August 14, 2018

EJRC Article Review

Fluid administration in critically ill patients: Pendular thinking?

EJRC Article Review


Fluid management in critically ill patients has increased attention in the recent years, as we all become more and more aware of the potential deleterious effects of fluid overload. The association between positive fluid balance poor clinical outcomes is old news [1,2], the question is what we can do about it. Some small trials and meta analysis [3,4] have suggested that active strategies of fluid “restriction” or even active “de-resuscitation” were associated with better outcomes. In 2012, Corcoran et al. reported a meta analysis among patients after major surgery, where goal-directed therapy rather than liberal fluid therapy was associated with better outcomes. The authors nicely speculated as to whether goal-directed therapy may actually be superior to a restrictive fluid strategy.

Myles et al. [5] performed a pragmatic, multicentre, randomised, assessor-blinded trial with 3000 patients (from 47 centres in 7 countries) who had an increased risk of complications while undergoing major abdominal surgery to receive a restrictive or liberal intravenous-fluid regimen during and up to 24 hours after surgery. The primary outcome was disability-free survival at 1 year. Secondary outcomes included acute kidney injury at 30 days, renal-replacement therapy at 90 days, and a composite of septic complications, surgical-site infection, or death. The liberal intravenous-fluid regimen was designed to reflect traditional practices for abdominal surgery, whereas the restrictive intravenous-fluid regimen was designed to provide a net zero fluid balance. 24 hours after surgery, the patients in the restrictive fluid group had a median intravenous-fluid intake of 3.7 litres (interquartile range, 2.9 to 4.9), as compared with 6.1 litres (interquartile range, 5.0 to 7.4) in the liberal fluid group (P<0.001). The rate of disability-free survival at 1 year was similar in both groups. The rate of acute kidney injury was 8.6% in the restrictive fluid group and 5.0% in the liberal fluid group (P<0.001). The rate of renal-replacement therapy was higher in the restrictive fluid group (0.9% vs. 0.3%, P = 0.048), but the between-group difference was not significant after adjustment for multiple testing. The rest of outcomes explored were similar between both groups.

This trial is well designed and conducted: participants were randomly allocated to different groups, they seem to have been treated equally in both groups apart from the fluid management strategy, with minimal loss after randomisation (0.6%) and with data available for 1-year outcome in 96.7%; data was analysed in a modified intention-to-treat fashion; assessment of outcomes was blinded, and although it was not “objective” for the primary outcome, it was using standardised and validated scale. Potential confounders are reported in the additional files, and they seem to be equally distributed between the two groups. All and all, the methodology seems to be robust enough to support the conclusions.

The authors’ conclude that a restrictive fluid regimen was not associated with a higher rate of disability-free survival than a liberal fluid regimen 1 year after surgery in patients at increased risk for complications while undergoing major abdominal surgery. However, the restrictive regimen was associated with a higher rate of acute kidney injury.

This conclusion reopens the controversy about the recent trend towards “restrictive’ fluid strategies or active “deresuscitation”. One may argue that the “liberal” strategy is not really representative of the standard practice, or it is already restrictive and that may affect the lack of differences between groups. However, in previous studies [6], the “liberal” group received a median of 1570 mL intraoperatively, in comparison with 3L in this study. A second point to highlight is that only 8-10% of patients in this study were septic, and the length of stay in ICU was only 1 to 3 days. Therefore, we cannot extrapolate these conclusions to patients in septic shock, who required longer treatment in the ICU. A final point of discussion is the multiplicity of outcomes. One may argue that the effect on acute kidney injury is only a secondary outcome, so no inference can be claimed. This is partially true. Assessment of secondary outcomes can be tricky. In this case, secondary endpoints are included because they are clinically relevant or may represent an important safety issue for any of study groups. In this case, no significant benefits were observed in the primary and secondary outcomes. However, the effect of the treatment in the incidence of acute kidney injury is very significant and then would raise concerns about the safety of the new treatment. This may need confirmation in a second trial, but given that no benefit was demonstrated in the primary outcome, a second trial becomes difficult to justify.

Administration of too few fluids is probably as dangerous as the administration of too much [7]. Although it is understandable that fluid overload is considered a significant problem, we cannot overlook the fact that mechanistic explanations for fluid deregulation in patients in shock are still needed. Hopefully then, we might be able to propose a safe therapeutic strategy.

Review prepared and submitted by Hollmann D. Aya, on behalf of the Cardiovascular Dynamics section.



  1. Brandstrup B, Tonnesen H, Beier-Holgersen R, Hjortso E, Ording H, Lindorff-Larsen K, Rasmussen MS, Lanng C, Wallin L, Iversen LH, Gramkow CS, Okholm M, Blemmer T, Svendsen PE, Rottensten HH, Thage B, Riis J, Jeppesen IS, Teilum D, Christensen AM, Graungaard B, Pott F (2003) Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomised assessor-blinded multicentre trial. Annals of surgery 238 (5):641-648.
  2. Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA (2011) Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 39 (2):259-265.
  3. Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettila V, Aaen A, Lodahl D, Berthelsen RE, Christensen H, Madsen MB, Winkel P, Wetterslev J, Perner A, Group CT, Scandinavian Critical Care Trials G (2016) Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med 42 (11):1695-1705.
  4. Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, Van Regenmortel N (2014) Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiology intensive therapy 46 (5):361-380.
  5. Myles PS, Bellomo R, Corcoran T, Forbes A, Peyton P, Story D, Christophi C, Leslie K, McGuinness S, Parke R, Serpell J, Chan MTV, Painter T, McCluskey S, Minto G, Wallace S, Australian, New sealand College of Anaesthetists Clinical Trials N, the A, New Zealand Intensive Care Society Clinical Trials G (2018) Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery. N Engl J Med 2018; 378:2263-2274. DOI: 10.1056/NEJMoa1801601.
  6. Corcoran T, Rhodes JE, Clarke S, Myles PS, Ho KM (2012) Perioperative fluid management strategies in major surgery: a stratified meta-analysis. Anesth Analg 114 (3):640-651.
  7. Malbrain M, Van Regenmortel N, Saugel B, De Tavernier B, Van Gaal PJ, Joannes-Boyau O, Teboul JL, Rice TW, Mythen M, Monnet X (2018) Principles of fluid management and stewardship in septic shock: it is time to consider the four D’s and the four phases of fluid therapy. Annals of intensive care 8 (1):66.





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