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Date: July 9, 2026

Reference: The ARISE FLUIDS Investigators. Vasopressors or Fluids in Early Septic Shock. NEJM June 2026. 

Guest Skeptic: Dr. Aaron Skolnik is an Assistant Professor of Emergency Medicine at the Mayo Clinic Alix School of Medicine and Vice Chair of Critical Care Medicine at Mayo Clinic Arizona.  He is board-certified in Emergency Medicine, Medical Toxicology, Addiction Medicine, Internal Medicine-Critical Care, and Neurocritical Care.  Aaron is a full-time multidisciplinary intensivist and enjoys serving as the medical student clerkship director for critical care.

Case: A 69-year-old man presents by EMS to the emergency department (ED) with fever, productive cough, confusion, and weakness. He has hypertension, type 2 diabetes, and mild chronic kidney disease. His initial vitals are Temperature 38.8°C, heart rate 118 bpm, blood pressure 82/48 mmHg, respiratory rate 28 bpm, SpO₂ 90% on room air, and Glasgow Coma Scale (GCS) score of 14. He looks mottled, has delayed capillary refill, crackles at the right base, and dry mucous membranes.

A chest x-ray suggests right lower-lobe pneumonia. Labs show white blood cell count (WBC) 17,000, creatinine 1.8 mg/dL, and lactate 3.4 mmol/L. Blood cultures are drawn, broad-spectrum antibiotics are started, and he receives 1 litre of balanced crystalloid. Thirty minutes later, his mean arterial pressure (MAP) remains around 60 mmHg. The resident asks: “Should we give more fluid to get to 30 mL/kg, or start norepinephrine now?”

Background: Sepsis remains one of the highest-stakes and humbling diagnoses in emergency medicine. It is not as simple as infection plus abnormal vitals. Sepsis-3 reframed sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, moving away from the older SIRS-based definition and retiring the term severe sepsis. Septic shock is now generally understood as sepsis with persistent hypotension requiring vasopressors to maintain a MAP of at least 65 mmHg, with lactate greater than 2 mmol/L despite adequate volume resuscitation.

For emergency physicians, the challenge is that sepsis is still largely a clinical diagnosis without a gold standard test. Systemic Inflammatory Response Syndrome (SIRS) is sensitive (true-positive) but not specific (true-negative). qSOFA may predict mortality, but it is not sensitive enough to rule out sepsis in the ED. Lactate is useful for risk stratification, but it’s not a magic wand, and procalcitonin is not accurate enough to rule in or rule out bacterial infection. The SGEM has repeatedly emphasized that sepsis screening tools, biomarkers, and bundles should be used with healthy skepticism rather than blind obedience.    

Treatment in the ED usually starts with the basics: recognize the patient may be septic, obtain cultures when appropriate without delaying care, give early appropriate antimicrobials, seek source control, and support perfusion. The resuscitation controversy has evolved over two decades. Early goal-directed therapy (EGDT) gave way to usual-care trials that challenged protocolized central venous pressure and ScvO₂ targets. Fixed fluid mandates have been questioned, and many clinicians now worry about both under-resuscitation and fluid overload. As SGEM has argued, whether rigid bundles based on low-certainty evidence improve patient-oriented outcomes (POO).    

That leaves a very practical bedside question: after an initial litre or two, should we keep pouring in crystalloid, or should we start vasopressors earlier? Fluids can improve preload and perfusion, but excessive fluid administration may worsen pulmonary edema, tissue edema, and organ dysfunction. Vasopressors can restore vascular tone and perfusion pressure, but raise concerns about ischemia, monitoring, IV access, and intensive care unit (ICU) resource use. This is exactly the kind of EM question that deserves a patient-oriented answer. As we say on the SGEM, they are called guidelines, not GODlines.

Clinical Question: In adult ED patients with early septic shock, does a strategy of restricted fluids and early vasopressors, compared with more liberal fluids and later vasopressors, increase days alive and out of hospital at 90 days?

Reference: The ARISE FLUIDS Investigators. Vasopressors or Fluids in Early Septic Shock. NEJM June 2026. 

  • Population: Adults presenting to the ED with clinically suspected infection, systolic blood pressure (SBP) <90 mmHg or MAP <65 mmHg despite at least 1000 mL IV fluid boluses, lactate >2 mmol/L, and IV antimicrobials started.
    • Exclusions: Key ones included >2000 mL IV fluids before enrollment, >6 hours since ED presentation, care limitations, immediate surgery, and clinician-determined unsuitability.
  • Intervention: Restricted fluid strategy with early vasopressors. IV resuscitation fluids were stopped after randomization; vasopressors were started, with 250 mL boluses permitted for specified signs of persistent hypoperfusion.  
  • Comparison: Greater fluid volume with later vasopressors. Patients received up to 1000 mL initially, then 500 mL boluses for persistent hypotension or hypoperfusion; 30 mL/kg within 3 hours was recommended unless contraindicated.  
  • Outcome:
    • Primary Outcome: Days alive and out of hospital from randomization to day 90.
    • Secondary Outcomes: Mortality at 28 and 90 days, survival time to day 90, days alive and at home at day 90, days alive and free from organ support at day 28; tertiary and safety outcomes included discharge timing, in-hospital mortality, organ support, pulmonary edema, ischemia, and peripheral vasopressor complications.
  • Type of Study: Investigator-initiated, multicenter, open-label, parallel-group randomized controlled trial.

Authors’ Conclusions: “Among adult patients who presented to the emergency department with septic shock, an approach that involved restricted fluid volume and early vasopressors did not result in a greater number of days alive and out of the hospital at day 90 than an approach involving greater fluid volume and later administration of vasopressors.”

Quality Checklist for Randomized Clinical Trials (Yes, No or Unsure):

  1. Did the study population include or focus on those in the emergency department? Yes
  2. Were the patients adequately randomized? Yes
  3. Was the randomization process concealed?. Yes
  4. Were the patients analyzed in the groups to which they were randomized? Yes 
  5. Were the patients recruited consecutively, with no selection bias? No
  6. Were both groups similar with respect to prognostic factors? Yes
  7. Were all participants, clinicians, and outcome assessors blinded to group allocation? No
  8. Were all groups treated equally except for the intervention? Unsure
  9. Was follow-up complete, meaning at least 80% for both groups? Yes
  10. Were all patient-important outcomes considered? Yes
  11. Was the treatment effect large enough and precise enough to be clinically significant? No
  12. Who funded the trial? The trial was funded by the Australian National Health and Medical Research Future Fund and the New Zealand Health Research Council. The appendix states the funders had no role in design, conduct, analysis, interpretation, or reporting.
  13. Did the authors declare any conflicts of interest? At least two authors had potentially relevant professional/industry disclosures. However, there were no obvious trial-specific commercial conflicts apparent.

Key Results: In adult ED patients with early septic shock, restricted fluids with early vasopressors did not improve days alive and out of hospital at 90 days compared with a more liberal fluid strategy and later vasopressors.

  • Primary Outcome: Median days alive and out of hospital at day 90 were 76 days in both groups: 76 days (IQR 55–83) vs 76 days (IQR 55–82), difference 0.0 days, 95% CI −2.7 to 2.7, P=1.00.
  • Secondary Outcomes: Mortality appeared similar: 28-day mortality 12.9% vs 10.0%, and 90-day mortality 16.4% vs 14.4%. Days alive and at home at day 90 were also similar. Invasive ventilation and renal replacement therapy were similar. Pulmonary edema was lower in the vasopressor group, 0.6% vs 5.0%, though the authors noted this could partly reflect reporting bias in an unblinded trial.

1. Modified Intention-To-Treat Analysis: The trial randomized 1000 patients, but 37 patients were excluded because informed consent or permission for data use was not obtained, leaving 963 patients in the analyzed population. This was balanced between groups and is unlikely to overturn the result, but it is not a pure intention-to-treat analysis (ITT). A strict ITT analysis preserves the prognostic balance created by randomization and avoids post-randomization exclusions.  

2. Selection Bias & External Validity: This trial applies to a selected group of adult ED patients with early septic shock after at least 1 L but not more than 2 L of IV fluid, lactate >2 mmol/L, antibiotics started, and randomization within a narrow ED time window. Many real-world septic shock patients were excluded, including those who had received >2 L of fluid, presented late, required immediate surgery, had treatment limitations, had imminent death, had low likelihood of 90-day survival, or were judged by clinicians to be unsuitable for one or both treatment arms. This makes the trial highly relevant to early ED septic shock, but less applicable to patients who are already fluid overloaded, profoundly hypovolemic, perioperative, late-presenting, transferred, palliative, or outside systems where peripheral vasopressors and ICU-level monitoring are readily available.  

Open Label

3. Open-Label: Patients and treating clinicians were not masked to group assignment. This is understandable for a fluids-versus-vasopressors strategy trial, but it can influence clinician-mediated decisions such as additional fluid boluses, vasopressor initiation, corticosteroid use, ICU admission, ED/ICU discharge timing, and reporting of adverse events. This is especially important for pulmonary edema, which was defined as related to the study intervention “in the opinion of the treating clinician,” with clinical documentation including respiratory distress, chest x-ray findings, diuretics, CPAP/PEEP, or increased oxygen. The statisticians and management committee were blinded until after the blinded analysis was complete, which helps, but does not remove bedside performance bias.

4. Substantial Clinician Discretion: This was not a tightly controlled efficacy trial of a single therapy. Fluid type, vasopressor type, vasopressor route, target MAP, fluid responsiveness assessment, corticosteroids, source control, antimicrobial management, and other aspects of care were left to treating clinicians. That makes the trial more generalizable to real ED/ICU practice, but it also makes it harder to isolate whether outcomes were driven by less fluid, earlier vasopressors, peripheral vasopressor practice, ICU availability, or other cointerventions. The pragmatic design improves applicability but weakens mechanistic clarity.  

5. Patient-Oriented Outcome: Days alive and out of the hospital at 90 days is a patient-oriented outcome (POO) and was chosen with patient input because it captures both survival and morbidity. However, it can still be influenced by discharge practices, readmissions, ICU capacity, rehabilitation access, and local health-system factors. More importantly, the main publication did not report the planned longer-term quality-of-life and disability outcomes. The protocol included death or disability at 6 and 12 months using WHODAS 2.0, quality of life at 6 and 12 months using EQ-5D-5L, and cost-effectiveness, but these were planned for separate reporting. Mortality is objective, but survival with severe disability or poor quality of life may be worse than death for some patients, so the absence of these outcomes in the main report limits bedside interpretation. We look forward to seeing that data published to further inform our care.

Listen to the SGEM podcast to hear additional information from Dr. Stephen MacDonald, Senior Investigator for the ARISE FLUIDS trial or click on this LINK. 

Comment on the Authors’ Conclusion Compared to the SGEM Conclusion: We generally agree with the authors’ appropriately conservative conclusion.

SGEM Bottom Line: In adult ED patients with early septic shock, don’t drown them in crystalloid and don’t squeeze them reflexively with vasopressors. Assess, individualize, and treat the patient, not the protocol.

Case Resolution: Your patient has pneumonia-associated septic shock with persistent hypotension after 1 L of crystalloid and lactate 3.4 mmol/L. You continue antibiotics, reassess perfusion, check lung ultrasound/IVC, or perform a passive leg raise if feasible, and give small additional boluses only if he appears fluid-responsive. Because he remains hypotensive, you start norepinephrine through a well-functioning peripheral IV while arranging ICU admission and ongoing monitoring. You do not reflexively chase 30 mL/kg if he is not fluid responsive or starts showing signs of pulmonary edema.

Dr. Aaron Skolnik

Clinical Application: This trial should not be interpreted as early pressors for everyone or 30 mL/kg for everyone. It supports a more nuanced approach: give initial fluid, reassess frequently, avoid automatic large-volume resuscitation, and start vasopressors when hypotension persists rather than waiting until the patient has received an arbitrary volume. The priority remains early recognition, antimicrobials, source control, hemodynamic support, and bedside reassessment.

What Do I Tell the Patient: You have a serious infection that is making your blood pressure dangerously low and putting stress on your organs. We are treating the infection with antibiotics and supporting your circulation. Some fluid is helpful, but too much can collect in the lungs and cause harm. We may also use a blood-pressure medicine through the IV to support blood flow to your brain, heart, and kidneys while the antibiotics start working. We will be watching you very closely and adjusting treatment based on how your body responds.

Keener Konest: Listen to the SGEM podcast for this week’s question. If you know the answer, then send an email to thesgem@gmail.com with “keener” in the subject line. The first correct answer will receive a shout-out.

Other Reviews of ARISE Fluid

Other SGEM Episodes on Sepsis:

  • SGEM #463: Like the Legend of the Phoenix… Criteria for Sepsis
  • SGEM #448: More than a Feeling-Gestalt vs CDT for Predicting Sepsis
  • SGEM #371: All of My Lovit, Vitamin C Won’t Work for You
  • SGEM #346: Sepsis-You were Always on My Mind
  • SGEM Xtra: Petition to Retire the Surviving Sepsis Campaign Guidelines
  • SGEM #207: Ahh (Don’t) Push It- Pre-hospital IV Antibiotics for Sepsis
  • SGEM #174: Don’t Believe the Hype – Vitamin C Cocktail for Sepsis
  • SGEM #168: HYPRESS – Doesn’t Got the Power
  • SGEM #92: Arise Up, Arise Up (EGDT vs Usual Care for Sepsis)
  • SGEM #90: Hunting High and Low (Best MAP for Sepsis Patients)
  • SGEM #69: Cry Me a River (Early Goal-Directed Therapy) Process Trial

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.