Reply to ‘Methodological considerations on early cumulative fluid balance and mortality in post-cardiac arrest shock’

We are grateful to Luo and Shen for their interest in our study and for raising important questions regarding its findings.¹ We fully agree that fluid balance is the result of the complex interplay of multiple factors: inflammation-induced vascular leakage following ischemia–reperfusion injury, hemodynamic status, fluid therapy and catecholamine use, mechanical ventilation settings, among others.

They questioned the potential role of diuretics in our study, which were more frequently administered to survivors. First, although our study highlighted an association between fluid balance and early mortality after resuscitated cardiac arrest, it was not designed to evaluate interventions aimed at controlling fluid balance (particularly diuretics, which may show important collinearity with fluid balance in simple multivariable models). From a pathophysiological perspective, diuretics may have dual effects depending on the patient’s volume status: beneficial in cases of fluid overload, but harmful in cases of hypovolemia. As stated in our article, we observed considerable heterogeneity among patients with respect to their input–output profiles, which likely reflects different hemodynamic states, particularly regarding volemia. The higher use of diuretics among survivors may therefore simply reflect a lesser degree of hemodynamic compromise in this group, combined with signs of fluid accumulation. Whether early fluid removal has an impact on outcomes after cardiac arrest will need to be carefully evaluated in future studies, taking into account this substantial hemodynamic heterogeneity, as others have suggested.²

They also raised the question of a possible interaction between catecholamine use and fluid balance. In our study, the vasoactive-inotropic score (VIS) did not show collinearity with fluid balance. This may indicate the use of fluid-responsiveness markers to guide fluid therapy in these patients.³ However, we recognize that statistical independence does not preclude biological interaction.⁴ We did not test for VIS × fluid balance interactions in our original analysis, which may be addressed in future studies.

Finally, we fully agree that age, among other factors, may strongly influence hemodynamic responses.⁵ Our decision to categorize age was based on clinical considerations and the distribution of our data, though we recognize that continuous modeling approaches such as restricted cubic splines could provide additional insights into potential non-linear relationships.

In summary, the only firm conclusion that can be drawn from our results is that fluid balance plays a major role in post-resuscitation circulatory failure. The impact of controlling fluid balance, and the optimal strategies to do so, will require future trials that account for patient heterogeneity and the multiple factors influencing this parameter.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Dr. Bréchot participates in an F4-Pharma advisory board, without any financial competing interest. He received a grant from the French Ministry of Health for a study evaluating FX06, a drug under development aiming at controlling vascular leakage. He receives fees from Findimmune and Getinge, outside the scope of this study. All authors contributed to the letter, and read and approved its final version. The artificial intelligence tool ChatGPT was used to assist with manuscript editing.’.