Cyanosis

Epidemiology

Cyanosis is a relatively rare presenting chief complaint in the emergency department (ED) and is usually noted in patients with a hypo-perfused state or known cardiopulmonary disease, including congenital heart disease. Although carbon monoxide poisoning and cyanide toxicity result in inadequate hemoglobin oxygenation and/or tissue hypoxia, these entities typically do not present with the clinical finding of cyanosis and are discussed in other chapters (see Chapter 148 ).

Pathophysiology

Cyanosis is evident on physical examination when the absolute amount of desaturated (unoxygenated) hemoglobin in the circulating capillary blood is elevated to ∼5 g/dL. It is not caused solely by a percentage of desaturated total hemoglobin mass or decreased amount of oxyhemoglobin. For this reason, patients with anemia exhibit cyanosis at lower arterial partial pressure of oxygen (Pa o ₂ ) and oxygen saturation (Sa o ₂ ) levels than those with normal hemoglobin, while patients with polycythemia may exhibit cyanosis at higher Pa o ₂ and Sa o ₂ levels. As such, cyanosis is an insensitive indicator of tissue oxygenation; its presence suggests hypoxemia, but its absence does not exclude it.

Primary causes of hypoxemia include ventilation-perfusion (V/Q) mismatch, hypoventilation, diffusion limitation, and low levels of inspired oxygen. V/Q mismatch is an imbalance between the ventilation and perfusion of alveolar-capillary units and is the most common cause of hypoxemia. High V/Q ratios (increased dead space) can be seen in diseases such as pulmonary emboli, emphysema, and pulmonary hypertension. Low V/Q ratios, with the most extreme example being a right-to-left shunt, occur in pneumonia, asthma, ARDS, and pulmonary edema. Anatomic right-to-left shunts are seen in developmental anomalies, such as congenital heart disease and patent ductus arteriosus. Hypoventilation lowers alveolar P o ₂ and is most commonly caused by depressed central respiratory drive, respiratory muscle weakness, or morbid obesity. Diffusion limitation refers to the impaired diffusion of oxygen across the alveolar-capillary interface and is seen in diseases such as interstitial pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). This may not cause hypoxemia at rest but may during exercise when the transit time for red blood cells (RBCs) in the pulmonary capillary bed is reduced. Lastly, low levels of inspired oxygen result in reduced alveolar P o ₂ levels and are seen primarily at high altitude.

Abnormal hemoglobin forms, most commonly methemoglobin, also contribute to cyanotic disease. Under normal conditions, RBCs contain hemoglobin with iron in the reduced ferrous state (Fe ²⁺ ). Ferrous iron binds oxygen readily to create oxyhemoglobin, and it reverts to the ferrous state when oxygen is released. The iron molecule may be oxidized to the ferric state (Fe ³⁺ ) spontaneously or by oxidative stress, producing methemoglobin. The ferric iron cannot bind oxygen, impairing the ability of hemoglobin to transport oxygen to the tissues. Any remaining ferrous (Fe ²⁺ ) binding sites on the hemoglobin molecule have a higher affinity for oxygen, shifting the oxygen-hemoglobin dissociation curve ( Fig. 10.1 ) to the left, further resulting in tissue hypoxia and subsequent lactic acid production.

Methemoglobin normally accounts for less than 1% of total hemoglobin. Cyanosis results when more than 1.5 g/dL of methemoglobin is present (∼10% to 25% of the total hemoglobin). Methemoglobin has a dark purple or chocolate-brown color, even when exposed to room air. It is primarily reduced to ferrous (Fe ²⁺ ) hemoglobin by nicotinamide adenine dinucleotide + hydrogen (NADH)−cytochrome b5 reductase, an enzyme system present in RBCs. A secondary system dependent on nicotinamide adenine dinucleotide phosphate (NADPH) reductase uses glutathione and glucose-6-phosphate dehydrogenase (G6PD) to reduce methemoglobin to ferrous hemoglobin. This secondary pathway plays a minor physiologic role but is accelerated significantly by methylene blue.

Primary methemoglobinemia is the result of congenital errors in metabolism caused by diminished levels of NADH reductase or an abnormally functioning enzyme. Patients may have stable compensated cyanosis. Acquired methemoglobinemia occurs when methemoglobin production exceeds the capacity of NADH reductase activity; this is usually a result of a drug reaction. The most common medications that cause methemoglobinemia are local anesthetics, both injected and topical, phenazopyridine, nitroglycerin, and metoclopramide. See Box 10.1 for additional causes. Newborns are at increased risk for methemoglobinemia due to relatively low NADH reductase activity compared with that of adults.