Chloride in the spotlight – the hidden driver of acid-base homeostasis

Chloride is the most abundant extracellular anion and contributes fundamentally to osmolality, electroneutrality, and acid-base balance. Despite this central role, it has often received less attention in clinical practice compared with sodium or bicarbonate. Recent advances in physiology and clinical research underscore chloride’s role as a key regulator of acid-base balance and a practical guide for diagnosis and therapy.

Chloride, as the dominant extracellular anion, has a direct influence on acid-base balance that goes beyond its traditional role as sodium’s counterpart. While the Henderson-Hasselbalch model describes pH regulation primarily through bicarbonate and pCO₂, it does not fully capture chloride’s contribution. To address this, Peter Stewart introduced an alternative framework, the strong ion theory. In this model, pH is determined by three independent variables: pCO₂, the total concentration of weak acids (mainly albumin and phosphate), and the strong ion difference (SID).¹ Strong ions are defined as electrolytes that are completely dissociated at physiological pH and therefore exist in solution entirely as charged particles. The SID represents the difference between the sum of strong cations and the sum of strong anions: