Early vasopressors or a fluid-liberal resuscitation strategy​ in sepsis-related hypotension?

Fluid resuscitation is the cornerstone of the established management of sepsis-related hypotension. Guidelines recommend an initial bolus of 30 ml/kg of crystalloids with administration of repeated boluses if the hemodynamic parameters continue to improve (1). The physiological rationale behind this approach is the extensive vasodilatation and capillary leak that characterize sepsis. Adequate intravascular volume expansion is considered to be the appropriate initial management, followed by the administration of vasopressors if severe hypotension persists. Rivers et al., in their landmark study, administered intravenous fluid boluses targeting central venous pressure; this resulted in a much larger volume of fluid being administered to the intervention group compared to controls during the initial hours of resuscitation (2). Subsequently, three randomized controlled studies further bolstered the “fluids first” approach; both control and intervention arms of these studies received similar volumes of fluid in the first few hours, suggesting that this approach has firmly entrenched into clinical practice over the years (3–5). However, a “fluid liberal” initial approach may have adverse consequences, with overfilling of the intravascular and interstitial compartments due to capillary leakage. Excessive fluid in the interstitial compartment may lead to tissue edema and precipitate organ failure (6). Furthermore, a central venous pressure targeted resuscitation strategy may result in increased venous pressures, thereby decreasing perfusion pressures in vital organs such as the kidneys (7). Is it time to re-evaluate the traditional fluid liberal resuscitation strategy considering the putative harm that may emanate from such an approach? Would it be appropriate to limit fluid resuscitation and administer vasopressors early in patients with sepsis? Such an approach may accelerate the process of resuscitation and result in a lower volume of fluids being administered.

In a study of African children with severe febrile illness and signs of impaired perfusion, an initial fluid bolus of normal saline or 5% albumin was compared to no bolus fluid. Intravenous maintenance fluid was administered to all children. Mortality at 48 h and 4 weeks was significantly lower in children who received no bolus fluid (8). Although this study was performed among children in resource-limited settings and may not be directly extrapolatable to adult practice, it underlines potential harm from excessive fluid resuscitation in the initial stage of sepsis.

Bai et al. conducted a retrospective cohort study on the timing of noradrenaline administration in patients with septic shock (9). They hypothesized that later administration of noradrenaline may lead to more prolonged hypotension resulting in impaired organ perfusion compared to early administration. Mortality at 28 days was significantly lower in patients who received noradrenaline within 2 h of the onset of septic shock compared with those who received it later. The mortality increased by 5.3% for every 1 h of delay in noradrenaline administration within the first 6 h of onset of septic shock. On multivariate logistic regression analysis, the time to noradrenaline administration was one of the independent predictors of mortality.

A multicentre randomized controlled study was conducted to assess the feasibility of a fluid-restrictive strategy after initial resuscitation. In the fluid-restricted group, after initial resuscitation, additional boluses were administered only if signs of severe hypoperfusion were noted. In the control group, continued boluses were administered if there was an improvement in hemodynamic parameters assessed using static or dynamic indices. Resuscitation volumes on day 5 and during ICU stay were the co-primary outcomes. The resuscitation volumes at both time points were significantly less with a restrictive strategy. The study was not powered to evaluate patient-centered outcomes; however, it suggested that a restricted fluid strategy was feasible among patients with septic shock.

In a recent randomized controlled study, noradrenaline was administrated in a dose of 0.05 mcg/kg/min within 1 hr of the diagnosis of septic shock (mean arterial pressure of less than 65 mm Hg and diagnosis of sepsis based on the Surviving Sepsis Guidelines) (10). The infusion was continued for a period of 24 h; the control group received a placebo infusion. Fluid resuscitation, antibiotic therapy, and organ support were based on physician discretion. If the mean arterial pressure remained below 65 mm Hg, open-label vasopressors were administered. The primary outcome was “shock control” at 6 h after the diagnosis of septic shock. Shock control was determined by a sustained mean arterial pressure of more than 65 mm Hg and evidence of adequate tissue perfusion, defined as a urine output of more than 0.5 ml/kg/h for 2 consecutive hours or a decrease in the serum lactate by more than 10% of the baseline levels. In this study, shock control after 6 h of initial resuscitation was significantly higher with early noradrenaline compared to placebo. The median time to noradrenaline administration was significantly less in the early noradrenaline group (93 vs. 192min; P<0.001). There was no difference in the 28-day and hospital mortality between groups. This study demonstrated that the early use of noradrenaline leads to more rapid attainment of resuscitation goals.

The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) study is a  multi-center randomized controlled trial that is currently recruiting patients (11). It aims to compare the impact of a restrictive fluid strategy with a liberal fluid strategy on the 90 d mortality. In the restricted fluids group, patients are randomized to receive noradrenaline after an initial fluid bolus of 1L; further boluses are administered as a rescue measure. In the fluid liberal group, repeated boluses of fluid are administered as the initial intervention; rescue noradrenaline is commenced only after either 5 L of fluid has been administered, signs of acute volume overload develop, or other predefined rescue criteria are met. The results of this study are eagerly awaited.


  • The conventional, guideline-based approach of the “fluids first” strategy may lead to excessive capillary leakage, interstitial edema, and impaired organ perfusion.
  • Early use of vasopressors may enable more rapid attainment of resuscitation goals and improved organ perfusion.
  • The optimal volume of fluid resuscitation prior to the commencement of vasopressors may be variable.
  • Clinical studies suggest that a fluid restricted resuscitation strategy with early use of vasopressors may improve outcomes.
  • Further prospective controlled studies are warranted to assess the impact of early vasopressor therapy in sepsis-related hypotension.



  1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304–77.
  2. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368–77.
  3. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683–93.
  4. ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496–506.
  5. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015 Apr 2;372(14):1301–11.
  6. Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care. 2014;4:21.
  7. Legrand M, Dupuis C, Simon C, Gayat E, Mateo J, Lukaszewicz A-C, et al. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study. Crit Care Lond Engl. 2013 Nov 29;17(6):R278.
  8. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 Jun 30;364(26):2483–95.
  9. Bai X, Yu W, Ji W, Lin Z, Tan S, Duan K, et al. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care Lond Engl. 2014 Oct 3;18(5):532.
  10. Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) : A Randomized Trial. Am J Respir Crit Care Med [Internet]. 2019 Feb [cited 2019 Feb 7]; Available from: https://www.atsjournals.org/doi/10.1164/rccm.201806-1034OC
  11. Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis – Full Text View – ClinicalTrials.gov [Internet]. [cited 2019 Feb 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT03434028



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