The Acid–Base Effects of Albumin in Sepsis: Reconciling the Stewart Physicochemical Approach with the Traditional Buffer–Base Paradigm

Albumin administration in sepsis and septic shock remains controversial because of uncertain clinical benefits and complex acid–base effects. Unlike crystalloids, albumin influences acid–base equilibrium through effects on chloride balance, strong ion difference (SID), buffering systems, and weak acid concentration. These effects may be interpreted differently by the traditional bicarbonate-centered framework and Stewart’s physicochemical approach. In the traditional paradigm, albumin acts mainly as a non-bicarbonate plasma buffer influencing base excess and anion gap interpretation. In the Stewart framework, albumin is a weak non-volatile acid contributing to total weak acids (Atot), thereby influencing hydrogen ion dissociation and pH regulation. This narrative review compares these two approaches to albumin-related acid–base physiology in sepsis, with emphasis on chloride balance, strong ion difference, hypoalbuminemia, dilutional effects, and cardiorespiratory interactions during mechanical ventilation and septic shock. We also contextualize these mechanisms within major randomized trials of albumin and resuscitation fluids and present illustrative conceptual simulations illustrating the directional acid–base effects of different fluid compositions. The narrative review focuses on masked acidosis in hypoalbuminemic patients and on the interpretation of pH changes after albumin administration. Finally, we propose an integrated bedside framework combining traditional, physicochemical, respiratory, and hemodynamic variables for acid–base interpretation during fluid resuscitation.