Plasma-lyte vs. Saline (0.9% NaCl): The PLUS Trial was a Negative Study

To begin, I will disclose my bias. I wanted plasma-lyte to outperform 0.9% NaCl, also called normal saline in critically ill patients. It turns out that after the publication of the PLUS trial, I have to chill the heck out to an extent. On this blog as well as social media, I have scrutinized 0.9% NaCl extensively and leaned heavily towards the utilization of balanced salt solutions such as plasma-lyte and lactated ringers. Youtube videos, podcasts, and other such content has been created, using evidence-based medicine, of course, to defend my position and ultimately bias. I created an entire IV Fluid Guide with most of these data. It’s a shame that this study is hidden behind a paywall at NEJM so you’re going to have to trust me unless you can obtain the paper yourself.

The PLUS Trial

To start off, this study was created and performed by the ANZICS group out of Australia and New Zealand. Outside of some questions on the timing of initiation of the study drugs in the VITAMINS trial about metabolic resuscitation, they generally do a fantastic job with their clinical research. To be frank I’ve known about this trial for several years and have been excited about learning the results. This was an “investigator-initiated, double-blind, parallel-group, randomized, controlled trial”. Only the best from these folks. It took them several years to recruit everyone for the trial, from September 2017 to December of 2020 in the 53 participating ICUs. The study was stopped early because of issues with funding due to you-know-what.

Physicians did not decide whether patients enrolled in the PLUS trial received plasma-lyte or 0.9% NaCl, but they were able to decide the rate and amount of fluid provided. They wanted to have a total of 8800 patients in the study but ended up with just over 5000. To account for the missing patients they conducted a number of statistical jumping jacks which included “imputations for missing data according to “worst–best” and “best–worst” scenarios and multiple imputation”. I don’t know what that means. That’s beyond my level of intelligence.

Quick Facts

  • These patients actually received IV fluids: 3.9 vs. 3.7L. This is important because other trials provided smaller volumes (SPLIT Trial)
  • There was no difference in urine output between the groups.
  • 4.1% vs. 5.0% of patients had their fluids terminated with the most common reason being pallative care transitions.
  • 42.3% of the patients had sepsis. I would’ve hoped this was higher. Why were all these other patients receiving fluids then?
  • 45.2% of patients came out of the OR or PACU. This seems to be a common theme in these studies (BaSICS by Zampieri).
  • 17.8% vs 19% came out of elective surgery. These folks are generally healthy to start, why enroll them?
  • The majority of patients were on the vent, approximately 76% in each group.

Death was the primary outcome of the PLUS trial

I sort of have an issue with this. The rationale lies behind it being not realistic to think that the choice of IV fluids leads to death. Does it lead to acute kidney injury? Potentially. Death? Well, I don’t think so. Whether the sample size is 8800 as initially intended versus over 5000 which is where they ended up, I never felt 0.9% NaCl was killing people. I just feel that it is not physiologic. It is my personal opinion, and I welcome being wrong, that this is not a good primary outcome.

It came as no surprise to me that 21.8% in the plasma-lyte group died vs. 22% in the 0.9% NaCl group. No statistically significant difference.

Secondary outcomes

This may be the most important part of the trial. They had numerous parameters that they were looking for amongst the secondary outcomes. These are rather ambitious and are listed below. Let me spoil this for you: there was no difference. This might end up being the place of most value of the trial.

  • peak serum creatinine level during the first 7 days after randomization
  • the maximum increase in creatinine level during ICU stay
  • receipt of new renal-replacement therapy
  • receipt and duration of treatment with vasoactive drugs
  • duration of mechanical ventilation in the ICU
  • length of ICU and hospital stays
  • death from any cause during ICU stay, during hospital stay, and within 28 days after randomization.

Final thoughts about the PLUS trial

First of all, perhaps 0.9% NaCl, aka. “normal saline” is not as dangerous as we thought. There was no difference in the number of adverse events between the two groups. Sure, there was a higher serum chloride in the 0.9% NaCl group as well as a lower pH, but did that change anything in their patients? Nope. Perhaps the pursuit of euboxia (making all the lab values normal) is a fools errand.

Maybe enrolling 3000 additional patients would not have changed a single thing. Rather than criticize the hard work this team did, I could instead try to conduct a similar trial myself. Truth is, though, that I won’t. Clinical trials such as these require an insane amount of work. Although my cognitive dissonance may not want me to accept these results, these are the best data we have. A definite hat tip to the authors.

I will keep on using balanced salt solutions in my patients such as plasma-lyte and lactated ringers, but I will not give such a hard time to those who are using 0.9% NaCl on their patients. Although I do think I’ve traumatized a person or two in the process. Oops. Also hat tip to Jordan Wallis for alerting me of this paper first.

Citation for the PLUS trial

Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults: Simon Finfer, M.D., Sharon Micallef, B.N., Naomi Hammond, Ph.D., Leanlove Navarra, B.S.N., Rinaldo Bellomo, M.D., Ph.D., Laurent Billot, M.Res., Anthony Delaney, M.D., Ph.D., Martin Gallagher, M.D., Ph.D., David Gattas, M.D., Qiang Li, M.Biostat., Diane Mackle, M.N., JayaFinfer S, Micallef S, Hammond N, Navarra L, Bellomo R, Billot L, Delaney A, Gallagher M, Gattas D, Li Q, Mackle D, Mysore J, Saxena M, Taylor C, Young P, Myburgh J; PLUS Study Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. N Engl J Med. 2022 Jan 18. doi: 10.1056/NEJMoa2114464. Epub ahead of print. PMID: 35041780.
Link to Article (NOT FREE)

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