formation of methemoglobin Hemoglobin in this state is brownish purple in color, is incapable of binding O2 , and results in cyanosis if the level exceeds 10% to 15% of total Hb Another important altered state of hemoglobin that affects O2 binding occurs with exposure to carbon monoxide and results in the formation of carboxyhemoglobin This abnormal form of Hb has a cherry red color, despite the fact that little O2 is bound to the Hb molecule The state of the circulation plays an important role in the development and degree of cyanosis The first circulatory state that can result in cyanosis is shunting, during which deoxygenated blood from the venous side of the circulation enters the systemic side, without traveling through the ventilated alveolar capillary bed Shunts may be intrapulmonary or intracardiac Some degree of intrapulmonary shunting occurs physiologically In the upright lung the apex is ventilated more than the base, and the base is perfused more than the apex In addition, 5% of blood entering the lungs bypasses the pulmonary capillaries through bronchial, pleural, and Thebesian veins This results in a ventilation/perfusion (V/Q) mismatch In healthy subjects, the contribution of V/Q inequality to lowering of PaO2 is not clinically relevant; however, cyanosis can develop in patients with diseased lungs where the degree of shunting increases with a consequently larger V/Q mismatch Intracardiac shunting occurs when venous blood directly enters the systemic circulation through an abnormal communication within the heart or at the level of the ductus arteriosus, bypassing the lungs If the shunt is large, the reduction in PaO2 can be severe, leading to marked cyanosis The second circulatory change that can result in cyanosis is a poor perfusion state which may be either systemic or localized Oxygen is normally unloaded to the tissues as blood travels through a capillary, with the relative concentration of deoxygenated Hb increasing from the arterial side of the capillary bed to the venous side Poor perfusion states and cold temperature cause sluggish movement of blood across the capillary bed and favor the unloading of oxygen, increasing the amount of deoxygenated Hb in the tissue capillaries with resulting cyanosis DIFFERENTIAL DIAGNOSIS The most common causes of cyanosis are respiratory and cardiac diseases but many other conditions can also cause a patient to appear blue ( Tables 21.1 and 21.2 ) Consideration of the pathophysiologic framework outlined previously allows an orderly approach to the differential diagnosis of cyanosis Lifethreatening causes of cyanosis are summarized in Table 21.3