A blood pH measurement device comprises a tube through which blood or other ion-containing fluid flows, at least one dry reference electrode, a proton diffusion differentiator, an ion-sensitive field-effect transistor, and a pH meter. The tube can comprise an annular wall with an entry, an exit, and a sensor floor. The dry reference electrode is preferably located within the tube between the entry and the exit and opposite the sensor floor. It is also contemplated that the dry reference electrode is surrounded by a membrane and is, at least partially, associated with the interior surface of the annular wall. The contemplated invention can also include a proton diffusion differentiator, such as an electrolyte separation layer, connecting the external surface of the sensor floor to an ion-selective field effect transistor (ISFET), wherein the ISFET measures the ion concentration of the blood.