BACKGROUND: The dissociation constant of nonvolatile weak acids in plasma (KA), expressed as pKA, is essential for electroneutrality-based acid-base analysis. To date, its normal value in human plasma has been determined in only one study involving eight healthy volunteers. We hypothesized that pKA would differ in ICU patients, whose plasma protein composition is altered by disease and medication, and that changes in protein charge-rather than undetected strong acids-could account for the unexplained anions observed in sepsis. METHODS: Using CO2 tonometry, we determined pKA and total weak nonvolatile acids (ATOT) in plasma from 30 healthy volunteers and two ICU cohorts (27 postoperative and 30 septic patients). Additionally, we calculated the strong ion gap in plasma and protein-free serum filtrates from 10 healthy volunteers and 20 septic patients. RESULTS: In healthy volunteers, pKA was 7.55 ± 0.16 (KA = 2.8 × 10⁻⁸) and ATOT was 15.9 ± 3.0 mmol/L (0.222 ± 0.043 mmol/g of TP). In postoperative and septic patients, ATOT was significantly reduced (10.1 ± 5.4 and 11.9 ± 4.0 mmol/L, p < 0.001), but pKA and ATOT/TP remained unchanged, yielding an average pKA of 7.55 ± 0.35 (KA = 2.8 × 10⁻⁸) and ATOT/TP of 0.230 ± 0.097 mmol/g. We found elevated strong ion gap in both plasma and protein-free filtrates of septic patients, which confirms the presence of unmeasured low-molecular-weight anions. CONCLUSION: Our findings confirm stable pKA and ATOT/TP values in human plasma in both health and disease, supporting the Staempfli-Constable model for clinical acid-base diagnostics. Unexplained anions in sepsis are attributed to low molecular weight strong ions rather than alterations in plasma protein dissociation.

Department of Anaesthesia and Intensive Care Medicine 3rd Faculty of Medicine Charles University and FNKV University Hospital Prague Czech Republic

Department of Anesthesia and Intensive Care Medicine Niguarda Ca' Granda Milan Italy

Department of Intensive Care Medicine Amsterdam Medical Data Science Amsterdam Public Health Amsterdam UMC Vrije Universiteit Amsterdam The Netherlands

Department of Medicine and Surgery University of Milano Bicocca Monza Italy

Department of Pathophysiology and Transplantation University of Milan Milan Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy

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