Discussion
In this systematic review and meta-analysis that included 2312 children with sepsis, FO was found to be associated with greater mortality when it occurred at any time after PICU admission. We found no relationship between FO and a higher frequency of MODS, although the included studies had high heterogeneity. We found that children with sepsis and FO needed MV more often and had a longer PICU stay.
Fluid therapy is ubiquitous in the care of critically ill children.1 3 8 Often, excess fluid in children with sepsis arises from excessive maintenance fluid, medication, nutrition and crystalloid boluses for fluid resuscitation.1 The first multicentre study to alert to increased mortality in children with the use of fluid resuscitation was the fluid expansion as supportive therapy study.32 The results showed that, while fluid resuscitation improved tissue perfusion in the children, it also significantly increased mortality compared with the control group. The findings of this study have led to a review of current clinical practice. It is suggested that the use of crystalloid boluses be tailored, with adequate monitoring of %FO. In addition, a fluid deresuscitation phase should be included in all children with septic shock to avoid the complications associated with excessive fluid administration.
In this regard, a recent systematic review and meta-analysis that included 44 observational studies and data from more than 7000 critically ill children concluded that FO was common in critical care, occurring in approximately 30% of the patients.12 FO was found to be strongly associated with greater morbidity and mortality. However, studies have been published on children with sepsis which have found no relationship between the degree of FO and mortality.33 Nevertheless, these studies share significant limitations with regard to design and a heterogeneous metric in the definition and variables used to evaluate the outcomes related to fluid accumulation. With the recent definitions of FO, more unified criteria have been used to perform studies and evaluate the impact of excess fluids on the paediatric population.23
Children with sepsis are more susceptible to fluid accumulation. Increased vascular permeability related to the associated inflammatory response, endothelial activation and glycocalyx degradation, among others, make them more prone to fluid accumulation outside of the intravascular space.17 18 20 21 Among the most important consequences of this overload and the inflammatory response are the progressive macrocirculation (cardiac output, heart rate, arterial pressure, etc) and microcirculation disturbances.26 In sepsis, excessive fluid accumulation in the interstitial space makes oxygen diffusion towards the tissues more difficult, facilitating tissue hypoperfusion and the resulting tissue hypoxia and dysoxia.34 35 This tissue oxygenation problem could be the final common pathway which would at least partially explain the higher FO-associated mortality found in our study in children with sepsis.
In addition, we found that patients with greater FO had more frequent respiratory failure requiring MV. Alobaidi et al12 found a greater association between FO and the need for prolonged MV. In fact, Acute Respiratory Distress Syndrome (ARDS) studies and the recent consensus recommendations suggest that a conservative fluid strategy and neutral or negative balances can improve pulmonary function and shorten the PICU stay.36 37 Valentine et al found that only 29% of patients with Acute Lung Injury (ALI) received restrictive fluid management in clinical treatment.38 The Fluid And Catheter Treatment Trial in adults found that a conservative fluid management strategy in the first 7 days of intensive care was associated with less time on MV and a shorter length of stay in intensive care than a liberal fluid management.39 These results should be studied in the future in the context of children with sepsis, since comorbidities, complications and organ dysfunction.
Interestingly, we found no association between FO and multiple organ dysfunction in the included studies. However, it seems that prolonged FO during intensive care is what is related to the onset of MODS. Recently, Chapalain et al found, in adults with sepsis, that MODS evaluated with the SOFA score was twice as high in the group without FO compared with the group with FO 24 hours after ICU admission.40 However, the cumulative fluid balance on the fifth day was three times higher in the group with FO, which was associated with an 85% rise in the SOFA score (delta). That is, a prolonged duration of FO during the ICU stay was the main factor associated with developing MODS. Active maintenance fluid control and a potential fluid deresuscitation phase are strategies increasingly used in both adults and children. These measures could limit the development of late-onset MODS associated in some studies with FO.
We consider that our study has several limitations. Only observational studies were included, describing an association between FO and mortality, which does not necessarily indicate causality. Unfortunately, we found no clinical trials in the literature which evaluated this outcome. Furthermore, some special patient subgroups (burns, trauma) were not described in the studies, which could limit the generalisation of our findings to these specific groups of children with sepsis. In this regard, a greater than 10% FO was taken as a dichotomous rather than continuous variable. This aspect should be kept in mind when interpreting the results in each application setting. Finally, the presence of FO was not consistently described throughout the PICU stay in most of the included studies. This limited our analysis because, as described in the MODS group, lack of fluid balance monitoring throughout the critical care stay can lead to an under-reporting of later-onset FO which can be associated with organ dysfunction and mortality.