Mediators of the Impact of Hourly Net Ultrafiltration Rate on Mortality in Critically Ill Patients Receiving Continuous Renal Replacement Therapy

Objectives: During continuous renal replacement therapy, a high net ultrafiltration rate has been associated with increased mortality. However, it is unknown what might mediate its putative effect on mortality. In this study, we investigated whether the relationship between early (first 48 hr) net ultrafiltration and mortality is mediated by fluid balance, hemodynamic instability, or low potassium or phosphate blood levels using mediation analysis and the primary outcome was hospital mortality. Design: Retrospective, observational study. Setting: Mixed medical and surgical ICUs at Austin hospital, Melbourne, Australia. Patients: Critically ill patients treated with continuous renal replacement therapy within 14 days of ICU admission who survived greater than 48 hours. Interventions: None. Measurements and Main Results: We studied 347 patients (median [interquartile range] age: 64 yr [53-71 yr] and Acute Physiology and Chronic Health Evaluation III score: 73 (54-90)]. After adjustment for confounders, compared with a net ultrafiltration less than 1.01 mL/kg/hr, a net ultrafiltration rate greater than 1.75 mL/kg/hr was associated with significantly greater mortality (adjusted odds ratio, 1.15; 95% CI, 1.03-1.29;p= 0.011). Adjusted univariable mediation analysis found no suggestion of a causal mediation pathway for this effect by blood pressure, vasopressor therapy, or potassium levels, but identified a possible mediation effect for fluid balance (average causal mediation effect, 0.95; 95% CI, 0.89-1.00;p= 0.060) and percentage of phosphate measurements with hypophosphatemia (average causal mediation effect, 0.96; 95% CI, 0.92-1.00;p= 0.055). However, on multiple mediator analyses, these two variables showed no significant effect. In contrast, a high net ultrafiltration rate had an average direct effect of 1.24 (95% CI, 1.11-1.40;p