Early phosphate changes as potential indicator of unreadiness for artificial feeding: a secondary analysis of the EPaNIC RCT

Abstract

As compared to withholding parenteral nutrition (PN) until one week after intensive care unit (ICU) admission, Early PN prolonged ICU dependency in the EPaNIC randomized controlled trial (RCT). The Refeeding RCT showed improved outcome by temporary macronutrient restriction in ICU patients developing refeeding hypophosphatemia, defined as a phosphate decrease of > 0.16 mmol/L to levels < 0.65 mmol/L. We hypothesized that early phosphate changes may identify critically ill patients who are harmed by Early PN, and that dynamic phosphate changes are more discriminative than an absolute threshold for hypophosphatemia. In this secondary analysis of the EPaNIC RCT, we studied whether absolute hypophosphatemia (AHP; < 0.65 mmol/L on the second ICU-day), relative hypophosphatemia (RHP; > 0.16 mmol/L decrease over the first 2 ICU-days), or a combination of both (CHP) interacted with the randomized nutritional strategy for its impact on outcome, adjusted for risk factors. In case of significant interaction, we studied whether the respective change could be predicted by baseline characteristics. Of 3520 patients with available phosphate measurements, AHP developed in 9.1%, RHP in 23.7%, and CHP in 5.3% of patients. RHP, but not AHP or CHP, interacted with the randomized intervention for its impact on outcome (p = 0.01). In RHP patients, Early PN independently associated with a lower likelihood of an earlier discharge alive from ICU (adjusted HR 0.75 [0.65–0.87]). In patients without RHP, Early PN did not significantly associate with this outcome (adjusted HR 0.93 [0.86–1.00]). Development of RHP was only poorly predicted by admission characteristics (adjusted pseudo R-squared = 1.7%). Development of RHP may identify patients who are particularly harmed by early PN. Future studies should prospectively validate the potential of including RHP in a ready-to-feed indicator.