In patients with septic shock, one of the key initial interventions is fluid resuscitation. The Surviving Sepsis Guidelines recommend an initial volume of resuscitation of 30 ml/kg, followed by additional boluses guided by volume responsiveness (1). In fact, most patients with septic shock receive around 5 liters of fluid in the first few hours of resuscitation (2).
Septic shock is characterized by widespread vasodilatation of vascular beds leading to hypotension. Besides, intravascular fluid leaks into the interstitial space due to capillary endothelial dysfunction. Administration of intravenous fluid enables filling up of the intravascular compartment and compensates for the loss of fluid into the interstitial space. Fluid replenishment may also improve perfusion pressures to the vital organs.
However, do the putative benefits of targeted fluid resuscitation lead to improved clinical outcomes in septic patients?
The evidence behind fluid resuscitation
In a landmark study, Rivers at al. randomized patients presenting to the emergency department with severe sepsis or septic shock to a protocolized, early, goal-directed therapy (EGDT) or to clinician-guided resuscitation targets (3). In the study arm, the resuscitative interventions included fluid boluses of 500 ml of crystalloid every 30 min targeting a central venous pressure of 8–12 mm Hg and vasopressors to achieve a mean arterial pressure of 65 mm Hg. The central venous oxygen saturation (ScvO2) was monitored continuously using a special catheter; packed red cells were transfused if the ScvO2 dropped below 70%. If the ScvO2 remained low in spite of all the above measures, a dobutamine infusion was commenced aiming to improve the cardiac output. Patients who received goal-directed therapy had significantly larger volumes of fluid resuscitation in the first 6 h (5.0 L vs 3.5 L). In-hospital mortality, the primary endpoint, was significantly lower in patients who received goal-directed therapy (30.5 vs. 46.5%, p = 0.009).
Several subsequent studies seem to ratify the findings of this single-center study from an emergency department in the US (4). However, it remained unclear whether the improvement in clinical outcomes was related to the overall impact of a “bundled” approach or due to specific elements of the bundle. Particularly, were the favorable effects due to earlier recognition of sepsis and appropriate antibiotic administration? Indeed, a recent meta-analysis suggests that the favorable effect on mortality may be more likely due to earlier administration of appropriate antibiotics compared to the effects of fluid resuscitation or attainment of hemodynamic targets (5).
More than a decade after the original EGDT trial, three randomized controlled studies were published that compared EGDT with usual care. The ProCESS (6), ARISE (7), and ProMISe (8)studies did not find any difference in any clinical outcomes, including mortality, with the use of EGDT. The volume of fluids administered during the first 6 h of resuscitation was similar across all the groups in these studies. However, it is important to note that the volume of fluid received by all the groups in the first 6 h was less than in either arm of the original EGDT study.
Can fluid resuscitation cause harm?
The Fluid Expansion as Supportive Therapy (FEAST) study was conducted among children in sub-Saharan Africa, who presented with a severe febrile illness and signs of impaired perfusion. In this provocative three-armed study, fluid boluses of 20 to 40 ml of 5% albumin or normal saline solution were compared with a control group who received no bolus fluid (9). The 48 h mortality was significantly higher in children who received bolus fluids compared to those who did not (10.5% vs. 7.3%, p = 0.003). Interestingly, although shock resolution occurred more often in the bolus groups, improved blood pressures did not translate to better survival.
The mean cumulative positive fluid balance has ranged from 5–11 liters in the first week of illness in previous studies among septic patients (10). Several observational studies have reported increased mortality with a higher cumulative fluid balance. The Vasopressin in Septic Shock Trial (VAAST) revealed a doubling of mortality among patients with the highest cumulative fluid balance (10). The Sepsis Occurrence in Acutely Ill Patients (SOAP) study also revealed similar findings, with a 10% excess mortality for every liter of positive fluid balance at 72 hours (11). A fluid-conservative strategy was evaluated during the first week of illness in patients with acute respiratory distress syndrome (12). The mean cumulative fluid balance was –136 ± 491 ml vs. 6992 ± 502 ml (p < 0.001) in the fluid-conservative and fluid-liberal groups. A fluid-conservative strategy resulted in significantly less duration of mechanical ventilation and ICU stay.
A fluid-restrictive approach
An alternative strategy to liberal fluid resuscitation would be to limit fluid administration and use vasopressors early to maintain perfusion pressures and preserve organ function. Excessive fluid administration may raise venous pressures, leading to a reduction in the perfusion pressure to vital organs. Vasopressors decrease the venous capacitance, thereby, effectively increasing the venous return and cardiac output without overloading vital organs with excessive fluid and tissue edema. A restrictive approach may be justified as the response to intravenous fluid boluses is often transient; furthermore, fluid accumulation occurs over time leading to organ dysfunction involving the lungs, kidneys, and the heart. Besides, the effect of a fluid bolus among patients in circulatory shock may be transient; further fluid boluses may not improve the hemodynamic status even among apparent fluid-responders (13).
A forthcoming multi-center randomized controlled trial (CLOVERS) aims to compare a conventional resuscitation strategy with a fluid-restrictive approach during the first 24 h in patients with septic shock. The liberal strategy will use conventional fluid therapy similar to the control arms of the ProCESS, ARISE, and ProMISe studies. The fluid-restrictive approach will involve early vasopressor administration with lower volumes of initial resuscitation fluid.
The bottom line
- The landmark EGDT study and subsequent accumulated evidence has led to widespread adoption of targeted fluid resuscitation in septic patients.
- Excessive fluid administration and a cumulative positive balance may lead to fluid overload, edema, and dysfunction of vital organs.
- Recent evidence supports the possibility of clinical harm from overzealous fluid administration.
- An alternative approach may be to restrict the volume of resuscitation fluid and use vasopressors early to maintain perfusion pressure to vital organs.
- The optimal volume of initial fluid administration and hemodynamic targets remain unclear and require further studies.
- Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018 Jun;44(6):925–8.
- Nguyen HB, Jaehne AK, Jayaprakash N, Semler MW, Hegab S, Yataco AC, et al. Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. Crit Care Lond Engl. 2016 Jul 1;20(1):160.
- Emanuel R, Bryant N, Suzanne H, Julie R, Alexandria M, Bernhard K, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med. 2001;10.
- Trzeciak S, Dellinger RP, Abate NL, Cowan RM, Stauss M, Kilgannon JH, et al. Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest. 2006 Feb;129(2):225–32.
- Kalil AC, Johnson DW, Lisco SJ, Sun J. Early Goal-Directed Therapy for Sepsis: A Novel Solution for Discordant Survival Outcomes in Clinical Trials. Crit Care Med. 2017 Apr;45(4):607–14.
- 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.
- 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.
- 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.
- 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.
- Boyd JH, Forbes J, Nakada T, Walley KR, Russell JA. Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality*. Crit Care Med. 2011 Feb 1;39(2):259–65.
- Vincent J-L, Sakr Y, Sprung C, Ranieri V, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: Results of the SOAP study*. Crit Care Med. 2006 Feb 1;34(2):344–53.
- National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564–75.
- Nunes TSO, Ladeira RT, Bafi AT, de Azevedo LCP, Machado FR, Freitas FGR. Duration of hemodynamic effects of crystalloids in patients with circulatory shock after initial resuscitation. Ann Intensive Care [Internet]. 2014 Dec [cited 2019 Apr 6];4(1). Available from: http://www.annalsofintensivecare.com/content/4/1/25