Personally, I find the normal saline versus balanced fluid debate pretty boring. I don’t really care which you choose. It seems incredibly unlikely that your choice of crystalloid will have any clinical impact on patients. I use saline, but I don’t really have a strong opinion. I don’t think anyone should have a strong opinion. Ironically, the people with the strongest opinions seem to stray the furthest from the evidence. Because of that, I guess I will continue to talk about these trials, and PRoMPT trial was a big one.
The question
Does balanced crystalloid improve outcomes in children with septic shock when compared to normal saline?
The PRoMPT trial
Balamuth F, Weiss SL, Long E, Thompson GC, Artis AS, Campos AB, Borland ML, Dalziel SR, Yock-Corrales A, Singh R, Williams A, Mickiewicz B, Hickey CP, Fitzgerald JC, Laskin BL, Hickey RW, Eckerle M, Alqurashi W, Alpern E, Ambroggio L, Badawy M, Baumer-Mouradian S, Berthelot S, Clukies LD, Craig S, Curtis SJ, Davis AL, Duffy S, Eisenberg MA, Emsley JG, Festekjian A, George S, Green R, Gripp KE, Jain PG, Jani S, Joubert GI, Judge P, Kam A, Kochar A, Koutroulis I, Kwok MY, Lane RD, Lithgow A, Lloyd J, Mansour K, McManemy JK, Morris C, Phillips N, Rao A, Rogers A, Sehgal A, Shayan Y, Silverman J, Tan E, Uspal NG, Vance C, Whyte E, Huang J, Freedman SB, Babl FE, Kuppermann N; PRoMPT BOLUS Investigators of the PECARN, PERC, and PREDICT Networks. Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock. N Engl J Med. 2026 Apr 24:10.1056/NEJMoa2601969. doi: 10.1056/NEJMoa2601969. PMID: 42028918 NCT04102371
Methods
This was a multi-center, pragmatic, open-label RCT. They enrolled children from 2 months to 18 years old with suspected septic shock who were being treated with fluid resuscitation for abnormal perfusion. If more than 40 mL/kg of fluid had already been given, patients were excluded. Patients were randomized to either balanced fluid (lactated Ringer’s solution, Plasma-Lyte, or Hartmann’s solution, depending on availability or clinician preference) or normal saline for the initial bolus and all ongoing maintenance fluid up to 2 days after enrollment. They used a composite primary outcome of “major adverse kidney event”, which included death, initiation of renal replacement therapy, or persistent kidney dysfunction.
Results
They enrolled a total of 9041 patients, about 6% of which declined to consent or withdrew from the trial, leaving 8482 in the final analysis. The groups both received about 85 mL/kg of fluid during the 1-2 days of the intervention.
There was no difference in the primary outcome, with 3.4% of the balanced fluid group and 3.0% of the saline group having the composite “major adverse kidney event” (absolute difference 0.4%, 95% CI -0.5 to 1.3). There were no important differences in the secondary outcomes.
My Thoughts
This trial was a huge effort, with almost 9,000 patients enrolled, but there are some issues.
First, it is an unblinded trial with a somewhat subjective composite outcome. To me, this seems like the perfect trial for blinding. The fluids look identical already. You just need to provide them in unlabelled bags. They say their decision to unblind the trial was a “practical necessity and to reduce the risk that clinicians might attribute electrolyte changes to the trial fluid and stop adhering to the protocol.” This seems like really bad logic to me. In order to mitigate the small bias that might occur because of protocol adherence, they introduced the biggest source of bias in all of research by removing blinding. A lack of blinding matters more the stronger the opinions are on a subject, and the supposed evils of normal saline are one of the strongest opinions you will find in modern resuscitation practice.
They also changed their primary outcome from the clinicaltrials.gov listing and do not discuss that decision in the manuscript. This might be a minor issue, as the change is listed within a month of the start of the trial, and so really couldn’t be based on outcome data. However, trial registries are really only valuable if they are adhered to, and any change really must be explicitly addressed in the manuscript. This is a consistent failure of journal editors and peer reviewers in papers I review.
Despite some very strong opinions to the contrary, I have been very skeptical of the value of balanced fluids. The SPLIT trial was a double blind RCT that showed no difference at all between saline and Plasma-Lyte 148. (Young 2015) The SMART trial, an unblinded cluster RCT of 15,000 ICU patients, did demonstrate a difference in their composite outcome of major adverse kidney events, but had numerous issues (and a fragility index of 0). (Semler 2018) The SALT-ED trial was performed simultaneously with SMART, and was an unblinded cluster RCT of 20,000 emergency department patients, and showed no difference in their primary outcome of hospital free days. (Self 2018) The BaSICS trial, a double blind RCT of 11,000 ICU patients, showed no difference in mortality between normal saline and Plasma Lyte 148. (Zampieri 2021) The PLUS trial, a double blind RCT, showed absolutely no difference in all cause mortality. (Finfer 2022) Every high quality trial in existence shows no difference between saline and balanced fluids.
The fervor around balanced fluids seems particularly silly to me in the modern era of resuscitation, where the total volume of resuscitation fluid we are giving is so low. There is just no way 2 litres of salty water is having an important impact on outcomes. I can drink 3 litres of very unbalanced gatorade during a round of golf, and have no concerns about the effects on my physiology. A couple litres of saline just isn’t going to matter if you have any working nephrons.
Low volume resuscitation hasn’t made its way into pediatrics as of yet (potentially with good reason, as insensible volume losses tend to be much higher). Both groups in this trial received 85 mL/kg over the first 36 hours, which is an astronomically high amount when compared to the adult world. That is almost 3 times as much fluid as you would give an adult. If we were ever going to see a benefit from balanced fluids, it would be in a population receiving these massive volumes, and this trial was pretty definitely negative.
That being said, children are always fine. They always bound back. I don’t expect to see a lot of renal failure in children, and I don’t expect children to have trouble handling any fluids I throw at them. Alone, I think it would be hard to extrapolate this trial to adult patients. However, the results here exactly match what we have seen in adult patients, and so I think this does add to the large amount of data that suggests that normal saline is a perfectly good resuscitation fluid.
Bottom Line
This is yet another RCT in a long line of RCTs that show no meaningful differences between normal saline and the so-called balanced cystaloids.
I don’t really care which you choose, but people really need to stop referring to balanced fluids as the standard of care and saline as devil water. For practical reasons, I mostly use saline, and with the amount of data we have now, I can’t imagine that will change any time soon.
Other FOAMed
References
Balamuth F, Weiss SL, Long E, Thompson GC, Artis AS, Campos AB, Borland ML, Dalziel SR, Yock-Corrales A, Singh R, Williams A, Mickiewicz B, Hickey CP, Fitzgerald JC, Laskin BL, Hickey RW, Eckerle M, Alqurashi W, Alpern E, Ambroggio L, Badawy M, Baumer-Mouradian S, Berthelot S, Clukies LD, Craig S, Curtis SJ, Davis AL, Duffy S, Eisenberg MA, Emsley JG, Festekjian A, George S, Green R, Gripp KE, Jain PG, Jani S, Joubert GI, Judge P, Kam A, Kochar A, Koutroulis I, Kwok MY, Lane RD, Lithgow A, Lloyd J, Mansour K, McManemy JK, Morris C, Phillips N, Rao A, Rogers A, Sehgal A, Shayan Y, Silverman J, Tan E, Uspal NG, Vance C, Whyte E, Huang J, Freedman SB, Babl FE, Kuppermann N; PRoMPT BOLUS Investigators of the PECARN, PERC, and PREDICT Networks. Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock. N Engl J Med. 2026 Apr 24:10.1056/NEJMoa2601969. doi: 10.1056/NEJMoa2601969. PMID: 42028918
Finfer 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
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]
Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults. The New England journal of medicine. 2018; 378(9):829-839. PMID: 29485925 [free full text]
Young P, Bailey M, Beasley R, et al. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015; 314(16):1701-10. PMID: 26444692
Zampieri FG, Machado FR, et al. Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA. 2021 Aug 10. doi: 10.1001/jama.2021.11684. PMID: 34375394
