ABSTRACT
BACKGROUND: We have previously shown that iatrogenic dehydration is associated with a shift to organic osmolyte production in the general ICU population. The aim of the present investigation was to determine the validity of the physiological response to dehydration known as aestivation and its relevance for long-term disease outcome in COVID-19. METHODS: The study includes 374 COVID-19 patients from the Pronmed cohort admitted to the ICU at Uppsala University Hospital. Dehydration data was available for 165 of these patients and used for the primary analysis. Validation was performed in Biobanque Québécoise de la COVID-19 (BQC19) using 1052 patients with dehydration data. Dehydration was assessed through estimated osmolality (eOSM = 2Na + 2 K + glucose + urea), and correlated to important endpoints including death, invasive mechanical ventilation, acute kidney injury, and long COVID-19 symptom score grouped by physical or mental. RESULTS: Increasing eOSM was correlated with increasing role of organic osmolytes for eOSM, while the proportion of sodium and potassium of eOSM were inversely correlated to eOSM. Acute outcomes were associated with pronounced dehydration, and physical long-COVID was more strongly associated with dehydration than mental long-COVID after adjustment for age, sex, and disease severity. Metabolomic analysis showed enrichment of amino acids among metabolites that showed an aestivating pattern. CONCLUSIONS: Dehydration during acute COVID-19 infection causes an aestivation response that is associated with protein degradation and physical long-COVID. TRIAL REGISTRATION: The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29).
Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Dehydration/etiology , Sodium , Urea , Potassium , Amino Acids , Glucose , Post-Acute COVID-19 SyndromeABSTRACT
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.