The use of intravenous fluid therapy is ubiquitous among critically ill patients to optimize tissue perfusion and oxygen delivery. Apart from intravenous fluids administered during initial resuscitation, fluid accumulation occurs from nutrition, maintenance fluids, and diluents used for intravenous drug therapy. An aggressive resuscitation strategy may be appropriate during the “ebb” phase of septic shock, characterized by widespread vasodilatation, intravascular hypovolemia, and capillary leak, leading to extravasation of fluid into the interstitial compartment. Typically, the “ebb” phase is followed by the “flow” phase, during which the body tries to eliminate excess fluid. However, normal physiological mechanisms may be overwhelmed, especially with the onset of acute kidney injury. In this situation, should we consider a “de-resuscitation” strategy aimed at the active removal of excess fluid?
Adverse consequences of fluid overload
Excessive fluid accumulation may be the harbinger of multiorgan dysfunction (1). Interstitial and intra-alveolar edema in the lung may lead to delayed weaning and prolongation of the duration of ventilator support. A rise in the venous pressure may impair renal blood flow, trigger interstitial edema, and result in compromised renal function. Myocardial edema may occur, leading to systolic and diastolic dysfunction. As the intra-abdominal pressure rises due to excessive gastrointestinal fluid accumulation, abdominal perfusion may be compromised. This may trigger increased intestinal permeability and bacterial translocation from the gut. The potential harm arising from injudicious fluid administration has been equated to adverse effects arising from inappropriate drug dosing (1).
What is de-resuscitation?
Among patients who respond to initial therapeutic interventions, shock resolution and circulatory stabilization typically occurs. By this time, a large positive fluid balance occurs among critically ill patients, particularly among those with sepsis. In a secondary analysis of the Vasopressin in Septic Shock Trial (VASST), the mean positive fluid balance was 4.2 L at 12 hours and 11.0 L on the 4th day of enrollment (2). It is important to take stock of the net fluid balance after the initial phase of resuscitation. The extent of fluid accumulation may be calculated using the formula (3):
[Cumulative fluid balance (liters) / baseline body weight (kg)] × 100
A fluid accumulation of more than 10% has been shown to be associated with poor clinical outcomes (3). During the “flow” phase, the body attempts to dispose of the accumulated fluid. Therapeutic fluid removal, using diuretics and ultrafiltration with renal replacement therapy, may be appropriate measures during this stage. Aggressive interventions to remove fluid may be combined with a fluid-restrictive strategy.
What is the evidence to support a de-resuscitative strategy?
Fluids administered during the early resuscitation phase may constitute only a small fraction of the fluid accumulated over time. A retrospective analysis was performed to evaluate the volume of fluids administered to 14,654 critically ill patients. In this study, maintenance and replacement fluids constituted 24.7% of the daily fluid administered, compared to only 6.5% of resuscitation fluids. Significant volumes of fluid (32.6% of the daily volume administered) were administered as diluents for intravenous or other medication (4).
Silversides et al. conducted a retrospective observational study across 10 ICUs in the United Kingdom and Canada to identify outcomes with de-resuscitative strategies and risk factors for positive fluid balance among critically ill patients. Four-hundred adult patients who underwent mechanical ventilation for a minimum period of 24 hours were included. Over the first 1–3 days, a positive fluid balance occurred in 87.3% of patients. Medications represented the largest volume of fluid administered (34.5%). The volume of bolus (26.5%) and maintenance fluids (24.4%) were lower compared to fluids administered as medication. A negative balance was observed on day 3 in 123 patients; a spontaneous negative balance, without the use of diuretics or ultrafiltration, occurred in 70 (56.9%) patients and was associated with lower 30-day mortality. De-resuscitative measures were employed in 52.3% of all patients, most frequently on the 2nd or 3rd day. On multivariate logistic regression, the fluid balance on day 3 was an independent predictor of 30-day mortality. A negative fluid balance achieved using active de-resuscitative measures, including frusemide administration and fluid removal using continuous renal replacement therapy, was associated with lower mortality (5).
A meta-analysis of 11 randomized controlled studies, including 2051 adults and children, was performed by Silversides et al. The study included patients with acute respiratory distress syndrome, sepsis, or the systemic inflammatory response syndrome (SIRS). Compared to a liberal approach, the authors found no significant difference in mortality reported at the longest time point between a conservative or de-resuscitative fluid management strategy. However, there was an increase in ventilator-free days and reduced length of stay in the ICU with a conservative or de-resuscitative approach (6).
The FFAKI-trial was a pilot randomized controlled trial that tested the feasibility of forced fluid removal compared to standard care among critically ill patients who were at moderate to high risk of acute kidney injury with more than 10% fluid accumulation. Active de-resuscitation was carried out with a bolus dose of furosemide, 40 mg, followed by a continuous infusion of up to 40 mg/hour or fluid removal using renal replacement therapy. The investigators aimed for a net negative fluid balance of >1 ml/kg/hour (ideal body weight) with a target cumulative fluid balance of less than 1000 ml from the time of ICU admission. The recruitment rate was low, with only 23 included among 1144 patients who were screened. Despite the small sample size, a conspicuous reduction in the cumulative fluid balance was observed with active de-resuscitative measures at 5 days after randomization. The mean difference in the cumulative balance between groups was 5,814 ml (95% CI 2063 to 9565, P = .003). Although not powered to evaluate clinical outcomes, no adverse effects were noted with forced fluid removal in this pilot study (7).
A combination of high PEEP, small volume resuscitation with 20% albumin, and diuretic treatment with furosemide (described as “PAL-treatment”) was evaluated among patients with acute lung injury by Cordemans et al., in a retrospective case-control study. The PEEP level (cm of H2O) was set at the level of the intra-abdominal pressure (mm of Hg). This strategy resulted in a lower extravascular lung water index, intra-abdominal pressure, and cumulative fluid balance compared to control patients. The use of the PAL strategy resulted in a shorter duration of mechanical ventilation and ICU stay. The 28-day mortality was also lower with this approach (8).
Possible harm from a de-resuscitative strategy?
The question of choosing the optimal time to commence de-resuscitation can be challenging. Fluid overload may be difficult to recognize in the clinical setting. The central venous pressure is a relatively ineffectual parameter; bedside echocardiography to assess fluid responsiveness vs. overload may not always be practicable due to suboptimal windows among ventilated patients. The clinician may often face the conundrum of when to resort to de-resuscitative measures after the initial stabilization of the hemodynamic status. In a secondary analysis of the Randomized Evaluation of Normal vs. Augmented Level of Renal Replacement Therapy (RENAL) trial, net ultrafiltration of more than 1.75 ml/kg/hour was associated with lower 90-day survival compared to ultrafiltration rates of less than 1.01 ml/kg/hour (9). Clearly, more robust evidence from controlled trials is required before the routine adoption of aggressive de-resuscitative measures.
The bottom line
- A net positive fluid balance after the initial phase of resuscitation (the “ebb” phase) is strongly associated with mortality.
- Positive fluid balance is an inherently modifiable risk factor that leads to adverse outcomes in critically ill patients.
- After the resuscitation phase, it is appropriate to adopt a conservative fluid strategy and consider active measures of de-resuscitation, including the use of diuretics and fluid removal using renal replacement therapy.
- It may be prudent to aim for a zero or negative balance by day 3 among patients in whom hemodynamic stabilization has been achieved.
- The routine administration of maintenance intravenous fluids to critically ill patients must be strongly discouraged. Besides, the volume of diluents used for intravenous drug administration should also be restricted to the minimum volume possible.
1. Malbrain MLNG, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, et al. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014 Dec;46(5):361–80.
2. 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;39(2):259–65.
3. O’Connor ME, Prowle JR. Fluid Overload. Crit Care Clin. 2015 Oct;31(4):803–21.
4. Van Regenmortel N, Verbrugghe W, Roelant E, Van den Wyngaert T, Jorens PG. Maintenance fluid therapy and fluid creep impose more significant fluid, sodium, and chloride burdens than resuscitation fluids in critically ill patients: a retrospective study in a tertiary mixed ICU population. Intensive Care Med. 2018 Apr;44(4):409–17.
5. Silversides JA, Fitzgerald E, Manickavasagam US, Lapinsky SE, Nisenbaum R, Hemmings N, et al. Deresuscitation of Patients With Iatrogenic Fluid Overload Is Associated With Reduced Mortality in Critical Illness. Crit Care Med. 2018;46(10):1600–7.
6. Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, et al. Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med. 2017 Feb;43(2):155–70.
7. Berthelsen RE, Perner A, Jensen AK, Rasmussen BS, Jensen JU, Wiis J, et al. Forced fluid removal in intensive care patients with acute kidney injury: The randomised FFAKI feasibility trial. Acta Anaesthesiol Scand. 2018;62(7):936–44.
8. Cordemans C, De Laet I, Van Regenmortel N, Schoonheydt K, Dits H, Martin G, et al. Aiming for a negative fluid balance in patients with acute lung injury and increased intra-abdominal pressure: a pilot study looking at the effects of PAL-treatment. Ann Intensive Care. 2012 Jul 5;2 Suppl 1:S15.
9. Murugan R, Kerti SJ, Chang C-CH, Gallagher M, Clermont G, Palevsky PM, et al. Association of Net Ultrafiltration Rate With Mortality Among Critically Ill Adults With Acute Kidney Injury Receiving Continuous Venovenous Hemodiafiltration: A Secondary Analysis of the Randomized Evaluation of Normal vs Augmented Level (RENAL) of Renal Replacement Therapy Trial. JAMA Netw Open. 2019 05;2(6):e195418.