In this study, patients with sepsis who received 40 to < 45 mL/kg of fluid volume within 3 h were more likely to survive, discontinue mechanical ventilation, and get discharged from the ICU compared with those administered 20 to < 25 mL/kg fluid volume within 3 h. Moreover, among those who received 40 to < 45 mL/kg of fluid, those who received fluid resuscitation for a shorter infusion time (≤ 3 h) had a lower mortality risk than those who received it for a longer infusion time (> 3 h). The findings of this large cohort study of patients with sepsis suggested the importance of the combined effect of volume and infusion time in fluid resuscitation in patients with sepsis.

An early analysis of the survival sepsis campaign database reported no association between 20 mL/kg of initial fluid resuscitation volume during 6 h with adjusted-risk assessment for hospital mortality¹⁷. The recent guidelines recommend 30 mL/kg of fluid volume within 3 h for initial resuscitation in patients with sepsis-induced hypoperfusion or septic shock³. However, our results suggested that resuscitation with fluid volume > 30 mL/kg within 3 h was associated with a better prognosis in patients with sepsis. A retrospective study showed that a higher proportion of total fluid amount in the first 3 h after 20 m L/kg of fluid resuscitation was significantly associated with a decreased risk of hospital mortality¹³. Similarly, children with septic shock who received 40 mL/kg fluid in the first hour had lower mortality than those who received < 20 mL/kg fluid volume¹⁸. Another retrospective study reported that higher fluid volumes with a plateau of 35–45 mL/kg by 3 h were correlated with decreased mortality¹⁰. A more recent study suggested that a fluid resuscitation rate of 0.25–0.5 mL/kg/min, which is equivalent to 45–90 mL/kg within 3 h was optimal¹¹. Findings from these previous studies and our results suggest an association between > 30 mL/kg of fluid infusion within 3 h and survival in patients with sepsis.

Fluid resuscitation aims to restore intravascular volume and increase cardiac output, thereby improving tissue perfusion in patients with sepsis¹⁹. Fluid resuscitation comprises four dynamic phases: resuscitation, optimization, stabilization, and evacuation²⁰. Most studies reporting the harmful effect of fluid overload analyzed the association between positive fluid balance after the stabilization phase^21,22. Whereas, studies comparing restrictive versus liberal fluid administration focused on the resuscitation phase, and consequently showed no survival benefit of the restrictive fluid strategy^23,24,25. Another study did not detect a difference in intubation incidence between guideline-based and restrictive fluid resuscitation in patients at a high risk of acute respiratory failure²⁶. A recent study demonstrated the potential harm of early vasopressor use without sufficient fluid resuscitation in patients with septic shock²⁷. Our results showed the best outcome for patients administered > 40 mL/kg of fluid within 3 h but not beyond 3 h. These findings collectively suggest that liberal fluid therapy in sepsis is important during the resuscitation phase, but not beyond that phase.

The curve of the restricted cubic spline model examining the dose–effect relationship between fluid resuscitation volume and mortality in this study showed a hormetic effect characterized by a dose-dependent variable response²⁸. We observed increased odds of mortality in patients who received 25 to < 30 mL/kg fluid compared to the lower volumes, and the odds of survival benefit were higher with increased fluid volume, plateauing at 45–50 mL/kg. The paradoxically deleterious effects of fluid resuscitation could be attributable to the cardiovascular physiology during sepsis²⁹. Studies have demonstrated the potential pathways through which fluid resuscitation may cause cardiovascular dysfunction including vasodilatation, cardiotoxicity, glycocalyx degradation, and inflammatory response^{30,31,32,33,34,35}. Two randomized controlled trials highlighted the cardiovascular harm associated with fluid resuscitation^36,37. Based on the findings from the two randomized trials the possible mechanism underlying the hormetic effect of fluid volume in our study could be explained. Although the cardiac output and blood pressure may appear to be restored at lower fluid volumes (25–40 mL/kg) during resuscitation efforts in patients with septic shock, these increases do not necessarily indicate restoration of tissue perfusion. However, a higher volume of fluid resuscitation (40–50 mL/kg) may offset cardiovascular dysfunction with a greater fluid volume, leading to better patient prognosis..

Previous studies demonstrated lower mortality in patients who received faster than 3 h of infusion times^9,11,12. By contrast, in this study, the infusion time of fluid per se was not associated with 28-day mortality unlike the fluid resuscitation volume. These differences may be due to the pharmacokinetics of fluid administration¹⁴. The context-sensitive half-time of the expansion of plasma volume after intravenous infusion of crystalloids varies over time³⁸. The peak volume expansion of the intravenous infusion of 1 L of crystalloids is higher over 1 h than 3 h; however, the amount of volume expansion between these two cases is reversed at 2 h. Finally, volume expansions beyond 3 h are similar between intravenous infusions over 1 h and 3 h. Thus, the net effect of fluid resuscitation seems to be determined by the dynamics of ‘infusion volume and rate’ rather than the isolated effects of either administered volume or rapidity of infusion.

In this study, only approximately one-third of the patients met the criteria for septic shock, but a substantial volume of fluid was administered across the entire cohort. This is likely to reflect the characteristics of the study population, many of whom may correspond to severe sepsis under the Sepsis-2 criteria³⁹. We included only patients who received at least 20 mL/kg of fluid resuscitation within the first 6 h. Given this inclusion criterion, most of these patients likely exhibited clinical signs of initial hypotension or hypoperfusion requiring fluid resuscitation, although they ultimately did not require vasopressors or meet the criteria for septic shock after fluid resuscitation. Interestingly, in our study population, the volume of fluid resuscitation was positively correlated with initial lactate levels (Figure S4 in the Supporting Information). In the multivariable linear regression analysis adjusting for covariates (body mass index, chronic kidney disease, hematologic malignancy, pulmonary infection, bacteremia, and steroid use), elevated lactate levels remained significantly associated with an increase in fluid volume. These findings may reflect protocol-based decision-making guided by lactate levels, as recommended in international guidelines. However, the strength of this association was modest, and the effect size was too small to suggest any meaningful clinical impact. Therefore, the actual influence of lactate elevation on fluid administration in clinical practice is likely to have been limited.

The strengths of this study include the nationwide, multicenter data, detailed information on covariables, and examination of both separate and joint associations of infusion time and fluid volume with mortality. Furthermore, we conducted a multivariate analysis to mitigate the potential reduction in statistical power due to the relatively small sample size. Covariate selection was controlled by clearly defined criteria to minimize the risk of overfitting. This approach helped improve the precision and robustness of our findings.The study limitations include an observational design, which limits findings of causality associations between fluid resuscitation volume and mortality. Second, although our study used data from a well-constructed registry, the possibility of inevitable measurement errors in fluid intake cannot be overlooked. We included all fluid intake such as oral intake, transfusion, and intravenous fluid after fluid resuscitation, which could result in an over-estimation of the fluid volume. However, the amount of other fluid intake except for resuscitation fluid was likely to account for a very small portion of all fluid intake because all patients were admitted to the ICU within 6 h of initiating fluid resuscitation. Third, there was a potential for selection bias. This study analyzed fewer than 10% of all patients in the registry due to inclusion and exclusion criteria, which limited to the cohort to patients with sepsis admitted to the ICU who received > 20 mL/kg of intravenous fluids within the first 6 h. Although statistical adjustments were performed, this might have influenced the outcomes of this study. Furthermore, the relatively small number of included patients after exclusion necessitated a cautious interpretation of the findings. Finally, due to the lack of guidelines supported by high-quality evidence, the volume and time of fluid administration were determined at the discretion of the attending physician at each participating center.

In conclusion, infusion time and fluid resuscitation volume were not significantly associated with 28-day mortality in this nationwide cohort study of patients with sepsis. However, compared with 20 to < 25 mL/kg of fluid volume within 3 h, 40 to < 45 mL/kg of initial fluid resuscitation (at least > 30% of the current recommendation) administered within 3 h was associated with decreased odds of 28-day mortality and increased odds of the patient being ventilator-free and discharged from the ICU at 28 days. Additionally, among patients who received 40 to < 45 mL/kg of fluid, those with a shorter infusion time (3 h or shorter) had a lower mortality risk. Our findings suggest that our findings suggest that careful coordination of administered volume and infusion time of fluid resuscitation may be associated with improved outcomes in patients with sepsis.