Cyanosis is a pathologic condition that is characterized by a bluish discoloration of the skin or mucous membrane. The word cyanosis is a derivative of the word cyan, a blue-green color. The presence of cyanosis can pose a serious diagnostic challenge. A careful and thorough evaluation with the proper diagnostic tools can help discern the cause.
Cyanosis, broadly speaking, is caused by disorders of deoxygenated hemoglobin and disorders of abnormal hemoglobin. Oxygen might not reach hemoglobin in an adequate or sufficient amount as a result of conditions affecting the respiratory system, cardiovascular system, and the central nervous system (CNS).
Disorders of deoxygenated hemoglobin are further divided into two broad groups: central cyanosis and peripheral cyanosis. Central cyanosis occurs when the level of deoxygenated hemoglobin in the arteries is below 5 g/dL with oxygen saturation below 85%. The bluish hue is generally seen over the entire body surface and visible mucosa. In contrast, peripheral cyanosis is usually only seen in the upper and lower extremities where the blood flow is less rapid. In peripheral cyanosis, there is a significant difference in the saturation between the arterial and venous blood. This occurs as a result of increased oxygen extraction by the peripheral tissue in the capillary bed. Low cardiac output, venous stasis, and exposure to extreme cold causing vasoconstrictions are some of the conditions that can cause peripheral cyanosis.
Common Causes of Central Cyanosis
Furthermore, cyanosis can be caused by the presence of abnormal hemoglobin. Hemoglobin is the major carrier of oxygen in the blood. It is made up of four subunits. Each of the four subunits is made of polypeptide chains, two alpha and two beta. At the center is a heme group which contains iron. The presence of abnormal hemoglobin causes significant impairment in the oxygen-carrying capacity of the blood. This can cause tissue hypoxia which can manifest clinically as cyanosis.
Methemoglobinemia is a condition that can produce congenital or acquired cyanosis. The condition arises when the iron in hemoglobin is converted from the ferrous (Fe2+) to the ferric (Fe3+) state. Approximately 2% of hemoglobin is present in this form. The presence of methemoglobin can impart a bluish tinge to the skin color. Methemoglobinemia can be triggered by exposure to the topical anesthetic agent dapsone, nitroglycerin, or other strong oxidizing agents. Congenital methemoglobinemia type I and II is an autosomal recessive condition that is caused by a mutation in the gene for cytochrome b5 reductase enzyme. The condition is extremely rare. The lack of enzymatic activity by cytochrome b5 reductase causes decreased reduction of methemoglobin.
Sulfhemoglobin is another rare cause of cyanosis that arises from sulfur binding to hemoglobin. This causes the uncoupling of oxygen from hemoglobin to be very difficult. The iron in the hemoglobin remains unchanged in its ferrous state in sulfhemoglobinemia.
Pseuodcyanosis is another uncommon condition that occurs as a result of contact with drugs such as amiodarone. Exposure to gold or silver salts also can cause pseuodcyanosis. Diagnosis can be easily established by careful review of medications.
Cyanosis typically occurs when the amount of oxygen bound to hemoglobin is very low. Oxygen in the blood is carried in two physical states. Approximately 2% is dissolved in plasma and the other 98% bound to hemoglobin. The presence of cyanosis might be an indication of inadequate oxygen delivery to the peripheral tissues. It also could be related to an increased oxygen extraction by the peripheral tissues. Several factors play a significant role regarding oxygen delivery to the end organs. Oxygen delivery is the product of the cardiac output and the arterial oxygen content. Cardiac output is determined by the preload, afterload, and contractility. The arterial oxygen content is the sum of oxygen bonded to hemoglobin and dissolved in plasma, approximately 1.34 mL per 1 g of hemoglobin and 0.003 mL of oxygen per 100 mL of plasma.
Typically, when the level of deoxygenated hemoglobin is around 3 to 5 g/dL, cyanosis becomes very evident. The presence of jaundice, skin color, ambient temperature, or light exposure might affect the assessment of cyanosis. Anemia or polycythemia also plays a role in cyanosis. The level of hypoxia required to produce clinically evidenced cyanosis varies for a given level of hemoglobin. Cyanosis is more difficult to discern when the level of hemoglobin is low. In other words, cyanosis might not be clinically evident in a patient with severe anemia.
The history and physical examination are very important in determining the cause of cyanosis and establishing an appropriate diagnostic algorithm. The onset of cyanosis in the early perinatal period is highly suggestive of a congenital cause whereas a more recent onset is most likely related to an acquired etiology. The next issue to clarify is if the cyanosis is central or peripheral. Central cyanosis suggests a cardiopulmonary disease. This is especially true if there is an associated digital clubbing.
In taking the history, an attempt should be made to find out any associated cardiopulmonary conditions that can lead to cyanosis. In patients with tachycardia and tachypnea with an associated low blood pressure, sepsis with septic shock is the most probable cause. History of exposure or physical contact with substances like dapsone, sulfur-containing drugs, and topical anesthetic agents should be sought as this may also help uncover the presence of hemoglobinopathies like methemoglobinemia. Current or frequent exposure to cold should be elicited in the history taking because vasospasm can cause peripheral cyanosis.
Physical examination is best done where there is adequate illumination as the assessment might be impaired if there is insufficient light exposure. The thickness of the skin and cutaneous pigmentation might also affect the physical assessment. The best area to assess for cyanosis is where the outer layer of the skin is very thin, and the blood supply is very generous such as the cheeks, nose, ears and oral mucosa.
Diagnosis of cyanosis is based on careful history, a thorough physical examination, and the use of ancillary studies. Since in most instances, the cardiopulmonary system is involved in the development of cyanosis, a focused assessment of both system is warranted. If a congenital heart condition is suspected, transthoracic and transesophageal echocardiography can be used to evaluate the cardiovascular system. To assess blood flow and shunting, cardiac Doppler is a very important diagnostic tool. Other tests include cardiac catheterization, CT scan, and MRI of the heart.
Pulmonary causes of cyanosis like pneumonia, pleural effusion, and pulmonary embolism can best be evaluated by using imaging studies like X-Ray, CT Scan, and ultrasound of the chest.
If hypoxemia is suspected as a cause of cyanosis, the primary assessment should include a pulse oximetry and an arterial blood gas. The arterial blood gas shows the partial pressure of dissolved oxygen in the blood as well as the saturation of hemoglobin. The pulse oximeter measures the absorption of light at only two wavelengths which correspond to that of oxyhemoglobin and deoxyhemoglobin. The drawback of measuring only two wavelengths is that it can create a misleading picture when evaluating a patient with cyanosis secondary to methemoglobinemia. This is because abnormal hemoglobin is not picked up by the pulse oximetry; therefore, in methemoglobinemia, the pulse oximetry reading is falsely elevated. Co-oximetry provides a more accurate evaluation of oxygen saturation because it measures the absorption of light at four different wavelengths corresponding to oxyhemoglobin, deoxyhemoglobin, carboxyhemoglobin, and methemoglobin. For a patient presenting with cyanosis in which abnormal hemoglobin is suspected, co-oximetry is a useful diagnostic tool.
Another abnormal hemoglobin that can cause congenital cyanosis is hemoglobin M. This hemoglobin is formed as a result of mild structural changes in the alpha and beta chains that keep it in an oxidized ferric state, thereby reducing the oxygen-carrying capacity. A routine hemoglobin electrophoresis can best detect this.
Cyanosis is a symptom of a disease process. The goal is to treat the underlying condition causing cyanosis. Surgical intervention is required for the correction of congenital heart disease causing cyanosis. In infants and neonate with cyanotic congenital heart disease like tetralogy of Fallot, tricuspid atresia, truncus arteriosus, or total anomalous venous return, prompt referral for cardiology assessment and intervention is necessary. If the cardiac lesion is ductal dependent for pulmonary blood flow, prostaglandin E1 infusion might be necessary to keep the ductus arteriosus open. In the management of neonates with cyanosis, careful attention should be paid to the correction of metabolic derangements like hypoglycemia and hypocalcemia.
Impairment of oxygen diffusion and transfer and other conditions affecting the respiratory system that lead to hypoxia also can cause cyanosis. Oxygen support can be provided to resolve the hypoxia. The regular nasal cannula, high flow nasal cannula, and in some instances, assisted ventilation might be required to provide adequate respiratory support.
For methemoglobinemia-induced cyanosis, the standard treatment is with methylene blue. Nicotinamide adenine dinucleotide phosphate helps in the conversion of methylene blue to leucomethylene blue. This end product helps reduce methemoglobin to normal hemoglobin.
Exposure to gold or silver salts also can produce cyanosis. The best therapy in this instance is to remove the offending agents.
In summary, treatment of cyanosis can be very challenging, and a multidisciplinary approach with different subspecialists might be needed in the management.