Sepsis remains one of the most significant challenges in modern medicine. Despite progress in antibiotic therapy, resuscitation medicine, and intensive care, sepsis is still associated with high mortality and severe complications. Septic shock is particularly dangerous—a state where a systemic inflammatory response triggered by an infection leads to severe circulatory disorders, a rapid drop in blood pressure, and organ hypoperfusion. In such patients, damage to the kidneys, liver, lungs, and central nervous system can develop very rapidly, significantly increasing the risk of lethality.
For decades, the rapid intravenous administration of large volumes of fluids has been considered one of the main pillars of septic shock treatment. The rationale behind this approach was the belief that vasodilation and capillary leak during sepsis reduce effective circulatory volume, meaning the body requires additional fluid. Based on this logic, international guidelines for many years recommended a rapid infusion of at least 30 mL/kg of crystalloids during the early stages of septic shock.
However, experience over time has shown that not all patients respond to fluid resuscitation in the same way. It is well known that in certain cases, large-volume infusions cause pulmonary edema, hypoxemia, the need for mechanical ventilation, increased intra-abdominal pressure, and worsening of renal function. Elderly patients, individuals with heart failure, and those who already had organ dysfunction are at particularly high risk. These observations have raised an important question: could additional fluids at a certain stage of septic shock harm the patient more than help?
Sepsis and Its Mechanism
The pathophysiology of sepsis partially explains this question. In response to infection, the body releases cytokines and other inflammatory mediators that cause endothelial damage, vasodilation, and increased capillary permeability. As a result, fluid leaves the vascular space and accumulates in the tissues. Under these conditions, simply administering additional volume cannot restore effective perfusion because part of the infused fluid continuously shifts into the interstitial space. At the same time, another leading cause of arterial hypotension is vasodilation, which is why restoring vascular tone with vasopressors could theoretically be more effective.
Vasopressors and Their Effect
Among vasopressors, norepinephrine is primarily used. It acts on alpha-adrenergic receptors and causes vasoconstriction, resulting in an increase in systemic vascular resistance and mean arterial pressure. Furthermore, norepinephrine improves venous return to some extent and may increase cardiac preload. In recent years, a hypothesis has emerged that introducing norepinephrine earlier to manage the process might reduce the need for large volumes of fluids and prevent the complications of fluid overload.
Vasopressors or Fluids During Early Septic Shock
What should be done when a patient has already received initial resuscitation but hypotension still persists? It is precisely in this context that the ARISE-FLUIDS study, titled “Vasopressors or Fluids During Early Septic Shock,” was published in the New England Journal of Medicine in 2026. The primary objective of the study was to determine whether the early use of norepinephrine, compared to additional fluids, yields better outcomes in the early phase of septic shock following initial resuscitation.
The study was a multicenter, randomized, controlled trial. It enrolled patients who presented with septic shock and had already received initial fluid resuscitation but still required further hemodynamic support. Participants were divided into two groups: in one group, priority was given to the early initiation of vasopressors, while the second group received additional intravenous fluids.
Researchers evaluated not only mortality but also organ function, duration of intensive care unit (ICU) stay, the need for renal replacement therapy, the frequency of mechanical ventilation, and other clinically significant indicators. The particular importance of the study lay in the fact that it reflected real clinical practice and answered a daily question that intensivists ask almost every hour: “When a patient with septic shock has already been given initial fluids, should the next step be even more fluids or earlier-initiated norepinephrine?”
The ARISE-FLUIDS study was placed right at the center of this debate, and its results may serve as one of the foundations for revising modern standards of septic shock management.
ARISE-FLUIDS Study Results, Clinical Significance, and the Future of Septic Shock Treatment
Although increasing evidence regarding the negative effects of fluid overload has emerged in recent years, inertia in clinical practice persisted for a long time. This is why the results of ARISE-FLUIDS are not perceived merely as data from a single study—they reflect a potential shift in the philosophy of sepsis management.
One of the most important results of the study was that the early use of vasopressors significantly reduced the total volume of intravenous fluids received by patients. While this seems like an expected outcome, it holds much greater significance from a clinical perspective. In intensive care units, it is well known that a positive fluid balance is considered an independent prognostic factor and is strictly monitored, while the risks of expected overload were discussed at the beginning of this article.
ARISE-FLUIDS also showed that the earlier initiation of norepinephrine was not associated with the development of serious adverse events. No, hypertension and its difficult regulation—no, high blood pressure is always better than fatally low pressure; for years, there was a fear that vasoconstriction could worsen tissue perfusion, especially when the volume deficit was not fully corrected.
According to modern concepts, the main problem in septic shock is not always hypovolemia. Systemic vasodilation and loss of vascular tone are no less important factors—and this is exactly what must be targeted in a timely manner. When blood vessels dilate uncontrollably, additional fluids often only temporarily increase intravascular volume, after which a large portion of them shifts into the interstitial space. Under these conditions, norepinephrine restores vascular tone, improves mean arterial pressure, and ensures better perfusion of vital organs with a much lower infusion load.
Admittedly, the study did not show a dramatic difference in all clinical outcomes, but this represents one of the characteristics of modern intensive care research. Today, patients with sepsis receive much better treatment than they did twenty years ago, making it increasingly difficult to demonstrate a significant reduction in mortality. Despite this, improving indicators such as fluid balance, preservation of organ function, reducing the need for mechanical ventilation, and the duration of intensive care is of paramount importance for clinical practice.
The results of ARISE-FLUIDS become particularly interesting when compared with other major recent studies. The CLASSIC study, published in 2022, showed that a more restrictive fluid strategy is safe and does not increase mortality compared to patients receiving standard care. Although CLASSIC failed to prove a clear superiority, it was the first to seriously challenge the old dogma that more fluid always yields better results.
The CLOVERS study, conducted around the same period, compared a restrictive fluid strategy with a more liberal infusion approach. The results again failed to show a significant difference in mortality, but it was reconfirmed that the earlier use of vasopressors is safe and does not worsen patient prognosis. It was this study that laid the groundwork for more targeted research in the future.
The even earlier published CENSER study showed that the early administration of norepinephrine reduced the progression of shock, and patients achieved hemodynamic stabilization faster. Although the study was relatively small in scale, it first proposed the idea that ARISE-FLUIDS later evaluated in a much broader population.
When these studies are considered together, a clear trend emerges. Modern resuscitation is gradually moving away from a one-size-fits-all approach toward individualized treatment. Today, the question being asked more frequently is not whether to give the patient fluid, but whether they are truly fluid-responsive. This distinction is fundamental. Modern hemodynamic monitoring, echocardiography, pulse pressure variation, and other methods allow clinicians to assess whether an additional infusion will bring real benefit to a specific patient. If the answer is negative, additional fluid may only become a source of complications.
Surviving Sepsis Campaign
A significant portion of experts already predicts that the recommendations of the Surviving Sepsis Campaign will be revised in the coming years. It is expected that the guidelines will emphasize individual patient assessment, objective determination of fluid responsiveness, and the earlier use of norepinephrine even more clearly. This does not mean that fluid resuscitation will lose its importance, but rather that its use will become more cautious and targeted.
Of course, the study also had certain limitations. Sepsis is an extremely heterogeneous syndrome. Different sources of infection, comorbidities, age, cardiac function, and immune status significantly alter a patient’s response to both fluids and vasopressors. Therefore, it is impossible to create a single universal algorithm that fits every clinical situation. This is why ARISE-FLUIDS should not be viewed as the final answer to all questions. Rather, it is another strong piece of evidence showing that modern intensive care is becoming more personalized.
