Females have a different metabolic response to critical illness, measured by comprehensive amino acid flux analysis

Nicolaas E.P. Deutz*, Pierre Singer, Raven A. Wierzchowska-McNew, Marina V. Viana, Itai A. Ben-David, Olivier Pantet, John J. Thaden, Gabriella A.M. Ten Have, Mariëlle P.K.J. Engelen, Mette M. Berger

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: The trajectory from healthy to critical illness is influenced by numerous factors, including metabolism, which differs substantially between males and females. Whole body protein breakdown is substantially increased in critically ill patients, but it remains unclear whether there are sex differences that could explain the different health outcomes. Hence, we performed a secondary analysis of a study, where we used a novel pulse isotope method in critically ill and matched healthy males and females. Methods: In 51 critically ill ICU patients (26 males, 15 females) and 49 healthy controls (36 males and 27 females), we assessed their general and disease characteristics and collected arterial(ized) blood in the postabsorptive state after pulse administration of 8 ml of a solution containing 18 stable AA tracers. In contrast to the original study, we now fitted the decay curves and calculated non-compartmental whole body amino acid production (WBP) and compartmental measurements of metabolism, including intracellular amino acid production. We measured amino acid enrichments and concentrations by LC-MS/MS and derived statistics using AN(C)OVA. Results: Critically ill males and females showed an increase in the WBP of many amino acids, including those related to protein breakdown, but females showed greater elevations, or in the event of a reduction, attenuated reductions. Protein breakdown-independent WBP differences remained between males and females, notably increased glutamine and glutamate WBP. Only severely ill females showed a lower increase in WBP of many amino acids in comparison to moderately ill females, suggesting a suppressed metabolism. Compartmental analysis supported the observations. Conclusions: The present study shows that females have a different response to critical illness in the production of several amino acids and changes in protein breakdown, observations made possible using our innovative stable tracer pulse approach. Clinical trial registry: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365).

Original languageEnglish
Article number155400
JournalMetabolism: Clinical and Experimental
StatePublished - May 2023


  • Amino acids
  • Critically ill
  • Females
  • Human
  • ICU
  • Males
  • Stable isotopes
  • sepsis


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