Cyanosis overview

# Overview
Cyanosis is the condition that there is inadequate oxygen delivery to peripheral tissue. Oxygen in the blood is carried in two physiologic states. Approximately 2% is dissolved in plasma and the other 98% is bound to hemoglobin. In central cyanosis there is increased level of deoxyhemoglobin around 3-5 g/dl.  In peripheral cyanosis there is  increased oxygen extraction by the peripheral tissues. Several factors can affect the appearance of cyanosis including skin pigmentation,Hemoglobin (Hb) levels, oxygen affinity to the hemoglobin (Hb). Cyanosis was first described by deSenac who was the physician for King Louis XV in 1749. He described it as the mixture of arterial and venous blood due to an abnormal connection between the two sides of the heart.  In 1761, Morgagini showed association of cyanosis with pulmonary stenosis due to stasis of blood. Cyanosis was described by Sandifort, a European, in 1777 as a "blue boy"  with tetralogy of Fallot. In 1892, Vaquez described the first case of polycythemia, as a cause of cyanosis. In 1919, Christen Lundsgaard quantified the amount of blood required to be deoxygenated to give the bluish discoloration of cyanosis. Blalock and Taussid performed the first anastomosis of subclavian to pulmonary artery on November 9, 1944 to lessen the cyanosis in tetralogy of Fallot. United States' Olympian and gold medalist Shaun White was born with tetralogy of Fallot and had cyanosis because of that. Cyanosis  may be classified into two groups including  central cyanosis and peripheral cyanosis. Right to left shunt in congenital heart disease causes central cyanosis. Secondary erythrocytosis (increased red blood cell mass due to hypoxia) and polycythemia (neoplastic proliferation of red blood cell) are different conditions and need different evaluation. Two mechanisms involved in the development of cyanosis including systemic arterial oxygen desaturation and increased oxygen absorption by tissues. Cyanosis is evident when arterial oxygen saturation falls below 85% or the concentration of deoxygenated hemoglobin (Hb) exceeds 5 gm/dl. Common causes  in the development of cyanosis include congenital heart diseases with right to left shunt, presence of abnormal hemoglobin, carbon monoxide poisoning, respiratory disorders associated with impaired gas exchange, impaired gas diffusion via the alveoli, embolism, pulmonary arteriovenous malformations, cold exposure, and raynaud's phenomenon. Different causes of cyanosis may include pulmonary, cardiovascular, hematological, neurological, and vascular diseases. Prenatal echocardiography and genetic testing are useful methods for early detection of cyanotic congenital heart disease. Postnatal pulse oximetry is recommended for diagnosis of cyanotic congenital heart disease. Central cyanosis  in the first hours or days of life in the neonate may happen and implies life-threatening conditions such as congenital cardiac abnormalities , airway obstruction , central nervous system problem, hemoglobinopathy. Peripheral cyanosis may happen in neonate called acrocyanosis. Prognosis is generally good if the underlying causes of cyanosis are determined and treated. Peripheral cyanosis improves with oxygen therapy. Conversely, central cyanosis does not respond to oxygen therapy because of the underlying  intrapulmonary or intracardiac shunt which is responsible for mixing the nonoxygenated  venous blood  and oxygenated arterial blood. All causes of central cyanosis may cause peripheral cyanosis. cyanosis is a symptom of a disease process, then  physical examination may include tachypnea, tachycardia, abnormal heart sounds or murmurs, wheezing, crackles, fever, clubbing, edema. In every neonate presented with cyanosis and shock, congenital heart disease dependent on patency ductus arteriosus should be considered. The physiologic constriction of ductus arteriosus after birth in a neonate whose pulmonary blood flow or aortic blood flow is dependent on PDA leads to shock and collapse in the neonate. Infusion of prostaglan E1  is life-saving and keeps patency ductus arteriosus. Treatment of underlying causes of cyanosis such as tamponade or cardiogenic shock  due to low cardiac output state or peripheral vasoconstriction is considered. Cardiac defects causing central cyanosis include Transposition of the great arteries, Tetralogy of fallot, Tricuspid atresia, Truncus arteriosus,Total anomalous pulmonary venous connection, Ebstein anomaly, critical Pulmonary stenosis or atresia, functional single ventricle. The palliative surgical shunt maybe done in such lesions to increase pulmonary blood flow even in the presence of cyanosis. Complete repair procedure leads to relief of cyanosis and shunt and also causes long-term complications. Effective measures for primary prevention in neonatal cyanosis include prenatal echocardiography and genetic testing for detecting congenital heart defects and prenatal corticosteroid therapy for prevention of neonatal respiratory distress syndrome and development of lung maturation. Secondary prevention in cyanotic congenital heart disease includes obtaining EKG Exercise stress test, Holter monitoring, Transthoracic echocardiography, Cardiac MRI, Cardiac CT Scan, Pulse oximetry every 12-60 months based on the stage of disease.

# Historical Perspective
Cyanosis was first described by deSenac who was the physician for King Louis XV in 1749. He described as admixture of arterial and venous blood due to an abnormal connection between two sides of the heart.  In 1761, Morgagini showed association of cyanosis with pulmonary stenosis due to stasis of blood. Cyanosis was described by Sandifort, a European, in 1777 as a "blue boy"  with tetralogy of Fallot. In 1892, Vaquez described the first case of polycythemia, as a cause of cyanosis. In 1919, Christen Lundsgaard quantified the amount of blood required to be deoxygenated to give the bluish discoloration of cyanosis. Blalock and Taussid performed the first anastomosis of subclavian to pulmonary artery on November 9, 1944 to lessen the cyanosis in tetralogy of Fallot. United States' Olympian and gold medalist Shaun White was born with tetralogy of Fallot and had cyanosis because of that.

# Classification
Cyanosis is classified into central cyanosis and peripheral cyanosis.

# Pathophysiology
Cyanosis is a bluish or purplish discoloration of the skin and mucous membranes. Two mechanisms involved in the development of cyanosis, Systemic arterial oxygen desaturation and increased oxygen absorption by tissues. Cyanosis is evident when arterial oxygen desaturation falls below 85% or the concentration of deoxygenated hemoglobin (Hb) exceeds 5 gm/dl. Several factors can affect the appearance of cyanosis including skin pigmentation, Hemoglobin (Hb) levels, oxygen affinity to the hemoglobin (Hb).

# Causes
In central cyanosis,  saturation of oxygen is less than 85% when there is reduced hemoglobin more than 5g/dl following intrapulmonary shunt or intracardiac shunt leading to mixing of arterial and venous oxygen content. In peripheral cyanosis, saturation of oxygen is normal and there is peripheral capillary bed vasoconstriction due to low cardiac output state or sepsis.

# Differentiating Cyanotic diseases from Other Diseases
The underlying causes of cyanosis are classified based on the type of cyanosis (central cyanosis or peripheral cyanosis). Different causes of cyanosis include pulmonary, cardiovascular, hematological, neurological, and vascular diseases.

# Epidemiology and Demographics
The prevalence of congenital heart disease is approximately 1,000 per 100,000 individuals worldwide. Data about the incidence of cyanotic congenital heart disease is inadequate. Congenital cyanotic heart disease is more commonly observed among neonates. Congenital cyanotic heart disease affects men and women equally. There is no racial predisposition for cyanotic congenital heart disease.

# Risk Factors
Cyanosis is the sign of underlying disease. Risk factors related to the presence of underlying conditions should be noticed. 
Common risk factors in the development of  congenital heart diseases with the right to left shunt include maternal age >35 years, no intake of the multivitamin, febrile illness in the first trimester, obesity, paternal age> 25 years.

# Screening
Prenatal echocardiography and genetic testing are useful methods for early detection of cyanotic congenital heart disease. Postnatal pulse oximetry is recommended for diagnosis of cyanotic congenital heart disease.

# Natural History, Complications, and Prognosis
Central cyanosis  in the first hours or days of life in the neonate may happen and implies life-threatening conditions such as congenital cardiac abnormalities , airway obstruction , central nervous system problem, hemoglobinopathy. Peripheral cyanosis may happen in neonate called acrocyanosis. If the underlying causes of cyanosis  are determined and treated, the prognosis is generally good.

# Diagnosis

## Diagnostic Study of Choice
Echocardiography is the gold standard test for the diagnosis of cyanotic congenital heart diseases

## History and Symptoms
The hallmark of  cyanosis is blue discoration of skin and mucous membranes. Obtaining the history is most important aspect because of its association with wide variety of disorders (cardiac, pulmonary, vascular, neurologic and neuromuscular disorders). History taking also provides clues to specific causes, precipitating factors and associated  comorbid conditions.

## Physical Examination
Physical examination of patients with cyanosis will show bluish discoration of lips, tongue, oral mucosa, nose tip, ear lobules, hands and feet. Because cyanosis is a symptom of disease process careful physical examination for associated symptoms include tachypnea, tachycardia, abnormal heart sounds or murmurs, wheezing, crackles, fever, clubbing, edema of extremities will be necessary to identify underlying disease process.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of  central cyanosis include Polycythemia due to secondary erythrocytosis, Elevated prothrombin time and partial thromboplastin time , decreased levels of factors 5,7,8,9 (qualitative and quantitative),Platelet disorder, increased fibrinolysis and paradoxical thrombotic tendency, Proteinuria, Hyperuricemia, Renal failure and nephrolithiasis.

## Electrocardiogram
An ECG may be helpful in the diagnosis of congenital cyanotic heart disease and helps differentiate the causes of cyanotic heart disease.

## X-ray
A chest x-ray may be helpful in the diagnosis of congenital heart diseases leading  central cyanosis and other life-threatening causes of cyanosis such as pneumothorax, tamponade, pulmonary edema.

## Echocardiography
Echocardiography is the gold standard test for the diagnosis of cyanotic congenital heart diseases

## CT scan
A cardiac CT scan plays an important tool in the assessment of cyanotic congenital heart disease and determines the volume and size of cardiac chambers and determines the relation between the cardiac chambers and great arteries and veins.

## MRI
A cardiac MRI is a noninvasive imaging for evaluation of cyanotic congenital heart disease and determines myocardial function and the area of fibrosis, the direction of flow and velocity across the palliative shunt and valves, the anomaly of connection of arteries and veins and correlation of anatomic and morphologic ventricles with great arteries in complex congenital heart disease.

## Other Imaging Findings
Cardiac catheterization is an invasive study for the anatomic and physiological assessment of patients with cyanotic congenital heart disease.

## Other Diagnostic Studies
Pulse oximetry may be helpful in the diagnosis of the type of cyanosis. Findings suggestive  of hypoxia following  central cyanosis include low oxygen saturation.

# Treatment

## Medical Therapy
In every neonate that presents with cyanosis and shock, congenital heart disease dependent on patency ductus arteriosus should be considered. The physiologic constriction of ductus arteriosus after birth in a neonate whose pulmonary blood flow or aortic blood flow is dependent on PDA leads to shock and collapse in the neonate. Infusion of prostaglandin E1 in such a neonate is life-saving and keeps patency ductus arteriosus. Treatment of underlying causes of peripheral cyanosis such as tamponade or cardiogenic shock due to low cardiac output state and peripheral vasoconstriction lead to disappearing of cyanosis.

## Surgery
Cardiac defect causing central cyanosis include transposition of the great arteries, tetralogy of fallot, tricuspid atresia, truncus arteriosus,total anomalous pulmonary venous connection, Ebstein anomaly, critical pulmonary stenosis or atresia, functional single ventricle. The palliative surgical shunt maybe done in such lesions to increase pulmonary blood flow even in the presence of cyanosis. Complete repair procedure leads to relief of cyanosis and shunt and also has long term complications.

## Primary Prevention
Effective measurement for primary prevention includes prenatal echocardiography and genetic testing for detecting cyanotic congenital heart disease and prenatal corticosteroid therapy for the prevention of neonatal respiratory distress syndrome and the development of lung maturation.

## Secondary Prevention
Secondary prevention in cyanotic congenital heart disease includes obtaining EKG Exercise stress test, Holter monitoring, Transthoracic echocardiography, Cardiac MRI, Cardiac CT Scan, Pulse oximetry every 12-60 months based on the stage of disease.