51: Cyanosis

During a physical examination, an infant appears blue. Cyanosis can be caused by a rise in deoxygenated hemoglobin (more common) or an abnormal hemoglobin disorder.

1. Does the infant have respiratory distress? If the infant has increased respiratory effort with increased rate, retractions, and nasal flaring, respiratory disease should be high on the list of differential diagnoses. Cyanotic heart disease usually presents without respiratory symptoms (“happy blue baby”) but can have effortless tachypnea (rapid respiratory rate without retractions). Blood disorders usually present without respiratory or cardiac symptoms.

2. Does the infant have a murmur? A murmur usually implies heart disease, but in infants with congenital heart malformations, <50% have a murmur in the newborn period. Transposition of the great vessels can present without a murmur (∽60%). Muffled heart sounds can indicate pericardial effusions or pneumopericardium.

3. Was the infant cyanotic at birth? Infants with transposition of the great vessels and tricuspid atresia can present almost immediately at birth with cyanosis. In the perinatal period, infants with truncus arteriosus, total anomalous pulmonary venous return, and tetralogy of Fallot can present with cyanosis.

4. Is the cyanosis continuous, intermittent, cyclical, sudden in onset, or occurring only with feeding or crying? Intermittent cyanosis is more common with neurologic disorders; these infants may have apneic spells alternating with periods of normal breathing. Cyclical cyanosis can occur with nasal obstruction. Continuous cyanosis is more commonly associated with intrinsic lung disease or heart disease. Cyanosis with feeding can occur with esophageal atresia and severe gastroesophageal reflux. Sudden onset of cyanosis may occur with an air leak, such as pneumothorax. Cyanosis that disappears with crying may mean choanal atresia. Cyanosis only with crying can occur in infants with tetralogy of Fallot. Cyanotic spells with no or minimal coughing can occur with pertussis. Crying may improve cyanosis in respiratory disease and worsen it in cardiac disease.

5. Is the pulse oximeter normal and the infant blue? The pulse oximeter measures oxygen saturation of hemoglobin that is available to bind oxygen. If there is abnormal hemoglobin, it will not be measured. If you see a normal pulse oximeter in a cyanotic infant, think methemoglobinemia.

6. Has the baby had the recommended pulse oximetry screening for congenital heart disease? This has been recommended by the American Academy of Pediatrics (AAP) in all newborns (see Newborn Physical Examination) as a useful method for screening for critical congenital cyanotic heart disease.

7. Is there differential cyanosis (DC)? Differential cyanosis is when there is cyanosis of the upper or lower part of the body only, and it usually signifies serious heart disease. The prerequisite for this to happen is the presence of a right-to-left shunt through the patent ductus arteriosus (PDA). To diagnose this, oxygen saturation should be measured in the preductal (right hand is preferred since it accurately reflects preductal value) and postductal (foot). There are 2 different types of differential cyanosis.

   1. Pink upper half of the body, cyanosis lower part of body (more common). (Oxygen saturation is greater in the right hand than in the foot.) It occurs with severe coarctation of the aorta or interrupted aortic arch. It can also occur with persistent pulmonary hypertension (PPH) with right-to-left shunting through the ductus arteriosus.

   2. Cyanosis in the upper half of the body, pink lower part of the body. This type is very rare (reversed differential cyanosis [RDC]) and occurs when oxygen saturation is lower in the right hand than in the foot. This is seen in complete transposition of the great arteries with shunt through the PDA with persistent pulmonary hypertension or aortic interruption/coarctation. It can also be seen in an infant with supracardiac total anomalous pulmonary venous connection (TAPVC) to the superior vena cava with a shunt through the PDA.

8. What is the prenatal and delivery history? Did the mother have a prenatal sonogram? It may show a cardiac anomaly. An infant of a diabetic mother has an increased risk of hypoglycemia, TTN, polycythemia, respiratory distress syndrome, and heart disease (TGA). Infection, such as that which can occur with premature rupture of membranes, may cause shock and hypotension with resultant cyanosis. Coxsackie B viral infections cause myocarditis in newborn infants. Amniotic fluid abnormalities, such as oligohydramnios (associated with pulmonary hypoplasia) or polyhydramnios (associated with esophageal atresia), may suggest a cause for the cyanosis. Cesarean section is associated with increased respiratory distress, transient tachypnea of the newborn (TTN), and persistent pulmonary hypertension of the newborn (PPHN). Pregnancy-induced hypertension can be associated with intrauterine growth restriction (IUGR), polycythemia, and hypoglycemia. Congenital infections can lead to cardiac abnormalities. Advanced maternal age can be associated with birth defects such as Down syndrome and Turner syndrome, which include heart defects. Certain perinatal conditions increase the incidence of congenital heart disease.

   1. Medications used by the mother can cause an increase in congenital heart disease. Anticonvulsants, lithium, indomethacin, nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen, sulfasalazine, thalidomide, trimethoprim, sulfonamide, vitamin A, selective serotonin reuptake inhibitors (SSRIs), marijuana, alcohol, cigarette smoking, cocaine, and exposure to organic solvents.

   2. Maternal illnesses that increase the risk of congenital heart disease. Untreated phenylketonuria (PKU), maternal pregestational diabetes, febrile illness during the first trimester, influenza, maternal rubella, epilepsy, and maternal lupus/connective tissue disease.

   3. Maternal congenital heart disease and/or congenital heart disease in a first-degree relative. Increased incidence of heart disease in the child.

Cyanosis becomes visible when there is >3–5 g/dL of deoxygenated hemoglobin/dL. The degree of cyanosis depends on both oxygen saturation and hemoglobin concentration. Cyanosis can be a sign of severe cardiac, respiratory, or neurologic compromise. The most common etiology of cyanosis in a newborn infant is respiratory. Cyanosis can also be caused by a reduced blood oxygen–carrying capacity secondary to an abnormal form of hemoglobin, such as methemoglobinemia. Cyanosis may not be apparent in a severely anemic infant or may be difficult to see in a darkly pigmented newborn. The causes of cyanosis can be classified as arising from respiratory, cardiac, central nervous system (CNS), or other disorders.

1. Respiratory diseases. Include primary pulmonary diseases, airway obstruction, and extrinsic compression of the lungs and congenital defects. Pulmonary diseases are the most common cause of cyanosis in the newborn.

   1. Primary pulmonary diseases. Respiratory distress syndrome (RDS), TTN, aspiration syndromes, pneumonia, bronchopulmonary dysplasia/chronic lung disease (BPD/CLD), pulmonary interstitial emphysema (PIE), pulmonary hemorrhage.

   2. Airway obstruction. Mucous plug, Pierre Robin syndrome, choanal atresia, vocal cord paralysis, macroglossia, atelectasis, and others.

   3. External compression of the lungs. Any air leak syndrome, pleural effusion, and others.

   4. Congenital defects. Congenital diaphragmatic hernia, pulmonary hypoplasia, cystic adenomatoid malformation, lobar emphysema, and others.

2. Infections. Sepsis is the second most common cause of cyanosis in infants. Sepsis causes increased oxygen utilization, which results in cyanosis. Meningitis can also present with cyanosis.

3. Hypotension and shock. This can be secondary to sepsis, cardiogenic, neurogenic, or hypovolemic, and all can present with cyanosis. (See Chapter 65.)

4. Cardiac diseases. The majority of congenital heart diseases that present in the first couple of weeks of life are ductal-dependent cardiac lesions.

   1. All cyanotic heart diseases which include the 5 T's. Transposition of the great arteries is the most common cyanotic congenital heart disease in newborns.

      1. Transposition of the great arteries.

      2. Total anomalous pulmonary venous return.

      3. Tricuspid atresia.

      4. Tetralogy of Fallot.

      5. Truncus arteriosus.

      6. Sixth T (“tons of others”/”terrible T's”) includes all the others: severe pulmonic stenosis, double outlet right ventricle, pulmonary atresia with intact ventricular septum/or with ventricular septal defect (VSD), variations on single ventricle, Ebstein anomaly of the tricuspid valve, hypoplastic heart syndrome with intact foramen ovale (no mixing at the atrial level), and others.

   2. Persistent pulmonary hypertension of the newborn (PPHN). In PPHN, infants do not transition from fetal to newborn circulation. Pulmonary hypertension causes right-to-left shunting of blood, a decrease in pulmonary blood flow, and cyanosis.

   3. Severe congestive heart failure. This can occur from cardiomyopathies (infant of diabetic mother [IDM], inborn errors of metabolism, genetic or neuromuscular disease), myocarditis (bacterial or viral), congenital cardiac disease, sepsis, perinatal asphyxia, and sustained tachyarrhythmias.

   4. Pneumopericardium or pericardial effusion.

   5. Other congenital anomalies such as those associated with cardiac malformations: Turner syndrome, Noonan syndrome, etc. Pulmonary arteriovenous malformation is a rare cause of cyanosis in the newborn.

5. Central nervous system diseases. CNS disorders can cause apnea, seizures, and decreased respiratory effort.

   1. Infectious. Bacterial or viral CNS infection (meningitis, encephalitis).

   2. Seizures. Infection, metabolic, CNS injury, genetic syndrome, congenital disorder, primary seizure disorder.

   3. Hypoxic ischemic encephalopathy (HIE).

   4. Hemorrhage. Periventricular/intraventricular hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, intracerebellar hemorrhage, infarction.

   5. Congenital disorders. Congenital hydrocephalus, spinal muscle atrophy, congenital central hypoventilation syndrome.

   6. Drug toxicity (opioid toxicity).

6. Neuromuscular disorders. Werdnig-Hoffman disease, Pompe disease, Barth syndrome, Duchenne or Becker muscular dystrophy, limb-girdle muscular dystrophy, congenital myopathy, neonatal myasthenia gravis, phrenic nerve injury, and congenital myotonic dystrophy.

7. Hematologic disorders. A hemoglobin disorder can interfere with the transport of oxygen and cause cyanosis.

   1. Methemoglobinemia (normal arterial O₂). Because the arterial blood is brown in color, it gives off a bluish hue in the skin of Caucasian people. It can be congenital (familial) or secondary to a toxin (medications such as eutectic mixture of lidocaine and prilocaine [EMLA], sulfonamides, others) or environmental substances.

   2. Polycythemia/hyperviscosity syndrome (normal arterial O₂). Infants with this can present with peripheral cyanosis, tachypnea, congestive heart failure (CHF), and cardiomegaly. Cyanosis is detectable at a higher value of Sao₂. Polycythemia can cause pulmonary hypertension.

   3. Severe anemia from hemorrhage or bleeding disorders.

8. Metabolic abnormalities can present with apnea and cyanosis

   1. Drug withdrawal.

   2. Hypoglycemia, hypermagnesemia, severe metabolic acidosis.

   3. Inborn errors of metabolism.

   4. Rarely abnormalities of calcium, potassium, and phosphorus can cause hypoxia and cyanosis. Calcium and potassium abnormalities can cause cardiac arrhythmias.

9. Other disorders

   1. Apnea and bradycardia

   2. Hypothermia

   3. Hypoadrenalism/hypopituitarism

   4. Abdominal distension with elevation of the diaphragm

   5. Respiratory depression secondary to maternal medications (eg, magnesium sulfate and narcotics) or sedation

10. Pseudocyanosis. Caused by fluorescent lighting.

Obtain a prenatal and delivery history (see Section II.H).

1. Physical examination

   1. Assess the infant for central, peripheral, acrocyanosis, versus differential cyanosis

      1. Central cyanosis. Skin, lips, and tongue appear blue. This indicates generalized cyanosis. This is caused by reduced arterial oxygen saturation.

      2. Peripheral cyanosis. Skin is bluish but the oral mucous membranes are pink. Seen in methemoglobinemia, caused by a normal arterial oxygen saturation and increased oxygen extraction.

      3. Acrocyanosis. Hands and feet are blue but nothing else. This can be present in normal infants in the first 24–48 hours. It is caused by immature vascular tone or vasoconstriction secondary to a cold environment. Less commonly it may indicate poor tissue perfusion or a decrease in cardiac output.

      4. Circumoral cyanosis. Blue appearance around the mouth. There is a venous plexus around the mouth that gets engorged during feeding. Usually a normal finding, it can be an expression of peripheral cyanosis.

      5. Poor peripheral perfusion with cyanosis. Seen in sepsis, hypoglycemia, dehydration, and hypoadrenalism.

      6. Differential cyanosis. Cyanosis of the upper or lower part of the body only (see Section II.G).

   2. Assess the heart. Check for any murmurs and for heart rate and blood pressure. Increased second heart sound intensity can be seen in pulmonary hypertension. Single second heart sound can be seen with transposition of the great vessels, aortic atresia, truncus arteriosus, pulmonary atresia, and conditions with pulmonary hypertension. Remember not all infants with congenital heart disease have a murmur. (Transposition of the great vessels can have no detectable murmur.) Muffled heart sounds can signify pneumopericardium or pericardial effusion. A displaced cardiac impulse may mean dextrocardia or dextroposition. Not all infants with murmurs have congenital heart disease.

   3. Assess the respiratory system. Is there retraction, nasal flaring, or grunting? Retractions are usually minimal in heart disease. Check the nasal passage for choanal atresia. Infants with pulmonary disease will have tachypnea and distressed breathing, whereas infants with cardiac disease do not.

   4. Assess the abdomen. Check for an enlarged liver. The liver can be enlarged in CHF and hyperexpansion of the lungs. A scaphoid abdomen may suggest a diaphragmatic hernia. Hepatomegaly can indicate high venous pressure.

   5. Check the pulses. In coarctation of the aorta, the femoral pulses are decreased. In patent ductus arteriosus, the pulses are bounding.

   6. Consider neurologic problems. Check for apnea and periodic breathing, which may be associated with immaturity of the nervous system. Observe the infant for seizures, which can cause cyanosis if the infant is not breathing during seizures.

   7. Assess for multiple malformations on the examination. These may suggest underlying heart or pulmonary defects (“CHARGE” or “VATER/VACTERL” anomalies).

2. Laboratory studies

   1. Arterial blood gas measurements on room air. If the patient is not hypoxic, it suggests methemoglobinemia, polycythemia, or CNS disease. If the patient is hypoxic, perform the hyperoxia test, described later. Pulse oximetry can be used to check arterial saturation but is not a good indicator of central cyanosis. An increased CO₂ can indicate pulmonary, PPHN, or CNS disorders. Metabolic acidosis can indicate sepsis, severe hypoxemia, or shock. A low or normal CO₂ can indicate cardiac disease.

   2. Complete blood count (CBC) with differential. This may reveal an infectious process. A central hematocrit of >65% confirms polycythemia.

   3. Sepsis workup. Blood culture and C-reactive protein (CRP), urine culture, and lumbar puncture (LP) if indicated.

   4. Serum glucose level. To detect hypoglycemia.

   5. Methemoglobin level. If the infant has methemoglobinemia, the blood will not turn red when exposed to air. It will have a chocolate hue. To confirm the diagnosis, the laboratory should perform a spectrophotometric determination.

3. Imaging and other studies

   1. Transillumination of the chest. (See Chapter 40.) Should be done on an emergent basis if pneumothorax is suspected.

   2. Chest radiograph. If normal, it suggests a CNS disease or other cause for the cyanosis (see Section III). It can verify lung disease, air leak, or diaphragmatic hernia. It can also help diagnose heart disease by evaluating the heart size and pulmonary vascularity. The heart size may be normal or enlarged in hypoglycemia, polycythemia, shock, and sepsis. In cardiac lesions with cyanosis and increased pulmonary blood flow there will be cardiomegaly. Decreased pulmonary vascular markings represent decreased blood flow through the pulmonary circulation and can be seen in tetralogy of Fallot, pulmonary atresia/stenosis, truncus arteriosus, and Ebstein anomaly. Increased pulmonary arterial markings can be seen in truncus arteriosus, single ventricle, and transposition of the great arteries. Increased venous markings can be seen in hypoplastic left heart syndrome and total anomalous pulmonary venous return. Shape of the heart can be important:

      1. Boot-shaped heart. Tetralogy of Fallot, tricuspid atresia

      2. Egg-shaped heart (“egg on a string”). Transposition of the great arteries

      3. Large globular heart. Ebstein anomaly

      4. Dextrocardia/mesocardia. Congenital heart disease

      5. “Snowman” or “figure 8.” Total anomalous pulmonary venous return

   3. Hyperoxia test. Because of intracardiac right-to-left shunting, the infant with cyanotic congenital heart disease in contrast to the infant with pulmonary disease is unable to raise the arterial saturation. Measure arterial oxygen on room air. Then place the infant on 100% oxygen for 10–20 minutes. Then remeasure arterial oxygen. It is best not to use pulse oximetry since it may not give an accurate result. Note: A value of >150 mm Hg does not always rule out cyanotic heart disease. Diagnosis of cardiac disease can be delayed from a misleading hyperoxia test and has been reported (pulmonary disease with cardiac disease, infracardiac total anomalous pulmonary venous connection with Pao₂ >250 mm Hg). Echocardiogram should be done if unsure.

      1. Normal infant. Pao₂ >300.

      2. Pulmonary disease. Pao₂ >150 mm Hg. In an infant with severe pulmonary disease, the arterial oxygen saturation may not increase significantly.

      3. Cardiac disease. Pao₂ <50–70 mm Hg. In cyanotic heart disease the Pao₂ most likely will not increase significantly (usually <100 mm Hg and often <70 mm Hg). The hyperoxia test can also help in differentiating the different types of heart disease. Infants with transposition of the great arteries or severe pulmonary outflow obstruction will usually have a Pao₂ <50 mm Hg. Infants with disease with both right-to-left and left-to-right shunting (truncus arteriosus, TAPVC without obstruction, hypoplastic left heart syndrome, single ventricle with PDA) can have an increase in Pao₂ but rarely >150 mm Hg.

      4. PPHN. In infants with PPHN, it may or may not increase significantly. If the Pao₂ increases to <20–30 mm Hg, PPHN should be considered.

      5. Neurologic disease. Pao₂ >150 mm Hg.

      6. Methemoglobinemia. Pao₂ >200 mm Hg but pulse oximetry remains low.

   4. Right-to-left shunt test. Done to rule out PPHN. Best way to do this is with pulse oximetry. Place 2 pulse oximeters on the infant (one preductal on the right hand, one postductal on either foot). If the simultaneous difference is >5% between preductal and postductal oxygen saturations, it is indicative of a right-to-left shunt. One can also draw a simultaneous sample of blood from the right radial artery (preductal) and the descending aorta or the left radial artery (postductal). If there is a difference of >10–15 mm Hg (preductal more than postductal), the shunt is significant.

   5. Hyperventilation test. Hyperventilating the infant for 10 minutes (lowering Paco₂ and increasing the pH) will result in a marked improvement in oxygenation (>30 mm Hg increase in Pao₂) in PPHN. This may help differentiate the infant with PPHN from that with cyanotic congenital heart disease (little or no response in CHD).

   6. Electrocardiography (ECG). Usually normal in patients with methemoglobinemia or hypoglycemia. With polycythemia, pulmonary hypertension, or primary lung disease, the ECG is normal but may show right ventricular hypertrophy. The ECG is usually nondiagnostic because of the normal neonatal right-axis deviation and dominant right wave in the right chest leads. It is very helpful in identifying patients with tricuspid atresia; it will show left-axis deviation and left ventricular hypertrophy. ECG can be normal in transposition of the great vessels.

   7. Echocardiography. Should be performed immediately if cardiac disease is suspected or if the diagnosis is unclear. It is the gold standard and definitive diagnostic test for congenital heart disease. It can confirm pulmonary hypertension.

   8. Computed tomography (CT) and CT angiography. May help identify anomalies of the pulmonary venous return.

   9. Ultrasonography of the head. Performed to rule out periventricular/intraventricular hemorrhage.

   10. Polysomnographic recording. Helps diagnose apnea and its type.

   11. Electroencephalogram (EEG). If seizure is suspected.

1. General management. Act quickly and accomplish many of the diagnostic tasks at once. Perform resuscitation (ABCs) if necessary and provide respiratory support, volume resuscitation if necessary, and antibiotics as indicated. Inotropic support and correcting metabolic acidosis are essential.

   1. Perform a rapid physical examination. What is the blood pressure? Other vital signs? Transilluminate the chest (see Chapter 40). If a tension pneumothorax is present, rapid needle decompression may be needed.

   2. Order immediate studies. For example, blood gas levels, CBC, and chest radiograph. Consider echocardiography.

   3. Perform the hyperoxia test. See Section IV.C.3.

2. Specific management

   1. Lung disease. (See the appropriate disease chapter.) Respiratory depression caused by narcotics can be treated with naloxone (Narcan) (see Chapter 148 for dosing).

   2. Air leak (pneumothorax). See Chapter 70.

   3. Congenital defects. Surgery is indicated for diaphragmatic hernia.

   4. Cardiac disease. Prostaglandin E₁ (PGE1) is indicated for any clinical condition in which blood flow must be maintained through the ductus arteriosus to sustain pulmonary or systemic circulation until surgery can be performed.

      1. Give PGE₁ to increase pulmonary blood flow for pulmonary atresia/stenosis, tricuspid atresia, tetralogy of Fallot, and Ebstein anomaly of the tricuspid valve. Other ways of improving pulmonary blood flow are with supplemental oxygen, maintaining a respiratory alkalosis, sildenafil, and inhaled nitric oxide.

      2. Give PGE₁ to increase systemic blood flow for hypoplastic left heart syndrome, coarctation of the aorta, critical aortic stenosis, aortic arch interruption.

      3. Give PGE₁ to improve mixing in transposition of the great arteries.

      4. PGE₁ is not recommended in respiratory distress syndrome, PPHN, total anomalous venous return with obstruction (PGE1 may minimize obstruction but does not help clinically), and dominant left-to-right shunt (patent ductus arteriosus, truncus arteriosus, or ventricular septal defect).

      5. If the diagnosis is uncertain, a trial of PGE1 can be given over 30 minutes in an effort to improve blood gas values.

      6. Other management. D-transposition of the great arteries requires urgent balloon atrial septostomy under echocardiogram in the nursery if hypoxia or acidosis occurs. TAPVR, transposition of the great arteries with VSD, and truncus arteriosus require further cardiac evaluation and possible surgery.

   5. PPHN. See Chapter 120.

   6. CNS disorders. Treat the underlying disease.

   7. Methemoglobinemia. Treat the infant with methylene blue only if the methemoglobin level is markedly increased and the infant is in cardiopulmonary distress (tachypnea and tachycardia). Administer intravenously 1 mg/kg of a 1% solution of methylene blue in normal saline. The cyanosis should clear within 1–2 hours.

   8. Shock. See Chapter 65.

   9. Polycythemia. See Chapters 71 and 122.

   10. Choanal atresia. Usually requires surgery (see Chapter 135).

   11. Hypothermia. Rewarming is necessary as described in Chapter 7.

   12. Hypoglycemia. See Chapter 62.