary outcome, there are some other caveats we need to consider. Most importantly, this is an unblinded trial at high risk of bias. Second, the difference, although statistically significant, is less than 1%. Finally, this already small difference in only in a composite outcome, and the vast majority of the difference is accounted for by the probably clinically meaningless doubling of a creatinine (in a study where baseline creatinines weren’t available for 35% of patients).

Bottom line

This is a negative trial. However, it is a negative trial with numerous methodological weaknesses, making definitive statements impossible.

When you combine the secondary outcomes here with the primary outcome of SMART, there is enough of a hint of benefit from balanced fluids to warrant further study, but not enough to warrant any wholesale practice change. For the most part, all three trials this week seem to demonstrate the general safety of using saline as a resuscitation fluid.

After reviewing this evidence, I will continue to use saline as my initial resuscitation fluid when crystalloid is required. However, the amount of fluid used in all 3 trials was quite small, so it is impossible to make any conclusions about large volume resuscitation. Observational data and physiologic theory caution again using large volumes of 0.9% saline. My practice has always been to pause after 2 litres and think: does this patient really need more fluid, and if so, what is the best fluid based on their physiology and lab results?

“Why not just change to balanced fluids?” is a reasonable argument that has been raised in the wake of these studies. If balanced fluids were the current standard, we certainly wouldn’t be switching to saline based on these results. I don’t have a strong opinion one way or another. I think it is reasonable to use balanced IV fluids, but I also would not criticize anyone for continuing to use saline.

There are some potential practical issues when moving away from saline. Drug monographs list important resuscitation medications like piperacillin-tazobactam and tranexamic acid as being incompatible with Ringer’s lactate. Blood products are also often considered incompatible, because the calcium in Ringer’s interacts with citrate. I am not sure whether these incompatibilities are based on good science, but the last thing I want in the middle of a resuscitation is for a medication to be delayed, or even for this question to be raised while I already have limited bandwidth available. That is the primary reason that I will continue grabbing saline first in the resus room.

Part 1 of this series looked at the SPLIT trial.

Part 2 looked at the SMART trial.

Other FOAMed

EMNerd: The Case of the Unbalanced Solution

St. Emlyn’s

PulmCrit- Get SMART: Nine reasons to quit using normal saline for resuscitation

The Bottom Line

EM Journal Club

The Resus Room: The Crystalloid Debate