The FRESH trial
The Fluid Response Evaluation in Sepsis Hypotension and Shock (FRESH) trial was a prospective, randomized clinical trial in adults with septic shock comparing PLR-guided SV responsiveness (intervention) as a guide for fluid management with usual care. Patients presented to the ER with sepsis-associated hypotension and anticipated ICU admission. In the intervention arm, patients were assessed for fluid responsiveness (FR) before any clinically driven fluid bolus or increase in vasopressors. If a patient’s stroke volume increased by ≥10% in response to a PLR, they were considered fluid responsive and fluid was recommended as the first therapy. If a patient’s stroke volume increased by <10% then the patient was considered not to be FR and vasopressors were recommended as first-line therapy. The control arm received usual care. The primary end point was the difference in positive fluid balance at the first of either 72 hours or ICU discharge. Patients had received ~2.3 L of crystalloid fluid prior to randomization (~3.5 h from initial presentation), in keeping with 30 mL/kg recommendations. Patients treated with the PLR-guided fluid and pressor protocol had a significant lower net fluid balance (1.37 L (95% CI: 2.53-0.21, P = .021) at 72 hours or ICU discharge. In addition, the intervention group experienced significantly less frequent requirement for renal replacement therapy with a difference of 12.4% (95% CI: 27%-1%, P = .042) as well as a decreased requirement for ventilator use with a difference of 16.42% (95% CI: 33%-0%, P = .044) (Douglas IS, et al. Chest. 2020;158[4]:1431-45).
FRESH demonstrated that PLR-guided FR drove lower fluid balance in patients with septic shock who present to the ER with sepsis and creates a paradigm for future management of fluid and pressor resuscitation beyond the initial 30 mL/kg bolus. Functional evaluation for lack of FR adequately identifies a group of patients with sepsis-associated hypotension who are unlikely to benefit from additional IV fluids to establish hemodynamically stability. It facilitated physiologically informed treatment decisions for the individual patient at a specific moment in their course of treatment as opposed to relying on static measurements and goals that may ultimately not be indicative of fluid responsiveness and circulatory effectiveness. This could reduce the likelihood of fluid overload and associated organ failure and, thus, improve patient outcomes.
Microcirculatory function is significantly impacted by sepsis with a decline in capillary density and inappropriate vasodilation/constriction resulting in insufficient tissue and organ perfusion and increased oxidative stress. Such dysfunction has been found to be associated with worsened patient outcomes, including mortality. However, microcirculatory function does not correlate well with traditionally used macrohemodynamic assessments and treating to improve macrohemodynamic values does not ensure that microcirculation will improve (Charlton M, et al. J Intensive Care Soc. 2017;18(3):221-7).
Ongoing studies are exploring if dynamic fluid-guided resuscitation has the potential to improve survival in sepsis by providing insight into whether the administration of fluid will impact the microcirculation and subsequent organ perfusion of the patient.
Future directions include expanding the dynamic treatment algorithm into other settings, such as rapid response calls, or other patient populations, including those initially presenting with undifferentiated hypotension. While FRESH was not sufficiently powered to detect differences in mortality, there are currently multiple large studies being conducted aimed at determining the impact of a restricted fluid and early vasopressor strategy as compared with a large initial IV fluid bolus on mortality. The results of these studies could be used to determine if the results of FRESH will translate into patient survival outcomes.