Current guideline recommendations for fluid resuscitation in sepsis patients calls for an initial crystalloid fluid bolus of at least 30 mL/kg (Rhodes, et al. Intensive Care Med. 2017;43[3]:304-77) For fluid management beyond this initial bolus, recommendations had previously called for using early goal-directed therapy (EGDT) with central venous pressure (CVP) and central venous oxygen saturation to guide the use of IV fluids, vasopressors, transfusions, and dobutamine, based on the results of one single-center study that found an improvement in mortality using EGDT as compared with standard therapy.
The triad of sepsis studies
In the following years, multiple concerns were raised regarding the generalizability of this study. Three large multicenter trials were conducted in multiple countries to test the recommendations for EGDT.
PROMISE: ProMISe was a 1,260-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 56 hospitals in England. There was no significant difference in the primary study endpoint with 90-day mortality rates of 29.5% and 29.2% (RR: 1.01, 95% CI: 0.85-1.20, P =.90) (Mouncey, et al. N Engl J Med. 2015;372[14]:1301-11).
PROCESS: ProCESS was a 1,351-patient randomized trial comparing the impact of protocol-based EGDT, protocol-based standard of care, and usual care on 60 day in-hospital mortality in patients with early septic shock at 31 hospitals in the United States. There was no significant difference in the primary study endpoint with 60-day mortality rates of 21.0%, 18.2%, and 18.9% (P = .83) or in the secondary outcome of 90-day mortality with rates of 31.9%, 30.8%, and 33.7% (P = .66) (ProCESS Investigators, et al. N Engl J Med. 2014;370[18]:1683-93).
ARISE: ARISE was a 1,600-patient randomized trial comparing the impact of EGDT vs usual care on 90-day all-cause mortality in patients with early septic shock at 51 hospitals in New Zealand and Australia. There was no significant difference in the primary study end point with 90-day mortality rates of 18.6% and 18.8% (RR: 0.98, 95% CI: 0.80-1.21, P = .90). There were also no significant differences in 28-day or in-hospital mortality, duration of organ support, or length of hospital stay (ARISE Investigators, et al. N Engl J Med. 2014;371[16]:1496-506).
In summary, all three “triad” trials found no improvement with EGDT over usual care (Rowan, et al. N Engl J Med. 2017;376[23]:2223-34) calling into question the recommended methods of universally protocolized approaches to fluid and pressor resuscitation. Probable reasons for why structured EGDT was ineffective at improving outcomes over usual care in the “triad” trials was that (a) liberal fluid volume administration was the “usual care” in most enrolled patients and (b) that macrocirculatory hemodynamics, such as BP, and static intravascular pressures such as CVP and pulmonary arterial wedge pressure are poor correlates and predictors of effective circulatory volumes and the presence of fluid responsiveness.
Counterintuitively, in situations of central hypovolemia, peripheral sympathetic activity remains high in many patients while stroke volume decreases. This provides insight into why some patients appear not to benefit from fluid administration as peripheral arterial pressure may be maintained despite low central filling pressure (Convertino VA, et al. Auton Neurosci. 2004;111[2]:127-34). Many patients with sepsis and septic shock initially present in an undifferentiated state and empiric treatment decisions regarding fluid and pressor treatments are then misaligned to functional physiological status.
Novel methods and approaches are needed to differentiate these patients and provide appropriate, physiologically guided fluid resuscitation. Dynamic measurement of stroke volume (SV) after a passive leg raise (PLR) or a small IV fluid challenge is an emerging method for determining fluid responsiveness. Evidence suggests that the use of SV-guided resuscitation can reduce net fluid balance, ICU length of stay, risk of mechanical ventilation, time on vasopressors, and risk of renal replacement therapy.(Latham HE, et al. J Crit Care. 2017;42:42-6).
In addition to the lack of efficacy from administering fluid to nonfluid responsive patients, there remains a risk of over-resuscitation from excessive fluid administration. Excessive fluid administration causes hypervolemia and is associated with a variety of negative patient outcomes including tissue edema, organ dysfunction, increased ICU length of stay, prolonged ventilator dependence, and higher mortality rates (Tigabu BM, et al. J Crit Care. 2018;48:153-9). Further, unnecessary initial fluid administration necessitates a “de-resuscitative” phase that can prolong hospital stay and is associated with amplification of sepsis-associated organ failures. Specifically, a 2017 analysis of hospital discharge data found that large volume fluid resuscitation in sepsis patients during the first 24 hours of care was associated with higher rates of hospital mortality than was predicted for patients’ disease severity (Mansoori JN, et al. Crit Care. 2020;24[1]:25).