ARISE-FLUIDS has … Arisen

ARISE FLUIDS: a “negative” trial that might just be telling us something useful

Peake SL, Macdonald SPJ, et al; the ARISE FLUIDS Investigators, the ANZICS Clinical Trials Group, and the ACEM Clinical Trials Network. Vasopressors or Fluids in Early Septic Shock. N Engl J Med. Published online June 11, 2026. DOI: 10.1056/NEJMoa2516225. (FREE PDF COPY HERE)

We’ve spent fifteen years slowly walking back the idea that septic shock is a problem you solve by drowning it. ARISE FLUIDS is the latest, biggest, and most carefully done step in that walk-back from our part of the world. It is, on its primary outcome, resoundingly negative. I want to argue that the negative result is a useful one. For those of us working a long way from a tertiary ICU, it quietly describes an approach we should probably already be using.

The clinical question:
Once a patient with septic shock has had their first litre or two, what do you reach for next? More fluid, or noradrenaline? The Surviving Sepsis Campaign still gives a weak recommendation for at least 30 mL/kg in the first three hours, on evidence everyone agrees is… watery. ARISE FLUIDS set out to test the alternative head-on in the emergency department, before that 30 mL/kg had been committed.

PICO
ARISE FLUIDS is an investigator-initiated, open-label RCT at 51 sites (Australia / NZ), Oct 2021–Nov 2025. 1000 randomised 1:1 → 963 ITT (481 vasopressor, 482 fluids). The allocated strategy ran for a minimum 6 h and up to 24 h in a critical care area (ED or ICU); after that, both arms reverted to usual care.

Patients — Adult ED septic shock (Sepsis-3 phenotype):

Clinically suspected infection, and
SBP <90 mmHg or MAP <65 mmHg despite ≥1000 mL fluid given as boluses (a bolus = 500–1000 mL over ≤60 min, including prehospital fluid), and Lactate >2.0 mmol/L, and
IV antimicrobial already commenced
Excluded: already received >2000 mL IV fluid; >6 h since ED presentation; a reason fluid restriction or the intervention was inappropriate (cardiac failure and other fluid-restriction states, imminent surgery, care limitations, clinician-judged unsuitability)

Intervention — Restricted fluids + early vasopressors:

Resuscitation fluids stopped at randomisation
Vasopressor started immediately and titrated to a clinician-chosen MAP target; agent, route and dosing all at clinician discretion
Further fluid given only as 250 mL boluses, and only for a defined trigger: refractory hypotension, persistent hypoperfusion (e.g. delayed cap refill), lactate >4 mmol/L or rising from the previous value despite ≥2 h resuscitation, persistent tachycardia, or oliguria (UO <0.5 mL/kg/h for ≥2 h) Maintenance fluids discouraged

Control — Liberal fluids + later vasopressors:

Initial bolus of up to 1000 mL over the first hour after randomisation Further 500 mL boluses for persistent hypotension or hypoperfusion A total of 30 mL/kg by 3 h from ED presentation recommended unless contraindicated (i.e. the current Surviving Sepsis target) Fluid type, fluid-responsiveness assessment, maintenance and MAP target all at clinician discretion Vasopressors started only once the target MAP wasn’t met and the clinician judged the patient fluid-replete or fluid-unresponsive; for the minority already on a pressor at randomisation, dosing was left to clinician judgement (no mandated weaning) Both arms: if critically hypotensive, concurrent fluids + vasopressors were allowed; patients reassessed at least hourly for 6 h, then as needed.

Outcomes:

Primary: “days alive and out of hospital” to day 90

Secondary: 28- & 90-day mortality, survival time, days alive & at home, organ-support–free days to day 28

Safety: peripheral-vasopressor complications, pulmonary oedema, organ ischaemia

What they found:

Good separation. This wasn’t a trial that failed because the two arms blurred together. Over 24 hours the vasopressor group received about 1.1 L less fluid (median 1140 vs 2248 mL; difference −1108 mL, 95% CI −1395 to −850), with most of the gap opening in the first 6 hours (500 vs 1500 mL). Vasopressors were used in 86.5% vs 67.6% (an 18.9 percentage-point difference), started about an hour earlier (median 0.4 vs 1.4 h), and were given peripherally in most patients in both arms – arms of the trial – not both arms of each patient ! (71.9% vs 55.4%).

The primary outcome was as flat as it gets. Median number of “days alive and discharged” at day 90 was 76 days in both groups (difference 0.0 days, 95% CI −2.7 to 2.7, P = 1.00). Adjustment, sensitivity analysis, and every prespecified subgroup told the same story.

Mortality — read this honestly. 90-day death was 16.4% (vasopressor) vs 14.4% (fluids), RR 1.14 (95% CI 0.85–1.54); 28-day death 12.9% vs 10.0%, RR 1.29 (0.91–1.85). Not statistically significant, and the trial wasn’t powered for mortality — but the point estimates sit on the wrong side for the vasopressor strategy, and intellectual honesty means saying so.

More patients in the vasopressor arm were admitted to ICU (76.5% vs 67.8%) – this tells us more about hospital protocols than actual patient factors…

The one signal that did separate: pulmonary oedema. 0.6% in the vasopressor group vs 5.0% in the fluids group (RR 0.12, 95% CI 0.03–0.39, P <0.001). The authors fairly note this may be partly reporting bias in an open-label trial — but a roughly eight-fold difference is difficult to wave away entirely, and it’s biologically exactly what you’d predict from a litre-plus of extra crystalloid.

Bottom line as written: restricted fluids with early vasopressors did not increase days alive and out of hospital. A clean null.

So, why is a null result important for a rural hospital? Here’s the thing about a genuinely flat primary outcome with tight confidence intervals: it doesn’t tell you the strategy is better, but it does tell you it’s not worse. And once two strategies are equivalent on patient-centred outcomes, the tie-breaker becomes everything else — deliverability, safety profile, and the resources you actually have in the room. That’s where this gets interesting for those of us in places where the nearest ICU is a retrieval flight away.

This is the end of a fifteen-year arc, and the arc points one way. Rivers’ EGDT (2001) gave us aggressive front-loaded fluids, central lines and ScvO2 targets.

Then ProCESS, ARISE and ProMISe (2014) showed the elaborate protocol and the invasive monitoring added nothing over good usual care.

CLASSIC and then CLOVERS (NEJM 2023) tested fluid restriction directly and found — like ARISE FLUIDS — no mortality benefit and no convincing harm.

ARISE FLUIDS now extends that to the earliest, ED-based, pre-30 mL/kg window in well-defined Sepsis-3 shock. Every one of these trials is “negative.”

Read together, they are a fifteen-year accumulation of evidence that less fluid is safe. Meanwhile, the two traditional objections to an early-vasopressor strategy have evaporated as the evidence evolved.

The first was “you need a central line” — no longer true. Peripheral noradrenaline is now the most-studied peripheral vasopressor, used safely in thousands of patients, with extravasation events that are uncommon (~5%) and almost always minor (a bit of blanching and local oedema). In ARISE FLUIDS itself, the majority of vasopressor patients in both arms were managed peripherally. I have just rewritten the local peripheral vasopressor guidelines to reflect this reality.

The second objection was “you need an arterial line to run pressors.” EVERDAC (Muller et al, NEJM 2025) randomised 1010 ICU shock patients to invasive versus non-invasive BP and found NIBP non-inferior for 28-day mortality (34.3% vs 36.9%), with arterial-line exposure slashed from 98% to 15%. Importantly – the complications of arterial lines also dropped significantly. You can run noradrenaline through a good peripheral line, titrated to an automated cuff, and the evidence says your patient does just as well.

Put those three threads together, and you have a resuscitation strategy that is purpose-built for a rural setting: a peripheral line, a bag of noradrenaline and a NIBP cuff cycling every few minutes, and a deliberate decision not to keep pouring in fluid you may not be able to get back out. None of that requires a central line, an art line, or an ICU bed you don’t have. And the downside of the liberal-fluid alternative is concentrated exactly where we’re least equipped to deal with it.

ARISE FLUIDS standout safety signal was pulmonary oedema — five times more common in the fluids arm. In a tertiary centre, fluid-overload pulmonary oedema is an inconvenience: more oxygen, some diuresis, a CPAP circuit, an ICU review, maybe some renal-replacement (aka dialysis). In a remote ED with a single doctor, a sick septic patient, and a retrieval team six hours away, iatrogenic pulmonary oedema in an already-shocked patient is a genuinely dangerous complication that can turn a stabilisation into an intubation. If two strategies give the same days alive and out of hospital, but one of them is far less likely to flood the lungs of a patient we then have to keep alive overnight – no retrieval flight in sight – that asymmetry matters enormously to me.

So what am I actually claiming? Not that early vasopressors save lives — ARISE FLUIDS clearly does not support that, and the numerically higher mortality in the vasopressor arm is a reason for humility – we need to be wary. This science will continue to evolve.

The defensible claim is narrower and, I think, more useful: early, peripheral, NIBP-monitored vasopressor support, with judicious rather than liberal fluids, is now a safe and reasonable first-line approach to ED septic shock — and in the rural and remote context its risk-benefit balance tilts further in its favour than the headline equivalence suggests.

Less (fluids, invasive lines, intubations) is not more, but it is probably just as good.

A note on US / echocardiography in this context. Stop deciding in the dark: ultrasound should be the go-to tool in septic shock.

Here’s what nags at me about the whole fluids-versus-vasopressors literature, ARISE FLUIDS included. These are pragmatic trials that deliberately treat septic shock as one thing and randomise everyone to the same lever. ARISE FLUIDS says so explicitly — neither resuscitation targets nor any specific measure of fluid responsiveness was mandated; the decision was left to clinician discretion. That’s a legitimate design choice and it’s why the result generalises. But it also means the trial answers “fluids or pressors for the average septic patient?” when the question I’m actually asking at 2am is “what does this patient in front of me need?”

Septic shock isn’t one average patient. Some are warm, vasodilated and genuinely empty — they’ll take fluid and improve. Others have a heart that’s already struggling — septic cardiomyopathy, or a long-standing poor ventricle — and every extra bag just backs up into the lungs. A single randomised lever can’t be right for both, which is probably a fair part of why these trials keep landing on “no difference”: benefit in one group is being cancelled by harm in the other. The good news is you don’t need to be a sonographer to get useful information at the bedside. The skill that matters here isn’t measuring anything — it’s recognising the patient who shouldn’t get more fluid. Three quick looks, all well attainable for a generalist with basic POCUS training.

Lungs. B-lines are extravascular lung water, and they appear before the sats drop or you hear crackles. A couple in isolation is normal; bilateral B-lines spreading across the chest mean the lungs are getting wet — stop the fluid. It’s the easiest view to learn and the most directly actionable, and it speaks straight to that 5% pulmonary-oedema signal: much of that is preventable if someone’s putting the probe on the chest between boluses.

The heart, eyeball it. Forget ejection fractions. You’re answering one question: is this ventricle squeezing down briskly, or is it sluggish and barely moving? A poorly contracting LV is your warning that fluid will pool behind it instead of boosting output — lean towards pressors and go very easy on volume. More experienced echonerds may also be able to spot dynamic LVOT obstruction. Which is not that rare and not too hard once you know how. This might be the patient who does need a little more fluid.

The IVC, at the extremes it can be useful. A full, non-collapsing IVC suggests the tank probably isn’t empty. One data point only — never in isolation, never the headline — but a plump IVC plus B-lines plus a tired-looking heart is three arrows pointing the same way: no more fluid. A small, hard-to-see IVC is also useful; this suggests low filling pressures, which both fluids and vasopressors may help fix. A flat IVC should not mandate a fluid bolus on its own.

That’s the whole kit. You don’t need VExUS, formal fluid-responsiveness manoeuvres or a cardiology-grade study to make this call — they’re fine if you have them and the training, but they’re beyond what most of us need, and chasing them is how people talk themselves out of scanning at all. Wet lungs, a weak heart, a full IVC: that’s enough to tell you the fluids arm of this trial is the wrong arm for this patient.

To be honest about the evidence: POCUS-guided resuscitation hasn’t been shown to lower mortality in sepsis, IVC variation is unreliable on its own, and the 2026 reviews say the same — no proven survival signal yet. So I’m not claiming the probe saves lives. The claim is more modest: when the big trials tell you the average choice doesn’t matter, the only way left to beat the average is to look at the patient in front of you — and three simple views let even a novice spot the one who’ll be harmed by another litre.

Reversibility in the bush: the beautiful thing about peripheral pressors is that they are entirely “switch-off-able” – if you had to make an error, this is the error to make. I would much rather call the ICU to say that the first-line pressors are not working than to call them to say that the patient is needing to be intubated after 4 litres. The morbidity and mortality (not to mention the cost) of an intubated aero-medical retrieval are not insignificant.

The honest caveats. This was open-label, so the pulmonary-oedema signal carries some ascertainment risk. The exclusions matter for our patients: anyone already past 2000 mL or with a fluid-restriction reason like cardiac failure was out, which is a meaningful slice of remote presentations. The mortality point estimates favour fluids, even if non-significantly, and nobody should run a vasopressor-first protocol believing it’s superior. And the findings explicitly may not generalise to low-resource settings — an irony worth sitting with, given that’s precisely the setting I’m arguing they help. But equipoise was the whole premise of the trial, and ARISE FLUIDS has largely resolved it: do whichever you can do well and safely. For a lot of us north of the Tropic of Capricorn, the thing we can do well and safely — without a central line, an art line, or an ICU — is start the noradrenaline early and ease off the fluids.

This trial gives us permission to keep doing exactly that. As always — read the paper, argue with me in the comments, and tell me where the Kimberley reality differs from the trial.

References

1. Peake SL, Macdonald SPJ, et al; ARISE FLUIDS Investigators. Vasopressors or Fluids in Early Septic Shock. N Engl J Med 2026. DOI: 10.1056/NEJMoa2516225.
2. The NHLBI PETAL Network (CLOVERS); Shapiro NI, Douglas IS, et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med 2023;388:499–510.
3. Meyhoff TS, Hjortrup PB, et al (CLASSIC). Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med 2022;386:2459–70.
4. Muller G, Contou D, Ehrmann S, et al; EVERDAC Trial Group. Deferring Arterial Catheterization in Shock. N Engl J Med 2025;393:1875–88.
5. Permpikul C, Tongyoo S, et al (CENSER). Early Use of Norepinephrine in Septic Shock: A Randomised Trial. Am J Respir Crit Care Med 2019;199:1097–105.
6. Munroe ES, Co IN, Douglas I, et al. Peripheral Vasopressor Use in Early Sepsis-Induced Hypotension. JAMA Netw Open 2025;8(8):e2529148.
7. Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines 2026. Crit Care Med 2026;54:725–812.
8. Dunay Silva AAA, Medina Tovar S, Usma Gutierrez JS, et al. Impact of Point-of-Care Ultrasound-Guided Resuscitation Protocols in the Treatment of Septic Shock: A Systematic Review of Hemodynamic Outcomes and Mortality. Cureus 2026;18(1):e100850.
9. Wang J, Blake LM, Orozco N, et al. Dynamic Measures of Fluid Responsiveness to Guide Resuscitation in Patients with Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Crit Care Explor 2025;7(9):e1303.