Central and Peripheral Cyanosis

Etiology

Causes of central cyanosis include:

• Hypoventilation due to conditions affecting the central nervous system, such as intracranial hemorrhage, tonic-clonic seizures, and heroin overdose.
• Pulmonary causes leading to ventilation-perfusion mismatch and impaired alveolar-arterial diffusion, for instance, bronchospasm (asthma), pulmonary embolism, pneumonia, bronchiolitis, pulmonary hypertension, hypoventilation, and COPD [4][5][6]
• Cardiovascular causes include heart failure, congenital heart diseases (right to left shunting), and valvular heart diseases.
• Hemoglobinopathies, including methemoglobinemia, sulfhemoglobinemia
• Polycythemia
• High altitude
• Hypothermia
• Obstructive sleep apnea [7][8]

 Peripheral cyanosis can be seen because of the following:

• Reduced cardiac output secondary to heart failure or shock
• Local vasoconstriction due to cold exposure, hypothermia, acrocyanosis, and Raynaud phenomenon
• Vasomotor instability
• Arterial obstruction causing regional ischemia secondary to peripheral vascular disease. Causes include atherosclerosis, Buerger disease, atheroembolism
• Venous stasis or obstruction, such as in deep vein thrombosis
• Hyperviscosity attributable to multiple myelomas, polycythemia, and macroglobulinemia

All causes of central cyanosis can also cause peripheral cyanosis. Cardiopulmonary causes and hemoglobin abnormalities are the common causes of central cyanosis. Differential cyanosis can be seen in patent ductus arteriosus with pulmonary hypertension.[9]

Pathophysiology

Cyanosis is due to inadequate oxygenation of blood. It results when the deoxyhemoglobin exceeds 5.0 g/dL. The bright red color of the blood is due to an adequate content of oxygen in the blood, which changes to a darker red with a reduced level of oxygen reflecting more blue light, making the skin appear to have a blue tint. However, the blue tint is more apparent with a high hemoglobin count.[10]

The pathophysiology of cyanosis is as follows:[11][12]

Hypoxic Hypoxia: The oxygen diffusion to the tissues is decreased due to decreased oxygen tension and content in arterial and venous blood.[13]

• Inspired air is low in oxygen content: Sea level, high altitude
• Decreased ventilation: Emphysema, respiratory center depression
• Decreased diffusion through the alveolar-capillary membrane: fibrosis, interstitial edema
• Right to left shunting of blood in the heart: patent ductus arteriosus (PDA), interventricular or interatrial defects

Stagnant Hypoxia: Hypoxia is due to reduced or uneven blood flow despite oxygen tension and content in the arterial blood is normal. As a result of the increased extraction of the available oxygen at the tissue level, the oxygen tension and content in the venous blood decrease.

• Generalized reduced blood flow: Congestive heart failure.
• Localized reduced blood flow: Peripheral vascular diseases such as Raynaud can lead to peripheral vessel spasms (the lack of blood flow leads to the white coloration of fingers, followed by bluish discoloration when the veins dilate to keep the blood flow going, finally returning to red color on the restoration of blood flow)

Asphyxia: In this, there is both hypoxia as well as increased levels of carbon dioxide (hypercapnia) 

Peripheral cyanosis occurs due to the inability of the body to deliver oxygen-rich blood to the peripheral tissues. Congestive peripheral cyanosis can be caused due to the slowing of blood flow. Ischemic peripheral cyanosis occurs when vasoconstriction leads to diminished peripheral blood flow. In peripheral cyanosis, there is normal arterial oxygen saturation but increased oxygen extraction by the peripheral tissue in the capillary bed in the setting of peripheral vasoconstriction and decreased peripheral blood flow. This results in a significant difference in the saturation between the arterial and venous blood, with increased deoxygenated blood on the venous side of the capillary beds.[14]

Reduced cardiac output in heart failure and shock can, if severe, lead to peripheral cyanosis. Lack of pressure prevents an adequate supply of oxygen-rich blood to the extremities. Also, hypotension produces reflex cutaneous vasoconstriction to shunt blood from the extremities to the internal organs. This redistribution of blood flow from the extremities causes cyanosis of the extremities. Exposure to cold increases the transit time through capillary beds, resulting in cyanosis due to increased oxygen unloading from the blood to the tissues. Benign vasomotor changes can cause acrocyanosis, a form of peripheral cyanosis. It can be a normal finding in babies and resolves within the first few days of life. Additionally, it can be seen in infancy when babies cry, vomit, regurgitate, cough, and hold their breath. It is not considered pathologic unless significantly low cardiac output leads to cutaneous vasoconstriction. In the Raynaud phenomenon, abnormal vasospasm occurs with exposure to changes in temperature and emotional events. The diminished blood flow causes a blue discoloration of the fingers and toes. About 98% of oxygen is normally bound to hemoglobin, with the remaining 2% dissolved in plasma.

History and Physical

A detailed history and physical examination are vital in determining the underlying cause of cyanosis. The provider should inquire about the onset, duration, intake, exposure to poisonous substances, exposure to the cold, site where cyanosis can be appreciated, and associated symptoms. If the cyanosis is present since birth, the cause is congenital. However, a more recent onset is highly suggestive of acquired etiology. It is essential to differentiate the central, peripheral, and differential cyanosis as each implies different etiologies.

In assessing cyanosis, the onset is an important clue to the underlying cause. In congenital heart diseases, the conditions that present with cyanosis in the first week are tricuspid atresia, Ebstein anomaly, critical pulmonary stenosis, etc. The conditions that usually manifest after the first week are tetralogy of Fallot, transposition of great arteries, truncus arteriosus, etc. Fever may be seen if the cause of cyanosis is infectious, such as croup, pneumonia, septic shock, etc. The presence of clubbing can most likely be seen in congenital heart conditions, right-to-left shunts, and pulmonary diseases. Respiratory symptoms are more commonly associated with central cyanosis.

Physical examination should be carried out in adequate light to assess cyanosis correctly. Poor light exposure, the thickness of the skin, and the pigmentation of the skin can affect the accuracy of physical assessment. Cheeks, nose, ears, and oral mucosa are the best areas to assess cyanosis as the skin in these areas is thin, and the blood supply is good. This can help determine if the cyanosis is generalized, limited to extremities, or if there is a difference in the bluish discoloration in different extremities. The prime sites of the bluish discoloration in central cyanosis are the oral cavity's lips, tongue, hands, feet, and mucous membranes. The depth of the color usually correlates with the amount of desaturated hemoglobin and, hence, the severity of cyanosis. Clubbing can be seen in some patients with long-standing central cyanosis. Methemoglobinemia or sulfhemoglobinemia should be high on differentials if central cyanosis does not improve with oxygen administration.

The inspection also includes looking for any thoracic cage deformity, accessory muscle use for respiration (nasal flaring, grunting, intrathoracic/supraclavicular retractions), asymmetry of chest expansion, discomfort in breathing, audible breath sounds, clubbing, posture, etc. These help narrow down the underlying causes, especially if the cause is cardiac or pulmonary. It is helpful to palpate brachial and femoral pulses, tactile and vocal fremitus, assess ventilation, and measure blood pressure in all 4 extremities. 

Peripheral cyanosis is characterized by the following:

• Localized cyanosis affecting only extremities
• Pink tongue as mucous membranes are rarely involved
• Cold extremities as compared to warm extremities in central cyanosis
• Clubbing is absent
• Pulse volume is usually low
• Capillary refill time more than 2 sec
• Disappears with massage and warming
• Dyspnea usually absent

In children, the most common etiologies for life-threatening central cyanosis are congenital heart disorders and polycythemia. The common causes of peripheral cyanosis in this age group are cold exposure and acrocyanosis.

Evaluation

The unexpected blue discoloration is alarming and should be quickly evaluated. The clinical history and physical examination are important, but the additional evaluation is also essential to determine the underlying cause of cyanosis. Oxygenation status can be assessed by determining the oxygen saturation of hemoglobin, partial pressure of oxygen, and total hemoglobin. Various devices can measure oxygen saturation, but the measured variables differ from each device. Co-oximetry and simple oximetry are spectrophotometry methods to measure arterial blood oxygenation. Pulse oximetry is a non-invasive method compared to co-oximetry, which requires a sample of arterial blood.

To begin with, pulse oximetry, a non-invasive and easily available test, should be done to rule out life-threatening hypoxemia as a cause. It assesses oxygenation but may falsely indicate hypoxemia in peripheral cyanosis and dyshemoglobinemias. For instance, the value may be low if measured on an affected limb in central and peripheral cyanosis.[15] Co-oximetry, in addition to measuring oxygen saturation, can be used for arterial blood gas analysis. Arterial blood gas analysis shows normal arterial oxygenation in peripheral cyanosis, ie, 85-100%. Contrary to this, the arterial oxygen saturation is low in central cyanosis. This test also determines the value of hemoglobin derivatives such as oxygenated hemoglobin, deoxygenated hemoglobin, and dyshemoglobins (methemoglobin, carboxyhemoglobin, sulfhemoglobin, etc.). It, therefore, only indicates low oxygen levels in hypoxemia due to central cyanosis. In pseudocyanosis, both pulse oximetry and co-oximetry reveal normal oxygen levels.[16][17][18]

Depending on the clinical scenario, peripheral blood film, hemoglobin concentration, blood glucose, and sepsis workup should be considered to evaluate the causes of cyanosis. Additionally, chest X-ray, ECG, and CT scan can be done to evaluate the cardiopulmonary cause. An echocardiogram and invasive cardiac evaluation may be necessary in some cases.

Treatment / Management

The treatment of central cyanosis, a clinical sign, is focused on managing underlying conditions.[19]

• Initial stabilization with oxygen support through a regular/high-flow nasal cannula is required for pulmonary oxygen diffusion impairment. In some conditions, assisted ventilation may be necessary.
• Metabolic abnormalities such as hypoglycemia and hypocalcemia should be corrected if present. Metabolic abnormalities can occur as a result of the inability to feed secondary to cyanotic heart diseases in children.
• Initial stabilization and airway management should be the priority for cyanotic heart diseases. Cardiology referral for assessment and intervention is necessary for cyanotic congenital heart diseases such as tricuspid atresia, tetralogy of Fallot, etc. For congenital heart disease correction, surgical intervention is required. Drugs such as prostaglandin E1 infusion are used for ductal-dependent conditions for pulmonary blood flow.
• Drugs such as diuretics, ACE inhibitors, and inotropic drugs are considered for heart failure.
• Antibiotic prophylaxis in cyanotic heart disease patients to prevent bacterial endocarditis.
• Methylene blue is used for treating methemoglobinemia-induced cyanosis. 
• Removing the offending agents is the best therapy for managing blue discoloration caused by exposure to gold and silver salts.

The goal of managing peripheral cyanosis is to identify and treat the underlying cause of vasoconstriction and the limited supply of oxygen-rich blood to the extremities. Peripheral cyanosis is usually reversible, restoring oxygenated blood flow to the extremities. It can rarely pose a life-threatening emergency. However, timely management is important to improve outcomes and prevent complications.[20]

• Gentle warming and massage of the affected parts provide symptomatic relief and reversal of peripheral cyanosis caused by exposure to cold and Raynaud phenomenon.
• In addition, longer-term lifestyle changes may be required in some conditions, such as the Raynaud phenomenon. Limiting the intake of caffeine and nicotine/smoking, both of which can cause blood vessel narrowing, is beneficial.
• Drugs that cause blood vessel relaxation may be used in peripheral cyanosis. These include antihypertensive drugs, antidepressants, and erectile dysfunction medications. In addition, drugs that constrict blood vessels, such as beta-blockers, pseudoephedrine-containing medications, birth control pills, and migraine drugs, should be avoided.
• When peripheral cyanosis is seen in sick-looking children with signs of shock, rapid treatment should be done. Airway and breathing management with further evaluation of the cause of shock is warranted. The therapy is based on the type of shock. Serious conditions, such as heart failure, must be treated in a hospital as an emergency.
• All causes of central cyanosis can also cause extremity cyanosis. Correcting the underlying cause is the key to managing such cases. 

An interprofessional approach involving various subspecialties is warranted to diagnose and manage the underlying cause of cyanosis.

Differential Diagnosis

The differential diagnosis for central and peripheral cyanosis includes the following:

• Reversed differential cyanosis is more common in the upper limbs than in the lower limbs and is seen in the transposition of great arteries.
• Pigmentary birthmarks
• Large tattoos
• Drugs causing gray-blue skin discoloration side effects, such as amiodarone and silver
• Blue clothing dye
• Consumption of blue-dyed food such as popsicles

Complications

Cyanosis is a clinical sign, not a disease. If not managed in time, it can worsen the underlying conditions.