The management of sepsis has evolved dramatically since I was a trainee, just after Manny Rivers published his seminal sepsis protocol. At this point, I think we mostly know what we are doing. We give antibiotics. We look for a source and get source control. We give some fluids, but not too much. Most importantly, we reassess the patient frequently and make sure they are improving clinically. Personally, I think we have plucked the low hanging fruit, and I am not overly excited about ongoing sepsis research, but there is a lot of ongoing research. One question is exactly how much fluids should these patients be getting? Or, phrased differently, when should we switch to vasopressors instead of fluids? This is the question that the ARISE FLUIDS trial attempted to answer.
The question
Does a fluid restrictive approach, with early vasopressors, reduce mortality in sepsis?
The ARISE FLUIDS trial
ARISE FLUIDS Investigators, the ANZICS Clinical Trials Group, and the ACEM Clinical Trials Network; Peake SL, Macdonald SPJ, Howe BD, Milford E, Jones P, Arendts G, Bailey M, Burcham J, Delaney A, Egerton-Warburton D, Fatovich D, Fraser JF, Higgins AM, Keijzers G, Udy AA, Williams P, Young PJ, Bellomo R. Vasopressors or Fluids in Early Septic Shock. N Engl J Med. 2026 Jun 11. doi: 10.1056/NEJMoa2516225. PMID: 42274006
The methods
This is a multi-centre, open-label, RCT that enrolled adult patients with sepsis and ongoing hypotension despite a 1,000 mL bolus, and randomized them to receive restricted fluids and earlier vasopressors (vasopressor group) or greater volumes of fluid and later vasopressors (fluids group). The recommended amount of fluids in the fluids group was 30 mL/kg within 3 hours. The primary outcome was days alive and out of the hospital from randomization to follow-up at day 90.
The results
Out of 2080 eligible patients, 1000 were randomized. The biggest reasons for exclusion were that the patients were hypovolemic and required fluid or had co-morbidities (CHF, ESRD) that limit fluid resuscitation. In other words, you need to apply judgement before treating, and these results only apply to the patients with clinical equipoise about fluids.
The groups did separate in terms of therapy, although not dramatically. Within 24 hours, 87% of the vasopressor group had received vasopressors as compared to 68% of the fluids group. By 24 hours the vasopressor group had received 1140 mL of fluid as compared to 2248 mL in the fluids group.
There was no difference in the primary outcome, with the median number of days alive and out of hospital by 90 days being 76 in both groups. Secondary outcomes were similar across the board. It is not statistically significant, but mortality is slightly higher in the vasopressor group, and this trial is relatively small. Obviously, pulmonary edema is a little higher in the fluids group (5% vs 1%).
My thoughts
Although this is an important trial, I think we already sort of knew the results. We saw the same thing in the CLOVERS trial and the CLASSIC trial, although those patients were enrolled a lot later and had already received more fluids. (Meyhoff 2022; Shapiro 2023)
The biggest strength of this trial is probably that patients were enrolled so early, making it highly applicable to emergency practice. We are always going to give 1-2 L of fluid. The question is what to do next, and that is exactly what was addressed by this trial.
It is an unblinded trial, which makes sense, but always adds a lot of room for bias. The outcome sounds objective, but discharge decisions are highly subjective, and highly influenced by systems issues. That being said, I am less worried about that subjectivity in this trial, because the clinicians making the decisions a week down the road were less likely to be involved in the first 24 hours of resuscitation, and are therefore somewhat less likely to be biased.
The pulmonary edema safety finding is highly believable, but it is also the most subjective. If you know your patient got 3 litres of extra fluid, you might be biased into seeing a slightly fluffier x-ray or a few extra b-lines on ultrasound.
Although I do not have to deal with silly sepsis metrics, I do get stuck with some silly debates around disposition. Sick patients warrant close observation, especially early in their course. The ICU will always provide better nursing and observation than the ward. Outside of the obvious patients who either need or should not get extra fluids, one of the primary drivers of my decision to start vasopressors has been my sense that the patient would benefit from the ICU. If I want the patient in the ICU, I for the issue by starting a pressor.
It is somewhat ridiculous to base the decision for an ICU admission entirely around a single medication. The patient is sick whether or not they need a low dose vasopressor. We know that early septic shock can have a labile course. One of the biggest mistakes we make in sepsis is to be falsely reassured by a normal blood pressure reading after a fluid bolus. That fluid will redistribute. The blood pressure will drop again. The question is whether you are watching close enough to catch it.
Great intensivists will recognize this. Great intensivists will accept sick sepsis patients to the ICU for monitoring even if they aren’t currently requiring vasopressors. Unfortunately, not all intensivists are great, and even if they are, overcrowded ICUs and bedspace pressures will always make this a difficult decision. In my setting, I worry that these trial results could be used inappropriately. I could imagine admitting services stating that these patients clearly don’t need vasopressors, and should just be treated with fluid boluses instead, making them candidates for the floor. If that means sending the patient to the end of the hallway where they will get vitals done twice a shift, it could be a grave mistake. Hopefully I am just overly cynical, but I have seen EBM weaponized in similar ways before.
Clinical judgement is important. Remember that these neutral results occurred after clinical judgement was applied. They eliminated patients who ‘needed fluid’. They eliminated patients who were at higher risk from receiving fluid. It is therefore absolutely essential that you apply clinical judgement, or you won’t be able to replicate even these neutral findings.
There may be room to tease this group apart further, finding subgroups that will do better with either fluids or vasopressors. I could imagine ultrasound being used to guide you in one direction or another, especially in the hands of expert users. It is a mistake to equate negative findings with nihilism. You still need to think carefully about your patient, and decide what you think is best.
At the end of the day, this trial won’t change much where I work. The results might be very important for people who have to deal with ridiculous surviving sepsis campaign guidelines and performance metrics derived from them, but for clinicians that have always been allowed to practice based on good clinical judgement, this study is just a nice statement that we are on the right track.
Bottom line
If you have a sick sepsis patient who remains hypotensive after the first bolus, this RCT tells you that it is probably equally appropriate to move to vasopressors early or to trial a few small fluid boluses. Clinical judgement is important, as always.
Morgenstern, J. ARISE FLUIDS – Fluids, pressors, neither, both?, First10EM, October 19, 2026. Available at:
https://doi.org/10.51684/FIRS.146627
Did you find this information useful? There are many other First10EM critical appraisals, which can be found here. Also, consider subscribing to this blog:
Other FOAMed
BroomeDocs: ARISE-FLUIDS has … Arisen
ARISE FLUIDS on Critical Care Reviews
Evidence based medicine is easy
Evidence based medicine resources
References
ARISE FLUIDS Investigators, the ANZICS Clinical Trials Group, and the ACEM Clinical Trials Network; Peake SL, Macdonald SPJ, Howe BD, Milford E, Jones P, Arendts G, Bailey M, Burcham J, Delaney A, Egerton-Warburton D, Fatovich D, Fraser JF, Higgins AM, Keijzers G, Udy AA, Williams P, Young PJ, Bellomo R. Vasopressors or Fluids in Early Septic Shock. N Engl J Med. 2026 Jun 11. doi: 10.1056/NEJMoa2516225. PMID: 42274006
Meyhoff TS, Hjortrup PB, Wetterslev J, Sivapalan P, Laake JH, Cronhjort M, Jakob SM, Cecconi M, Nalos M, Ostermann M, Malbrain M, Pettilä V, Møller MH, Kjær MN, Lange T, Overgaard-Steensen C, Brand BA, Winther-Olesen M, White JO, Quist L, Westergaard B, Jonsson AB, Hjortsø CJS, Meier N, Jensen TS, Engstrøm J, Nebrich L, Andersen-Ranberg NC, Jensen JV, Joseph NA, Poulsen LM, Herløv LS, Sølling CG, Pedersen SK, Knudsen KK, Straarup TS, Vang ML, Bundgaard H, Rasmussen BS, Aagaard SR, Hildebrandt T, Russell L, Bestle MH, Schønemann-Lund M, Brøchner AC, Elvander CF, Hoffmann SKL, Rasmussen ML, Martin YK, Friberg FF, Seter H, Aslam TN, Ådnøy S, Seidel P, Strand K, Johnstad B, Joelsson-Alm E, Christensen J, Ahlstedt C, Pfortmueller CA, Siegemund M, Greco M, Raděj J, Kříž M, Gould DW, Rowan KM, Mouncey PR, Perner A; CLASSIC Trial Group. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022 Jun 30;386(26):2459-2470. doi: 10.1056/NEJMoa2202707. Epub 2022 Jun 17. PMID: 35709019
National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network; Shapiro NI, Douglas IS, Brower RG, et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Jan 21. doi: 10.1056/NEJMoa2212663. PMID: 36688507
