Metabolic acidosis and the role of unmeasured anions in critical illness and injury

Acid–base disorders are frequently present in critically ill patients. Metabolic acidosis is associated with increased mortality, but it is unclear whether as a marker of the severity of the disease process or as a direct effector. The understanding of the metabolic component of acid–base derangements has evolved over time, and several theories and models for precise quantification and interpretation have been postulated during the last century. Unmeasured anions are the footprints of dissociated fixed acids and may be responsible for a significant component of metabolic acidosis. Their nature, origin, and prognostic value are incompletely understood. This review provides a historical overview of how the understanding of the metabolic component of acid–base disorders has evolved over time and describes the theoretical models and their corresponding tools applicable to clinical practice, with an emphasis on the role of unmeasured anions in general and several specific settings.