Discussion
critically ill, deterioration of renal function, ARDS, hypotension, hypernatremia, renal damage, VFDs
CRITICALLY ILL, ELECTROLYTE DISTURBANCE, EVENTS, SECONDARY, SEPARATION, SEPTIC SHOCK, HYPERNATREMIA, ARDS
Intention-to-treat CRA and RBAA led to insignificant results regarding the effect of the POINCARE-2 strategy on 60-day mortality and all secondary outcomes, except hypernatremia.To our knowledge, POINCARE-2 is the largest trial assessing the effectiveness of a strategy targeting fluid balance control in a broad range of critically ill patients. A recent meta-analysis by Silversides et al. [Intention-to-treat analyses are commonly used to assess effectiveness of interventions. Considering patients from the control group unexposed to the strategy and patients from the strategy group optimally exposed, whatever their actual exposure to the strategy, can result in attenuated between-group differences [First, although less frequent, daily weighing was also performed during the control period; and both furosemide and albumin were also prescribed during the control period as part of standard of care, resulting in possible contamination (i.e. exposure to [at least part of] the POINCARE-2 strategy during the control period). In addition, CRA results showed that furosemide was prescribed more in the control than strategy group, which could result from a greater need of diuretics in patients without water/salt restriction, or by residual unbalance between groups. Because furosemide was slightly (though not significantly) more prescribed in the strategy group in RBAA (Additional file Therefore, contamination during the control period and suboptimal application of the POINCARE-2 strategy during the strategy period might have resulted in incomplete group separation and subsequent underestimation of the POINCARE-2 strategy effect. In addition, the POINCARE-2 strategy was flexible and its application was left at the discretion of the intensivist to meet the patients’ needs. Accordingly, during the strategy period, departure from the strategy protocol might have occurred in patients not ready for de-resuscitation on Day 2, such as patients with severe septic shock, thus resulting in apparent suboptimal application of the strategy and further incomplete separation between groups. At this point, only additional results from per-protocol, as-treated, and subgroup analyses, as planned in the POINCARE-2 protocol [To avoid a too early “de-resuscitation”, the POINCARE-2 strategy was started at Day 2 after ICU admission. Both mean (Day 7–Day 0) weight difference and average fluid balance were positive but lower than expected, as compared to that observed in trials included in the meta-analysis by Silversides et al [Although the timing for fluid management was strict in the POINCARE-2 strategy, the strategy itself was more of a set of recommendations than a restrictive standardized procedure. Although hypothetical, intensivists’ attitudes toward the POINCARE-2 strategy could explain part of the observed contamination: in other words, they might have been convinced of the beneficial effect of a conservative approach before the POINCARE-2 trial started, and might have implemented it earlier than planned during the trial. Only a complete process evaluation [Potential deleterious consequences of conservative fluid management or de-resuscitation include hemodynamic disturbances, deterioration of renal function, and electrolyte disturbances. The occurrence of arterial hypotension, major ischemic events, and renal damage, as well as VFDs and RRTFDs, did not differ between groups, in both CRA and RBAA. Altogether, these results suggest that a conservative approach was safe for hemodynamic and renal function.Severe hypernatremia was more frequent in the strategy group whatever the analyses. Similar results were observed in the trial conducted by the ARDS network [The POINCARE-2 trial has some strengths. First, the number of critically ill patients were prospectively included in a timely manner, as planned, which is critical in a stepped wedge trial and could otherwise compromise the design. Second, the thorough monitoring of the data by an ISO 9001-certified research lab (However, the POINCARE-2 trial also has some limitations.First, the trial was powered to detect a 15% absolute difference in 60-day mortality, which might seem high with regard to the 3% difference actually observed.The magnitude of the difference that was assumed to determine the size of the POINCARE-2 trial was based on results of previous studies assessing fluid balance control [Second, the intra-period correlation coefficient was lower than the intra-cluster correlation coefficient. This situation might threaten the validity of CRA. These analyses were chosen as primary analyses in 2013, at the time the trial got funded, on the basis of a previous publication [Third, contamination might have threatened the validity of the intention-to-treat analyses. Although assessment of adherence to the strategy suggested some difference in fluid accumulation between groups, these differences were statistically non-significant, resulting in a lower than anticipated difference in strategy effect between groups. One could argue that a better monitoring of adherence to the strategy would have prevented such contamination. However, adherence of investigators and ICU nurses to conservative strategies might have affected their will to participate in the trial and their implementation of the strategy. In addition, components of the POINCARE-2 strategy are commonly used in ICUs. Unfortunately, even if stepped wedge randomized controlled trials are best fit to handle investigators’ preference toward the intervention under scrutiny, they cannot totally prevent its anticipated implementation.Fourth, the POINCARE-2 strategy was based on a pragmatic approach, targeting fluid balance control by using few human and material resources. Accordingly, daily weighing was used as a proxy of fluid balance assessment. Although cumulative fluid balance evolution from Day 0 to Day 14 corroborated findings from average weight evolution over the same period in our results, we cannot firmly state that weight was an accurate proxy of fluid balance in ICU patients.