Iatrogenic dehydration drives organic osmolyte production in critical COVID-19.

Fluid removal with concomitant dehydration is a common treatment strategy in acute respiratory distress syndrome (ARDS). We have previously shown that iatrogenic dehydration during treatment in the intensive care unit (ICU) is associated with a shift to organic osmolyte production in the general ICU population. In this study we investigate the development of estimated osmolality (eOSM = 2Na+2K+glucose+urea) over time in ICU, as well as the relationship between the major osmolytes and eOSM. The study includes 370 COVID-19 patients admitted to the ICU at Uppsala University Hospital between March 13. 2020 and June 11. 2021. Complete data was available for 176 of these patients, which were used for the analysis. The results show that eOSM increases with time spent in ICU (R2 = 0.75, P<0.001), which indicates iatrogenic dehydration. Further, increasing eOSM is correlated with increasing role of urea as an osmolyte (R2 = 0.6, P<0.001), while the role of sodium and potassium are inversely correlated to eOSM. This is consistent with the aestivation response where dehydration with increased osmolality drives production of organic osmolytes through gluconeogenesis and urea synthesis. Interestingly, glucose shows a weak negative correlation to eOSM (R2 = 0.01, P<0.01), which we interpret as a sign of iatrogenic control using insulin treatment. Acute Kidney Injury with reduced kidney function is an alternative explanation for increasing urea concentration. However, although there is a correlation between urea and the GFR-markers creatinine and cystatin-C the effect size cannot explain more than part of the association. In conclusion, iatrogenic dehydration causes an aestivation response in critical COVID-19 where urea plays an increasing role as an osmolyte with increasing total osmolality.