IV Fluid Resuscitation
Adherence to the study protocol was high (94.5%): six participants randomized to the restrictive group were crossed over to the usual care group. The reasons for crossover are presented in Supplementary Table 3 (Supplemental Digital Content 1, http://links.lww.com/CCM/E536). In the primary intention-to-treat analysis, participants in the restrictive fluid group received 14.0 mL/kg (95% CI, 3.5–24.5) less resuscitative IV fluid, as compared with usual care participants (47.1 vs 61.1 mL/kg; p = 0.01) over the 72-hour study period (Table 2). The 14.0 mL/kg difference between groups represents an 823 mL volume difference (Supplementary Table 4, Supplemental Digital Content 1, http://links.lww.com/CCM/E536). Median IV fluid values are presented in Supplementary Table 5 (Supplemental Digital Content 1, http://links.lww.com/CCM/E536). The restrictive group also received a lower fraction of IV fluid per TBV and less nonresuscitative IV fluid than the usual care group. In the per-protocol analysis, the difference in resuscitative IV fluid administered between groups was larger: 23.3 mL/kg (41.2 vs 64.5 mL/kg; p ≤ 0.0001), or 1,384 mL (Supplementary Tables 6 and 7, Supplemental Digital Content 1, http://links.lww.com/CCM/E536). There were no differences between groups in adjunct resuscitative measures administered (albumin, packed RBC transfusion, or stress dose steroids) (Table 2).
By day 30, 12 participants (21.8%) in the restrictive group and 12 participants (22.2%) in the usual care had died (OR, 1.02; 95% CI, 0.41–2.53) (Fig. 2 and Table 2). A per-protocol analysis yielded similar results (Supplementary Table 8, Supplemental Digital Content 1, http://links.lww.com/CCM/E536). Adjusting for the baseline imbalances in chronic kidney disease and the amount of nonresuscitative IV fluid administered yielded no changes in observed 30-day mortality risk between groups (Supplementary Table 9, Supplemental Digital Content 1, http://links.lww.com/CCM/E536). There were no deaths among the four protocol violations removed prior to analysis.
Secondary Outcomes and Adverse Events
There were no differences in 60-day mortality, ICU or hospital lengths of stay, rates of new organ failure, or changes in electrolytes between study groups (Table 2; and Supplementary Table 7, Supplemental Digital Content 1, http://links.lww.com/CCM/E536). Fifteen participants (28.3%) in the restrictive group and 17 participants (31.5%) in the usual care group required new mechanical ventilation (p = 0.67). Although we did not observe a significant difference between groups in the number of ventilator-free days among the 32 participants with respiratory failure, the restrictive group spent 22 fewer hours mechanically ventilated compared with usual care (p = 0.02) (Table 2). The number of participants who required vasopressors, the total number of vasopressor hours, and vasopressor doses were similar between the study groups (Table 2; and Supplementary Table 10, Supplemental Digital Content 1, http://links.lww.com/CCM/E536). There were no differences in serious adverse events between study groups.
We conducted a pilot randomized trial to examine the feasibility and initial effects of limiting the amount of resuscitative IV fluid administered over the first 72 hours to patients with severe sepsis and septic shock. The restrictive strategy significantly reduced the amount of IV fluid administered to critically ill septic patients compared with usual care. Although our study was not powered to detect differences in patient-centered primary or secondary outcomes, and a larger trial is needed to determine if our findings hold, we observed no increased rates of death, organ dysfunction, or adverse events with a restrictive strategy. Our results suggest that following effective initial resuscitation (30 mL/kg), a strategy of fluid minimization, using less IV fluid than previously given, may be appropriate for patients with severe sepsis and septic shock. The recently initiated National Heart, Lung, and Blood Institute “Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial” will be powered to answer questions of mortality and may shed further light on lung injury outcomes (22). For CLOVERS to make the maximal clinical impact, their design should ensure a larger fluid difference between study arms than we obtained in RIFTS.
There is growing concern in emergency and critical care medicine that high-volume IV fluid resuscitation is harmful to patients (23). Clinicians are favoring resuscitation strategies that initiate early vasopressors and use lower volumes of IV fluid to achieve blood pressure goals, but there is limited evidence to support this practice (13–18). In our trial prior to randomization, participants received 34.4 mL/kg (restrictive) and 36.2 mL/kg (usual care) of IV fluid, an amount consistent with the 2016 Surviving Sepsis Campaign guidelines (24), the Centers for Medicare & Medicaid Services Sep-1 Core Measure (25), and recent sepsis trials (2–4). Yet, following randomization, both groups received a small volume of additional resuscitative fluid over the remainder of the trial (12.7 vs 24.9 mL/kg). In fact, the total amount of resuscitative IV given in either group, 47.1 mL/kg (restrictive) and 61.1 mL/kg (usual care), is two- to three-fold less than what was administered in the Rivers (168 mL/kg), ProCESS (108–130 mL/kg), ProMISe (98 mL/kg), or ARISE (108–109 mL/kg) trials (Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/CCM/E536) and in comparison, both groups could be considered restrictive. An internal review of the medical records of 374 patients admitted to our medical ICUs in the 18 months immediately preceding RIFTS, showed that patients with severe sepsis and septic shock received an average of 75.5 mL/kg of IV fluid over 72 hours. This suggests the Hawthorne effect influenced physician behavior and reduced the amount of IV fluid administered to RIFTS participants. In effect, this created two study arms that tested fluid minimization, one more limited than the other, and notably, neither group produced high rates of organ dysfunction or serious adverse events. This, coupled with our observed mortality rates that are similar to contemporary sepsis outcomes (2–4), suggests that reducing the amount of IV fluid used to resuscitate septic patients to amount far below what was used in previous research may be safe (Fig. 3), and should inform future trial design.
Our findings align with the 2016 Restricting volumes of resuscitation fluid in adults with septic shock after initial management (CLASSIC) trial that suggests a restrictive IV fluid resuscitation strategy is safe for septic ICU patients (26). The CLASSIC restrictive study arm received a total of 8,057 mL of fluid (4,800 mL of resuscitative IV fluid and 3,257 mL of nonresuscitative fluid with medication), in the first 72 hours. In contrast, our study’s restrictive group patients received 23% less combined resuscitative and nonresuscitative fluid (6,213 mL; 70.8 mL/kg), suggesting an even lower volume of IV fluids might be safe for a restrictive resuscitation strategy. It may be that following the initial bolus of resuscitative IV fluid, critically ill septic patients require little if any further fluid boluses because they receive enough daily IV fluid with medications to sustain organ perfusion. Notably, our restrictive group received significantly less nonresuscitative IV fluid compared with the usual care group (23.7 vs 37.6 mL/kg). This difference might be due to chance or could be a downstream effect of a restrictive strategy. If a restrictive strategy limits organ edema and dysfunction, it may decrease the patient’s critical illness severity and thereby reduce the amount of medications (i.e., vasopressors, sedatives, antibiotics) needed to treat them.
We also observed that intubated patients who received a restrictive strategy required fewer hours of mechanical ventilation as compared with those patients in the usual care group (16.8 vs 33.6 hr; p = 0.01). Although this finding is hypothesis generating and might be driven by the small number of intubated patients (n = 32), it nevertheless suggests that a restrictive resuscitation strategy may limit lung injury. The concept that the liberal use of IV fluids induces lung injury is supported by observations in acute respiratory distress syndrome research (27) and warrants further investigation in sepsis research.
Our study has limitations. First, the sample size of our pilot trial makes it underpowered to detect superiority or noninferiority in mortality and secondary outcomes. With our sample size of 109 patients, assuming a baseline mortality rate of 22%, we estimate that we could have detected an absolute morality difference of greater than or equal to 19% (α = 0.05; power 80%), which indicates that very large samples are needed to detect small differences in mortality or assess noninferiority. Second, the patients and providers were not blinded to the intervention, which may have allowed for the introduction of bias in fluid administration practices. Future trials could consider implementing a step-wedge approach across randomized enrolling departments to mitigate this effect. Third, the relatively small difference in IV fluid between study arms (14 mL/kg or 823 mL) may not reach the threshold of clinical significance. However, a recent multicenter trial of balanced salt solutions versus normal saline showed a reduced combined outcome of death and renal dysfunction with a 1,000 mL difference of IV fluid between study arms, suggesting that limiting even moderate amounts of IV fluid may confer clinical significance (28). Fourth, our study did not incorporate a formalized measurement of participant volume status or fluid responsiveness. Future efforts may find improved outcomes with strategies that include a patient-tailored approach to fluid resuscitation. Finally, the large number of patients with altered mental status and those who had received more than 60 mL/kg of IV fluid were excluded from the study. This may have introduced a selection bias that favored a less-sick study cohort; however, a mean participant Acute Physiology and Chronic Health Evaluation score of 35 and the observed 30-day mortality rates argue against this.
A restrictive resuscitation strategy that significantly limited the amount of IV fluid administered to patients with severe sepsis and septic shock did not appear to increase mortality, organ dysfunction, or adverse events. Our data contribute to the current state of clinical equipoise surrounding the use of IV fluids in sepsis, support a larger multicenter trial addressing this topic, and inform future study design.
We are grateful to the ICU nurses, research staff, and physicians as well as the participants and their families. Without your collective generosity, this trial would not have been possible.
1. Rivers E, Nguyen B, Havstad S, et al.; Early Goal-Directed Therapy Collaborative Group: Early goal-directed therapy in the treatment of severe sepsis and septic shock
. N Engl J Med 2001; 345:1368–1377
2. Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation
for patients with early septic shock
. N Engl J Med 2014; 371:1496–1506
3. Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock
. N Engl J Med 2014; 370:1683–1693
4. Mouncey PR, Osborn TM, Power GS, et al.; ProMISe Trial Investigators: Trial of early, goal-directed resuscitation
for septic shock
. N Engl J Med 2015; 372:1301–1311
5. Alphonsus CS, Rodseth RN. The endothelial glycocalyx: A review of the vascular barrier. Anaesthesia 2014; 69:777–784
6. D’Orio V, Wahlen C, Rodriguez LM, et al. Effects of intravascular volume expansion on lung fluid balance in a canine model of septic shock
. Crit Care Med 1987; 15:863–868
7. Brooks HF, Moss RF, Davies NA, et al. Caecal ligation and puncture induced sepsis in the rat results in increased brain water content and perimicrovessel oedema. Metab Brain Dis 2014; 29:837–843
8. Glassford NJ, Eastwood GM, Bellomo R. Physiological changes after fluid bolus therapy in sepsis: A systematic review of contemporary data. Crit Care 2014; 18:696
9. Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care 2014; 4:21
10. Marik PE. Early management of severe sepsis: Concepts and controversies. Chest 2014; 145:1407–1418
11. Marik P, Bellomo R. A rational approach to fluid therapy in sepsis. Br J Anaesth 2016; 116:339–349
12. Byrne L, Van Haren F. Fluid resuscitation
in human sepsis: Time to rewrite history? Ann Intensive Care 2017; 7:4
13. Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation
in septic shock
: A positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011; 39:259–265
14. Micek ST, McEvoy C, McKenzie M, et al. Fluid balance and cardiac function in septic shock
as predictors of hospital mortality. Crit Care 2013; 17:R246
15. Kelm DJ, Perrin JT, Cartin-Ceba R, et al. Fluid overload in patients with severe sepsis and septic shock
treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock 2015; 43:68–73
16. Marik PE, Linde-Zwirble WT, Bittner EA, et al. Fluid administration in severe sepsis and septic shock
, patterns and outcomes: An analysis of a large national database. Intensive Care Med 2017; 43:625–632
17. Sakr Y, Rubatto Birri PN, Kotfis K, et al.; Intensive Care Over Nations Investigators: Higher fluid balance increases the risk of death from sepsis: Results from a large international audit. Crit Care Med 2017; 45:386–394
18. Andrews B, Semler MW, Muchemwa L, et al. Effect of an early resuscitation
protocol on in-hospital mortality among adults with sepsis and hypotension: A randomized clinical trial. JAMA 2017; 318:1233–1240
19. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250–1256
20. Kaukonen KM, Bailey M, Pilcher D, et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015; 372:1629–1638
21. Lemmens HJ, Bernstein DP, Brodsky JB. Estimating blood volume in obese and morbidly obese patients. Obes Surg 2006; 16:773–776
22. Self WH, Semler MW, Bellomo R, et al.; CLOVERS Protocol Committee and NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Investigators: Liberal versus restrictive intravenous fluid
therapy for early septic shock
: Rationale for a randomized trial. Ann Emerg Med 2018; 72:457–466
23. Reuter DA, Chappell D, Perel A. The dark sides of fluid administration in the critically ill patient. Intensive Care Med 2018; 44:1138–1140
24. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock
: 2016. Intensive Care Med 2017; 43:304–377
26. Hjortrup PB, Haase N, Bundgaard H, et al.; CLASSIC Trial Group; Scandinavian Critical Care Trials Group: Restricting volumes of resuscitation
fluid in adults with septic shock
after initial management: The CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med 2016; 42:1695–1705
27. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354:2564–2575
28. Semler MW, Self WH, Wanderer JP, et al.; SMART Investigators and the Pragmatic Critical Care Research Group: Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018; 378:829–839
intravenous fluid; restrictive fluid strategy; resuscitation; septic shock
Supplemental Digital Content
Copyright © 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.