Case: A 74-year-old woman with hypertension and stage 3 chronic kidney disease presents to the emergency department (ED) with fever, vomiting, dysuria, and right flank pain. She is confused, mottled, and has delayed capillary refill. Her temperature is 39.1°C, heart rate 116 beats per minute, blood pressure 84/50 mmHg, respiratory rate 20 breaths per minute, and oxygen saturation 95 percent on room air.

Laboratory testing demonstrates a white blood cell count of 18,000, creatinine of 2.0 mg/dL, and lactate of 3.6 mmol/L. Urinalysis supports pyelonephritis. Cultures are obtained, broad-spectrum antibiotics are started, and she receives 1 L of balanced crystalloid. Thirty minutes later, her mean arterial pressure remains near 60 mmHg. The nurse asks, “Should we keep giving fluid to reach 30 mL/kg or start norepinephrine now?”

Background: Sepsis remains one of the most humbling diagnoses in emergency medicine. It is a clinical syndrome without a gold standard test. Systemic inflammatory response syndrome criteria are sensitive but not specific. The quick sequential organ failure assessment may help identify patients at increased risk of death, but it is not sensitive enough to rule out sepsis. Lactate can help with risk stratification, but it is not a magic wand.

Treatment begins with the basics: Recognize the possibility of sepsis, give appropriate antimicrobials, obtain source control, and support perfusion. The controversy is how best to provide that support. Early goal-directed therapy gave way to trials challenging rigid hemodynamic targets.^1-3 Fixed fluid mandates have also been questioned as clinicians increasingly recognize the potential harms of fluid overload.⁴

Fluids may improve preload and cardiac output. Too much fluid may worsen pulmonary and tissue edema. Vasopressors restore vascular tone and perfusion pressure but introduce concerns about ischemia, vascular access, monitoring, and intensive care resources. This leaves us with a common bedside dilemma: After the first liter or two, should we keep pouring or start squeezing?

Clinical Question: In adult ED patients with early septic shock, does restricting fluids and starting vasopressors earlier, compared with giving more fluid and delaying vasopressors, increase days alive and out of the hospital at 90 days?

Reference: The ARISE FLUIDS Investigators. Vasopressors or Fluids in Early Septic Shock. N Engl J Med. 2026. doi:10.1056/NEJMoa2516225.

• Population: Adults with suspected infection, systolic blood pressure below 90 mmHg or mean arterial pressure below 65 mmHg after at least 1 L of intravenous fluid, lactate above 2 mmol/L, and antimicrobials started. Exclusions: More than 2 L of fluid before enrollment, more than six hours since ED presentation, immediate surgery, limitations on care, or clinician-determined unsuitability.
• Intervention: Restricted resuscitation fluid with early vasopressors. Additional 250 mL boluses were permitted for specified signs of hypoperfusion.
• Comparison: Greater fluid administration with later vasopressors. A total of 30 mL/kg within three hours was recommended unless contraindicated.
• Primary Outcome: Days alive and out of the hospital through day 90.
• Study Design: Multicenter, open-label, 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.”

Results: The analyzed population included 963 patients. Median days alive and out of the hospital at day 90 were identical: 76 days in each group. The estimated difference was 0.0 days, with a 95 percent confidence interval from −2.7 to 2.7 days.

Mortality was also similar. Twenty-eight-day mortality was 12.9 percent with restricted fluids and early vasopressors versus 10.0 percent with greater fluids and later vasopressors. Ninety-day mortality was 16.4 percent versus 14.4 percent, respectively. There were no important differences in days alive at home, invasive ventilation, or renal replacement therapy.

Pulmonary edema was reported less often with early vasopressors, 0.6 percent versus 5.0 percent, although interpretation of this finding is complicated by the open-label design.

Key Result: A restricted-fluid, early-vasopressor strategy was not superior to a greater-fluid, later-vasopressor strategy for days alive and out of the hospital at 90 days.

Talk Nerdy

1. Selection Bias:This was a selected ED population with early shock physiology who had received at least 1 L, but no more than 2 L, of fluid. Antibiotics had already been started, and enrollment occurred within a narrow window. Of the patients who met the inclusion criteria, many were not randomized because clinicians considered one or both strategies unsuitable. This can introduce selection bias, and the findings are also most applicable to patients who look like the trial participants and less so to other types of patients.
2. Open-Label Pragmatic Design:Masking clinicians to fluid and vasopressor strategies would be difficult, but knowing the allocation can lead to performance bias. Fluid type, vasopressor route, target pressure, assessments of fluid responsiveness, and other co-interventions were largely left to the treating team. This makes the trial more reflective of real practice but makes it harder to determine which part of the overall strategy drove the results. It also means the pulmonary edema finding should be interpreted cautiously because its diagnosis includes clinician judgment.
3. Patient-Oriented Outcomes:Days alive and out of the hospital is a patient-oriented outcome that captures both mortality and morbidity. That is better than relying only on a surrogate such as blood pressure, lactate clearance, or total fluid volume. However, hospital-free days can still be influenced by local discharge practices, access to rehabilitation, readmissions, and intensive care unit capacity.

SGEM Bottom Line: In adults with early septic shock, do not drown them in crystalloid and do not squeeze them reflexively with vasopressors. Reassess, individualize, and treat the patient, not the protocol.

Case Resolution: You continue antimicrobial therapy and reassess her perfusion, cardiac function, and lungs. A passive leg raise does not produce a meaningful increase in stroke volume, and lung ultrasound shows scattered B-lines. Because hypotension persists, norepinephrine is started through a well-functioning proximal peripheral intravenous line while intensive care unit admission is arranged. Additional small fluid boluses will be considered only if subsequent reassessment suggests fluid responsiveness. You do not continue crystalloid merely to satisfy an arbitrary volume target.

Thank you to Dr. Aaron Skolnik for his help with this critical appraisal and to the ARISE FLUIDS investigators for asking an important emergency medicine question.

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

Dr. Milne is a staff physician at the Strathroy Middlesex General Hospital in Strathroy, Ontario, Canada, and is an associate professor in the Department of Medicine (Division of Emergency Medicine) and Department of Family Medicine at the Schulich School of Medicine and Dentistry.

References

1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377.
2. ARISE Investigators; ANZICS Clinical Trials Group; Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496-1506.
3. ProCESS Investigators; Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370(18):1683-1693.
4. Meyhoff TS, Hjortrup PB, Wetterslev J, et al.; CLASSIC Trial Group. Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med. 2022;386(26):2459-2470.