Overview of cyanosis in the newborn

INTRODUCTION — Cyanosis is a bluish discoloration of the tissues that results when the absolute level of reduced hemoglobin in the capillary bed exceeds 3 g/dL [1-3]. The appearance of cyanosis depends upon the total amount of reduced hemoglobin rather than the ratio of reduced to oxygenated hemoglobin. Cyanosis is a common clinical finding in newborn infants. Neonatal cyanosis, particularly central cyanosis, can be associated with significant and potentially life-threatening diseases due to cardiac, metabolic, neurologic, infectious, and parenchymal and non-parenchymal pulmonary disorders (table 1).

The etiology, evaluation, and initial management of the newborn with cyanosis will be reviewed here.

CENTRAL VERSUS PERIPHERAL CYANOSIS

Peripheral cyanosis — Patients with peripheral cyanosis have normal systemic arterial oxygen saturation and increased tissue oxygen extraction that leads to a widened systemic arteriovenous oxygen difference of 60 percent (from the normal 40 percent) resulting in an increased concentration of reduced hemoglobin on the venous side of the capillary bed. Peripheral cyanosis typically affects the distal extremities and sometimes the circumoral or periorbital areas [1]. The extremities may be cool or clammy. Peripheral cyanosis may be associated with peripheral vasoconstriction or many causes associated with central cyanosis. In neonates with peripheral cyanosis, the mucus membranes remain pink, which differentiates it from central cyanosis

Acrocyanosis — Acrocyanosis is often seen in healthy newborns and refers to the peripheral cyanosis around the mouth and the extremities (hands and feet) (picture 1). It is caused by benign vasomotor changes that result in peripheral vasoconstriction and increased tissue oxygen extraction and is a benign condition [4]. Acrocyanosis is differentiated from other causes of peripheral cyanosis with significant pathology (eg, septic shock) as it occurs immediately after birth in healthy infants. It is a common finding and may persist for 24 to 48 hours.

Central cyanosis — Central cyanosis is caused by reduced arterial oxygen saturation. Newborn infants normally have central cyanosis until up to 5 to 10 minutes after birth, as the oxygen saturation rises to 85 to 95 percent by 10 minutes of age [5]. Persistent central cyanosis is always abnormal and should be evaluated and treated promptly.

Pathogenesis — Neonatal central cyanosis is most commonly due to hypoxia due to one or more of the following mechanisms:

●Alveolar hypoventilation – Although the primary effect of alveolar hypoventilation is hypercarbia (eg, recurrent apnea), decreased ventilation of the lung can cause hypoxemia resulting in reduced oxygen saturation and cyanosis. Causes of hypoventilation include central nervous system depression (eg, perinatal asphyxia), airway obstruction (choanal atresia), or neuromuscular disorders (eg, spinal muscular atrophy type 1).

●Ventilation-perfusion mismatch – Normally, areas of decreased ventilation are matched with decreased blood flow. Alterations of this relationship can cause hypoxemia (eg, neonatal pneumonia, pneumothorax) resulting in reduced oxygen saturation and cyanosis.

●Right-to-left shunt – In right-to-left shunting, systemic venous blood bypasses ventilated alveoli and returns to the left side of the heart without being oxygenated, resulting in reduced oxygen saturation and cyanosis. The site of shunting can be intracardiac (eg, cyanotic congenital heart disease [CCHD]), through the ductus arteriosus (eg, persistent pulmonary hypertension), or intrapulmonary (eg, perfusion of non-ventilated areas of the lung). (See "Cardiac causes of cyanosis in the newborn" and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

●Diffusion impairment – Oxygen molecules must diffuse from the alveoli to the pulmonary capillaries to oxygenate hemoglobin. Interference with alveolar-arterial diffusion (eg, pulmonary edema) results in reduced oxygen saturation.

In addition, reduced arterial oxygen saturation can be caused by hemoglobinopathies that inadequately transport oxygen or polycythemia.

The etiology of persistent central cyanosis varies from a wide range of disorders that include cardiac, metabolic, neurologic, infectious, hematologic, and parenchymal and non-parenchymal pulmonary disorders (table 1). (See 'Causes of central cyanosis' below.)

FACTORS THAT AFFECT CYANOSIS DETECTION — The following factors can affect the detection of cyanosis:

●Hemoglobin concentration

●Fetal hemoglobin

●Skin pigmentation

●Physiological conditions that affect oxygen dissociation curve

Hemoglobin concentration — The total hemoglobin concentration affects the level of oxygen saturation at which cyanosis can be detected because the appearance of cyanosis is dependent on the absolute concentration of reduced hemoglobin, not the ratio of reduced hemoglobin to oxyhemoglobin. Cyanosis is visually perceptible when reduced hemoglobin exceeds 3 g/dL, which generally corresponds to an oxygen saturation level below 85 percent in a neonate with a hemoglobin concentration of 15 g/dL (figure 1). However, cyanosis is detected at higher levels of oxygen saturation in polycythemic patients, whereas significant oxygen desaturation can be present in an anemic patient without clinically detectable cyanosis. As examples, cyanosis (3 g/dL of reduced hemoglobin) is detected when the oxygen saturation is 86 percent in a patient with hemoglobin of 20 g/dL and 67 percent in a patient with a hemoglobin concentration of 9 g/dL.

Fetal hemoglobin — Fetal hemoglobin, the predominant form of hemoglobin in newborn erythrocytes, binds oxygen more avidly than adult hemoglobin, which aids in fetal uptake of oxygen from the placenta but results in less oxygen delivery to the tissues. The oxygen dissociation curve for fetal versus adult hemoglobin is shifted to the left, so that for a given level of arterial oxygen tension (PaO₂), the arterial oxygen saturation (SaO₂) is higher in newborns than older infants or adults (figure 2) [6]. So for a given level of SaO₂, there is a lower PaO₂ value in newborns compared with older patients. As examples, when SaO₂ is 50 percent, PaO₂ is 20 mmHg in newborns and 27 mmHg in older patients; at SaO₂ of 80 percent, PaO₂ is 35 mmHg in newborns and 45 mmHg in older patients [7].

As a result, cyanosis is detected at a lower PaO₂ in newborns who have predominantly fetal hemoglobin compared with older patients. This observation should prompt the measurement of PaO₂ (eg, arterial blood gas) when evaluating a cyanotic newborn as the PaO₂ provides more complete data than SaO₂. (See 'Arterial blood gas' below.)

Skin pigmentation — Cyanosis is often less apparent in patients with darker skin pigmentation. For this reason, examination should include the nail beds, tongue, and mucous membranes, which are less affected by pigmentation.

Other physiologic factors — Other physiologic factors common in sick newborns affect the oxygen dissociation curve (figure 2).

●Factors that increase the affinity of hemoglobin for oxygen include alkalosis, hyperventilation (low PCO₂), cold temperature, and low levels of 2,3 diphosphoglycerate [6]. In these conditions, the oxygen dissociation curve is shifted to the left, which decreases the concentration of reduced hemoglobin at a given PaO₂ and lowers the PaO₂ at which cyanosis first appears.

●In contrast, acidosis, fever, or increased concentration of adult hemoglobin shifts the curve to the right, thereby lowering oxygen affinity. As a result, at a given PaO₂, these conditions increase oxygen delivery to the tissues resulting in a greater concentration of reduced hemoglobin, and promote the appearance of cyanosis at a higher PaO₂.

CAUSES OF PERIPHERAL CYANOSIS — Peripheral cyanosis is due to increased oxygen extraction that generally results from sluggish movement of blood through the capillary circulation. Causes include:

●Cold exposure and benign acrocyanosis (see 'Acrocyanosis' above)

●Shock (see "Neonatal shock: Etiology, clinical manifestations, and evaluation")

●Sepsis (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation")

●Elevated venous pressure or venous obstruction (eg, venous thrombosis) (see "Neonatal thrombosis: Clinical features and diagnosis")

●Polycythemia (see "Neonatal polycythemia")

CAUSES OF CENTRAL CYANOSIS — Causes of central cyanosis in the newborn can be categorized based on their primary pathophysiology (hypoventilation, ventilation/perfusion mismatch, diffusion impairment, right-to-left shunting and hematologic disorders) (table 1). (See 'Pathogenesis' above.)

Hypoventilatory disorders — Hypoventilation resulting in hypoxemia may be due to airway abnormalities, and neurologic or metabolic disorders.

Airway abnormalities — Most airway abnormalities will present shortly after birth; cyanosis due to the following conditions is generally a result of alveolar hypoventilation secondary to airway obstruction [8].

●Choanal atresia – While choanal atresia is usually unilateral, bilateral atresia will present immediately after birth (picture 2A-B) and should be suspected in an infant who develops respiratory distress and cyanosis while in a quiet state but becomes pink while crying. The diagnosis is suspected by the inability to pass a suction catheter through the nose into the oropharynx, and computed tomography will confirm the diagnosis (image 1). Placement of an oral airway should relieve the obstruction until definitive surgical therapy can be performed. Severe choanal stenosis also may present with respiratory distress and cyanosis [9]. (See "Congenital anomalies of the nose", section on 'Choanal atresia'.)

●Micrognathia or retrognathia – Micrognathia or retrognathia that is severe enough to be symptomatic is readily apparent on physical examination. Airway obstruction is caused by the posterior tongue obstructing the retropharyngeal airway while the infant is supine. Generally, obstruction is relieved by placing the infant prone, but an oral airway may be necessary. Although some infants may require tracheotomy, surgical mandibular distraction may be performed in the newborn period and avoid the need for a tracheotomy [10]. (See "Congenital anomalies of the jaw, mouth, oral cavity, and pharynx", section on 'Micrognathia' and "Syndromes with craniofacial abnormalities", section on 'Pierre Robin sequence'.)

●Laryngeal and tracheal abnormalities – Laryngeal and tracheal abnormalities include congenital laryngomalacia, vocal cord paralysis, tracheal stenosis, and vascular rings that cause external compression of the trachea. These conditions may all present soon after birth with airway obstruction, stridor, and cyanosis [11]. Stridor and cyanosis is especially evident while the neonate is crying because the increased negative thoracic pressure causes greater airway obstruction. (See "Congenital anomalies of the larynx", section on 'Laryngomalacia' and "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula", section on 'Congenital tracheal stenosis' and "Vascular rings and slings".)

Neurologic disorders — Neurologic dysfunction, such as hypoxic ischemic encephalopathy, intracranial hemorrhage, or seizures may cause hypoventilation and apnea resulting in hypoxemia and cyanosis. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy" and "Germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) in the newborn: Pathogenesis, clinical presentation, and diagnosis".)

Metabolic disorders — Metabolic disorders such as severe hypoglycemia may be complicated by apnea leading to intermittent episodes of hypoxemia and cyanosis. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Clinical presentation' and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Clinical manifestations'.)

Pulmonary disorders

Ventilation-perfusion mismatch — Pulmonary disease resulting in ventilation-perfusion mismatch is the most common cause of neonatal cyanosis. Newborn infants who present with cyanosis from lung disease will almost always have some degree of respiratory distress.

Specific causes associated with ventilation-perfusion mismatch, which are discussed in detail separately, include the following:

●Respiratory distress syndrome (RDS) (see "Clinical features and diagnosis of respiratory distress syndrome in the newborn")

●Transient tachypnea of the newborn (see "Transient tachypnea of the newborn")

●Meconium aspiration syndrome (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")

●Neonatal pneumonia (see "Neonatal pneumonia")

●Air leak syndromes (see "Pulmonary air leak in the newborn")

●Congenital abnormalities of the lung and diaphragm, including congenital diaphragmatic hernia and cystic adenomatoid malformation (see "Congenital diaphragmatic hernia in the neonate" and "Congenital pulmonary airway malformation")

Impaired alveolar-arterial diffusion — Pulmonary edema is the major cause of impaired alveolar-arterial diffusion that results in neonatal cyanosis. Pulmonary edema may be associated with both pulmonary and nonpulmonary disease. Examples of nonpulmonary causes of pulmonary edema include:

●Sepsis – In the early stages of sepsis, tachypnea is often a finding due to increased respiratory drive resulting in respiratory alkalosis in response to sepsis-related metabolic acidosis. In the later stages of sepsis, capillary leak may result in pulmonary edema with impaired alveolar-arterial diffusion and ventilation-perfusion mismatch. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Clinical manifestations'.)

●Arteriovenous or venous malformations – Very large arteriovenous or venous malformations (eg, Vein of Galen malformation) may cause high-output cardiac failure and pulmonary edema resulting in respiratory distress and cyanosis. (See "Causes and pathophysiology of high-output heart failure", section on 'Causes and their mechanisms'.)

●Heart failure in patients with cyanotic congenital heart disease (CCHD). (See "Cardiac causes of cyanosis in the newborn", section on 'Left-sided obstructive lesions'.)

Disorders with right to left shunting — Conditions that result in right to left shunting of deoxygenated blood to the systemic circulation include intracardiac lesions and persistent pulmonary hypertension. Intrapulmonary lesions resulting in impaired ventilation/perfusion of affected alveoli also causes right to left shunting. (See 'Pulmonary disorders' above.)

Cyanotic congenital heart disease — Whenever a newborn presents with cyanosis, especially if respiratory distress is not present, CCHD should always be considered as a potential etiology. Neonates with CCHD may also develop pulmonary edema due to heart failure resulting in impaired alveolar-arterial diffusion, which contributes to cyanosis. The causes, evaluation, and initial management of CCHD are discussed separately. (See "Cardiac causes of cyanosis in the newborn" and "Diagnosis and initial management of cyanotic heart disease in the newborn".)

Persistent pulmonary hypertension of the newborn — Persistent pulmonary hypertension of the newborn (PPHN) is a condition in which the normal circulatory transition from fetal to newborn circulation fails to occur. In newborns with PPHN, the pulmonary vascular resistance remains abnormally elevated after birth, and right to left shunting of blood persists through the fetal circulatory channels (ductus arteriosus and foramen ovale). This shunting leads to severe hypoxemia and cyanosis. PPHN is most frequently associated with parenchymal lung disease, including meconium aspiration syndrome, neonatal pneumonia, and RDS. As a result, the majority of infants with PPHN will present with respiratory distress and cyanosis. However, idiopathic PPHN may also occur unaccompanied by underlying parenchymal lung disease. PPHN including its pathophysiology, clinical features, diagnosis, and management is discussed separately. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis" and "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome".)

Hematologic causes

Hemoglobinopathies — Hemoglobinopathies that inadequately transport oxygen can result in cyanosis. These disorders include methemoglobinemia (a genetic disorder in which the iron of heme is oxidized to the ferric state, which is unable to bind oxygen) and other rare variants of hemoglobin with low oxygen affinity. (See "Hemoglobin variants that alter hemoglobin-oxygen affinity" and "Hemoglobin variants that alter hemoglobin-oxygen affinity", section on 'Low oxygen affinity hemoglobin variants: Cyanosis'.)

Polycythemia — Neonatal polycythemia, usually defined as a hematocrit >65 percent or a hemoglobin concentration >22 g/dL, occurs in approximately 1 to 5 percent of births. It is observed more frequently in infants of diabetic mothers, with delayed clamping or stripping of the umbilical cord, chronic fetal hypoxia, and fetal growth restriction. (See "Neonatal polycythemia".)

Polycythemia can cause cyanosis by one of the two following mechanisms.

●Polycythemic infants may appear cyanotic with a normal oxygen saturation and PO₂ because of their elevated hemoglobin concentration. However, cyanosis is unlikely to occur in infants with arterial oxygen saturation above 90 percent (figure 1).

●Polycythemia with associated hyperviscosity may interfere with pulmonary perfusion and result in PPHN [12]. (See 'Persistent pulmonary hypertension of the newborn' above.)

EVALUATION — The goals of evaluation are to identify and provide supportive care to the critically or potentially critically ill infant, and determine the underlying cause of neonatal cyanosis so that intervention can be focused on correcting or addressing the consequences of the specific disorder. Evaluation of the cyanotic infant should systematically assess the infant for airway, pulmonary, cardiovascular, or other causes.

For patients who are critically ill, immediate intervention should be given to maintain adequate cardiorespiratory support to ensure sufficient organ/tissue perfusion and oxygenation. (See 'Initial management' below.)

In the stable cyanotic neonate or after stabilizing the critically ill infant, the evaluation is focused on confirming cyanosis (pulse oximetry screening) and differentiating amongst the possible causes of cyanosis.

Pulse oximetry measurement — Measuring oxygen saturation by pulse oximeter will confirm the presence of clinical cyanosis. It is useful to obtain both preductal (right hand) and post-ductal (foot) to determine if there is right-to-left shunting at the level of the ductus arteriosus. Differential saturations are frequently seen in infants with persistent pulmonary hypertension of the newborn (PPHN), as well as in some cardiac lesions (eg, severe coarctation of the aorta). However, in infants with PPHN, if right-to-left shunting is predominantly through the foramen ovale rather than the ductus, pre- and post-ductal saturations may not be different. These cases are difficult to differentiate from cyanotic heart disease. (See "Newborn screening for critical congenital heart disease using pulse oximetry".)

History — The history may provide clues to the underlying etiology of neonatal cyanosis and should include a complete assessment of the following:

●Pregnancy and labor – Maternal diabetes may be associated with cyanotic heart disease, neonatal polycythemia, and hypoglycemia. Other important pregnancy and labor historical factors include the following:

•Polyhydramnios is associated with fetal airway, esophageal, and neurological conditions.

•Oligohydramnios is associated with renal defects and pulmonary hypoplasia. (See "Evaluation of congenital anomalies of the kidney and urinary tract (CAKUT)", section on 'Amniotic fluid'.)

•Prolonged rupture of the fetal membranes and peripartum maternal fever may be associated with neonatal sepsis. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Maternal risk factors'.)

•Meconium staining of the amniotic fluid is associated with meconium aspiration syndrome and PPHN. (See "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis", section on 'Pulmonary findings' and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Clinical manifestations'.)

●Family risk factors including a history of cyanotic heart disease or underlying hemoglobinopathy. (See "Diagnosis and initial management of cyanotic heart disease in the newborn" and "Identifying newborns with critical congenital heart disease", section on 'Risk factors'.)

Physical examination — The physical examination is central to determining the cause of cyanosis. In particular, signs of respiratory distress (eg, tachypnea, inter- and subcostal retractions, nasal flaring, and audible grunting) are suggestive of pulmonary disease, whereas abnormal cardiac findings (eg, abnormal heart rate and sounds, and pathologic murmurs) indicate a cardiac etiology [4].

However, some cardiac lesions may have a prominent component of respiratory distress (eg, obstructed total anomalous pulmonary venous return and left-sided obstructive disease); thus, its presence does not rule out congenital heart disease. As a result, congenital heart disease as well as sepsis should be considered as the underlying diagnosis in any critically ill infant who presents with respiratory distress, cyanosis, poor perfusion and/or shock. Left-sided obstructive lesions in which ductal closure has severely affected systemic blood flow may be indistinguishable from severe sepsis on physical exam and usually requires echocardiographic confirmation of the diagnosis.

Respiratory assessment includes:

●Respiratory rate – The respiratory rate should be counted for a full minute to account for variations in rate and rhythm. A normal early rate in the newborn period is 40 to 60 breaths per minute. Neurologic or metabolic causes of cyanosis are usually associated with slow or irregular respirations or intermittent apnea, whereas pulmonary and cardiac disorders are associated with tachypnea.

●Chest wall movement – Neonates with respiratory disorders or airway obstruction may have intercostal, subcostal, or subxiphoid retractions in the highly compliant newborn chest wall.

●Other signs of neonatal respiratory disease include grunting, nasal flaring, and increased use of accessory respiratory muscles.

●Airway assessment – Signs of airway abnormalities include noisy breathing or stridor that may be indicative of laryngomalacia.

Cardiac examination includes:

●Assessment of heart rate, pulses, and perfusion

●Cardiac auscultation to detect any abnormality in the second heart sound or the presence of a heart murmur

●Four-extremity blood pressure (BP) to assist in detection of severe coarctation of the aorta or interrupted aortic arch lesions (see "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Neonates')

Cardiac findings suggestive of critical congenital heart disease are described separately (table 2). (See "Identifying newborns with critical congenital heart disease", section on 'Physical examination'.)

Initial tests — The initial laboratory testing includes measurement of arterial oxygenation, complete blood count, blood glucose, blood culture and a chest radiograph. In some cases, these studies may be sufficient to determine the underlying cause of neonatal cyanosis.

Arterial blood gas — Measurement of an arterial blood gas is standard in the evaluation of cyanosis. However, the pain associated with an arterial puncture may cause agitation in the newborn, and a resultant decrease in the PO₂. In cases of methemoglobinemia, oxygen saturation will be low, but the measured PO₂ will be normal, which would not be the case in other causes of cyanosis.

An elevated PaCO₂ suggests pulmonary disease. A metabolic acidosis on a blood gas indicates poor perfusion, which may be due to inadequate cardiac output or oxygen delivery, or shock. Many blood gas analyzers can also measure a lactate level, which provides additional information about perfusion and oxygen delivery to the tissues.

Other blood tests — Other laboratory studies include:

●Complete blood count and differential will reveal a high hematocrit and hemoglobin in cases of polycythemia. Many infants with sepsis will have a low rather than high white blood cell count, and a low absolute neutrophil count or an elevated immature to total neutrophil ratio [13]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Complete blood count'.)

●Blood glucose, as cyanosis due to apnea and poor blood perfusion can be seen in neonates with significant hypoglycemia. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Clinical presentation'.)

●Blood culture, as cyanosis may be observed in neonatal sepsis. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Clinical manifestations'.)

Chest radiograph — Examination of the chest radiograph is central to assessment of the cyanotic newborn because there may be findings that help differentiate between cardiac and pulmonary etiologies.

●Findings suggestive of cardiac disease (see "Diagnosis and initial management of cyanotic heart disease in the newborn" and "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Chest radiograph'):

•The situs of the heart, stomach, and liver should be examined because abnormal locations of these organs (eg, dextrocardia, situs inversus) strongly suggest cardiac disease.

•Cardiac size and shape may also be abnormal in specific congenital heart lesions, such as Tetralogy of Fallot ("boot-shaped" heart) (image 2) and transposition of the great arteries ("egg-on-a-string"-shaped heart).

•Decreased pulmonary vascular markings may be seen in both cyanotic cardiac lesions as well as idiopathic pulmonary hypertension of the newborn.

●In most cases of pulmonary disorders, the lung fields will be abnormal (see "Overview of neonatal respiratory distress and disorders of transition"):

•The chest radiograph in transient tachypnea of the newborn (TTN) usually exhibits characteristic bilateral perihilar linear streaking secondary to engorged lymphatic or blood vessels. Patchy infiltrates that clear within 24 to 48 hours may also reflect the fluid retention of TTN but make initial differentiation from pneumonia problematic. Lung ultrasound has been proposed as an imaging technique for reliable early diagnosis and differentiation of TTN (image 3) [14].

•In respiratory distress syndrome (RDS), atelectasis results in the classical radiographic findings of a diffuse, reticulogranular, ground glass appearance with air bronchograms, and low lung volume (image 4).

•Most congenital lesions of the lung and diaphragm (eg, lobar emphysema (image 5), congenital pulmonary airway malformation [also referred to as cystic adenomatous malformation] (image 6), and congenital diaphragmatic hernia [CDH] (image 7)) will be evident on an initial chest radiograph, and may evolve in appearance over time.

Further testing — After the initial evaluation, the underlying etiology of neonatal cyanosis may still be unclear. Although the hyperoxia test may be helpful in distinguishing cyanotic heart disease from etiologies, echocardiography is generally the definite test in separating between cardiac and non-cardiac causes of neonatal cyanosis.

Hyperoxia test — Historically, the hyperoxia test was used to distinguish cyanotic congenital heart disease (CCHD) with right-to-left shunting from pulmonary and other causes of cyanosis (table 3). However, in our center, we usually prefer to directly perform an echocardiography if there is suspicion of cardiac disease and forgo the hyperoxia test because of the potential harmful effects of 100 percent oxygen especially in preterm infants. Hyperoxia test should only be used if reliable echocardiography is not immediately available. The hyperoxia test and its interpretation are discussed in detail separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Hyperoxia test'.)

Echocardiography — Echocardiography generally differentiates between cardiac and non-cardiac causes of neonatal cyanosis. It should be performed in infants in the following clinical setting:

●Cyanosis out of proportion to lung pathology on chest radiography

●Persistent cyanosis despite supplemental oxygen and/or positive pressure ventilation

●Findings on physical exam and/or chest radiography suggestive of heart disease (table 2)

●Poor perfusion or shock.

INITIAL MANAGEMENT — Newborns with persistent central cyanosis after birth should be promptly evaluated, and empirical treatment should be initiated until the underlying cause is determined.

Initial management begins with general care that includes cardiorespiratory support and monitoring to ensure sufficient organ/tissue perfusion and oxygenation. Vital signs should be monitored and vascular access established for sampling of blood and administration of medications. Placement of secure intravenous and intraarterial catheters is most easily accomplished via the umbilical vessels. This will enable efficient correction and monitoring of acid-base balance, metabolic derangements (eg, hypoglycemia, hypocalcemia), and blood pressure. Other initial therapeutic measures include:

●If there is respiratory compromise, an adequate airway should be established immediately and supportive therapy (eg, supplemental oxygen and/or mechanical ventilation) instituted as needed. Supplemental oxygen (initially via head box) is provided to bring the oxygen saturation up to 85 to 95 percent, if possible. If infants have evidence for airway obstruction, prone positioning or an oral airway may be adequate to relieve the cyanosis. For infants with respiratory distress and carbon dioxide retention, continuous positive airway pressure (CPAP) or intubation for positive pressure ventilation should be considered. (See "Overview of mechanical ventilation in neonates".)

●In infants who are cyanotic but do not have respiratory distress, intubation is generally not necessary while the evaluation proceeds.

●Patients with hypotension or poor perfusion require cardiopulmonary resuscitation. Prompt treatment with administration of fluids is initiated in any infant with impaired circulation, and inotropic therapy may be necessary to correct hypotension.

●Cyanosis may be an initial finding of sepsis. As a result, unless another specific etiology is promptly identified, broad spectrum antibiotics should be initiated (ampicillin and gentamicin) after obtaining blood cultures. (See "Management and outcome of sepsis in term and late preterm neonates", section on 'Initial empiric therapy' and "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Empiric antibiotic therapy'.)

●Monitoring and maintaining adequate blood glucose levels of >45 to 50 mg/dL in the first 24 hours after delivery and >50 mg/dL thereafter [15]. (See "Management and outcome of neonatal hypoglycemia".)

●If cyanotic heart disease is suspected, a pediatric cardiology consultation and echocardiogram should be promptly performed. Until a definitive diagnosis is made, prostaglandin E1 (alprostadil) should be initiated as a continuous intravenous infusion at 0.01 to 0.05 mcg/kg per min, which is increased as needed to a maximum dose of 0.1 mcg/kg per min. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1'.)

Subsequent therapy is directed towards correcting or managing the consequences of the underlying etiology.

SUMMARY AND RECOMMENDATIONS — Cyanosis is a bluish discoloration of the tissues that results when the absolute level of reduced hemoglobin in the capillary bed exceeds 3 g/dL. It is a common clinical finding in newborn infants.

●Neonatal cyanosis, can be associated with significant and sometimes life-threatening diseases due to cardiac, metabolic, neurological, infectious, sepsis, and parenchymal and non-parenchymal pulmonary disorders. (See 'Central versus peripheral cyanosis' above.)

●Factors that affect the detection of neonatal cyanosis include hemoglobin concentration, the presence of fetal hemoglobin, skin pigmentation, and other physiologic factors that affect the oxygen dissociation curve (eg, acid-base balance, temperature of the infant, low PCO₂ level, and levels of 2,3 diphosphoglycerate) (figure 2).

●Central cyanotic lesions can be classified based on their pathophysiology as follows (table 1):

•Ventilation-perfusion mismatch – Pulmonary disease (such as respiratory distress syndrome [RDS], neonatal pneumonia, meconium aspiration syndrome, and air leak syndromes) resulting in ventilation-perfusion mismatch is the most common cause of neonatal cyanosis. (See 'Pulmonary disorders' above.)

•Alveolar hypoventilation – Hypoventilation resulting in hypoxemia may be due to airway obstructive lesions, or neurologic or metabolic disorders. (See 'Hypoventilatory disorders' above.)

•Right to left shunt – Disorders with right-to-left shunting include intracardiac lesions, persistent pulmonary hypertension through a patent ductus arteriosus, or intrapulmonary disease (eg, perfusion of non-ventilated areas of the lung). (See 'Disorders with right to left shunting' above and "Cardiac causes of cyanosis in the newborn" and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

•Inadequate transport of oxygen by hemoglobin – Hemoglobinopathies that inadequately transport oxygen include methemoglobinemia and rare variants of hemoglobin with low oxygen affinity. (See 'Hemoglobinopathies' above.)

•Diffusion impairment – Pulmonary edema is the most common cause of impaired diffusion of oxygen from the alveoli to the pulmonary capillaries.

●Infants with persistent cyanosis after birth should be promptly evaluated and treated as they are at-risk for significant and potentially life-threatening disease. The goals of evaluation are to identify and treat critically ill patients, and to determine the underlying cause of cyanosis so that treatment can focus on correcting or managing the specific disorder.

•The history may identify maternal or perinatal conditions, or family history that provides clues to the underlying cause. (See 'History' above.)

•The physical examination may provide information that helps determine the underlying cause of neonatal cyanosis. In particular, signs of respiratory distress (tachypnea, inter- and subcostal retractions, nasal flaring, and audible grunting) are suggestive of pulmonary disease, whereas abnormal cardiac findings (eg abnormal heart rate and sounds, and pathologic murmurs) indicate a cardiac etiology. (See 'Physical examination' above and "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Physical examination'.)

•Laboratory studies that may be helpful in differentiating among the variety of underlying causes of neonatal cyanosis include complete blood count, blood culture, blood glucose, chest radiograph, hyperoxia test, and cardiac echocardiography. (See 'Initial tests' above.)

●The initial management of newborns with cyanosis includes general supportive care to ensure adequate tissue perfusion and oxygenation. (See 'Initial management' above.)

Other therapeutic interventions include:

•Because the differential diagnosis for neonatal cyanosis includes sepsis, we recommend administering empiric antibiotic therapy after obtaining blood cultures in neonates with cyanosis in whom no underlying cause has been identified (Grade 1A). (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Differential diagnosis' and "Management and outcome of sepsis in term and late preterm neonates", section on 'Initial empiric therapy'.)

•When cyanotic heart disease is suspected, a pediatric cardiology consultation and echocardiogram should be promptly performed. Until a definitive diagnosis is made in an infant suspected of having cyanotic heart disease, we recommend administering prostaglandin E1 (alprostadil) as an initial continuous intravenous infusion at 0.01 mcg/kg per min (Grade 1A). (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1'.)