Several homeostatic mechanisms defend against extracellular pH disturbance:

• Excess plasma hydrogen ions are buffered rapidly by other blood constituents. In particular, negatively charged proteins such as albumin and haemoglobin have a large capacity for binding hydrogen ions. The concentration of these proteins therefore influences the buffering capacity of the blood.
• Hydrogen ions may be taken up across cell membranes, often in exchange for potassium ions.
• Through sensing of the hydrogen ion concentration by arterial and central chemoreceptors, metabolic acid-base disturbances often result in respiratory compensation. This typically starts within minutes and can lead to profound changes in alveolar ventilation, particularly in the setting of acidosis.
• Metabolic compensation for acid-base disturbance can be mediated through changes in bicarbonate handling within the kidney. Changes in the plasma bicarbonate concentration may begin within hours, but typically progress over several days, so the presence of significant metabolic compensation is a marker of chronicity in acid-base disturbances.

In some cases, compensation for acid-base disturbance will be partial, such that the pH remains abnormal. Alternatively, a disturbance may be fully compensated. The latter is common, for example, in patients with longstanding type 2 respiratory failure due to chronic obstructive pulmonary disease (COPD), in whom the arterial partial pressure of CO₂ (PaCO₂) is likely to be chronically elevated, but the pH normal, due to a compensatory rise in plasma bicarbonate. Beware of attributing any pH disturbance to overcompensation, which is much less likely than a mixed disturbance.