The Contribution of Plasma Urea to Total Osmolality During Iatrogenic Fluid Reduction in Critically Ill Patients

Abstract

Hyperosmolality is common in critically ill patients during body fluid volume reduction. It is unknown whether this is only a result of decreased total body water, or an active osmole-producing mechanism similar to that in aestivating animals where muscle degradation increases urea levels to preserve water. We hypothesized that fluid volume reduction in critically ill patients contributes to a shift from ionic to organic osmolytes similar to mechanisms of aestivation. We performed a post-hoc analysis on data from a multicenter observational study in adult ICU patients in the post-resuscitative phase. Fluid, electrolyte, energy and nitrogen intake, fluid loss, estimated glomerular filtration rate (eGFR) and estimated plasma osmolality (eOSM) were registered. Contributions of osmolytes Na+, K+, urea and glucose to eOSM expressed as proportions of eOSM were calculated. 241 patients were included. eOSM increased (median change 7.4 mOsm/kg (IQR −1.9–18) during the study. The of sodium's and potassium's proportions of eOSM decreased (P < 0.05 and P < 0.01 respectively), whereas the urea's proportion increased (P < 0.001). Urea's proportion of eOSM was higher in patients with negative vs. positive fluid balance. The urea's proportion of eOSM increased with eOSM (r = 0.63; adjusted for eGFR r = 0.80), but not nitrogen intake. In patients without furosemide and/or renal replacement therapy (n = 17), urea's proportion of eOSM and eOSM correlated strongly (r = 0.92). Urea's proportion of eOsm was higher in patients not surviving to 90 days. In stabilized ICU patients the contribution of urea to plasma osmolality increased during body water volume reduction, statistically independently of nitrogen administration and eGFR. The shift from ionic osmolytes to urea during body fluid volume reduction is similar to that seen in aestivating animals. ClinicalTrials.org Identifier: NCT03972475

Of Snails, Earthworms, and Men: Insights into Strategies to Preserve Water

“…In this issue of Function , Sandra Nihlén and colleagues 8 hypothesised that patients who experience fluid losses also activate systems akin to those observed in aestivating animals. Their paper is elegantly written and needs no detailed explanation here.…”

“…Nihlén et al . 8 studied 241 critically ill patients in the postresuscitative phase who had an initial event that required administration of large amounts of fluids and were now in a period of fluid offloading. Of course, they found that total osmolality increased in this phase, and this will be largely driven by a net loss of water.…”

“…Nihlén et al . 8 highlight a potentially important mechanism for protein catabolism in patients experiencing active or passive fluid losses. Further to this, the authors convincingly show that the increase in serum urea concentration is not driven by external nitrogen load (ie nutrition), but by catabolism driven by the critical illness.…”

“…The paper by Nihlén et al . 8 comes with many limitations. These range from the retrospective and somewhat observational nature of the study to limitations with precise measurements of key parameters including some of the osmolytes and osmolality itself.…”

“…Nihlén et al . 8 have impressively demonstrated that research is possible in this setting and that it can take advantage of the extremes of physiology that patients experience during critical illness. The recipe is simple: Focus on mechanisms that could play a role across multiple pathologies; define a clear-cut research question based on understanding of physiology and pathophysiology; and include a sufficiently large number of patients in order to compensate for some of the inherent limitations of such research.…”