Neonatal cyanosis may be a signal of serious underlying pathology, and these patients require prompt and comprehensive evaluation when they present to the emergency department. This article will review the differential diagnosis, evaluation, and management of these infants in the ED setting.

Definition

Cyanosis is categorized as either central or peripheral. Peripheral cyanosis, also known as acrocyanosis, is a bluish discoloration of hands and feet caused by peripheral vasoconstriction. It is a common benign condition in the newborn.
By contrast, central cyanosis, a bluish discoloration of mucous membranes, lips, skin, and nailbeds, should be considered pathological until proven otherwise. It takes 3-5 g/dL of desaturated hemoglobin to manifest clinically as cyanosis, so it is important to keep in mind that an anemic patient may not look cyanotic despite a low pulse oximetry reading. Put another way, equal amounts of desaturated hemoglobin (producing comparable degrees of overt cyanosis) correspond to lesser oxygen saturation in the anemic patient. For example, a patient with a hemoglobin level of 18 and 3 g/dL of desaturated hemoglobin would have an oxygen saturation of 83%, whereas a patient with a hemoglobin level of 9 who has 3 g/dL of desaturated hemoglobin would have an oxygen saturation of 67%.

Epidemiology

When a cyanotic neonate presents to the emergency department, the differential diagnosis must include congenital heart disease (CHD), respiratory disorders, hematologic disorders, and infectious processes.

Cyanotic Congenital Heart Disease

Congenital heart disease that presents with cyanosis is associated with lesions causing blood to shunt from the pulmonary to the systemic circulation. The most common etiologies of cyanotic CHD are listed in Table 1.

In order to understand the pathophysiology and presentation of neonatal congenital heart disease, it is essential to recall the transitional circulatory changes of the newborn. In utero, the placenta oxygenates fetal blood. The deoxygenated fetal blood bypasses the lungs due to high pulmonary vascular resistance (PVR) and travels via the umbilical artery to the placenta, where it is oxygenated and returns to the fetus via the umbilical vein.

About a third of the oxygenated blood in the right atrium is shunted through the foramen ovale to the left atrium, and the remaining blood mixes with deoxygenated blood and flows to the right ventricle. Blood from the right ventricle flows to the pulmonary artery, but because of the high fetal PVR, the majority of the blood shunts through the ductus arteriosus. Soon after birth the increased negative intrathoracic pressure and a number of circulatory changes allow for the pulmonary vasculature to dilate and decrease the PVR, allowing the lungs to transition as the sole organ for gas exchange.

Within the first 24 hours, there is a functional closure of the ductus arteriosus and foramen ovale, with a complete anatomic closure of the ductus arteriosus usually within 2-3 weeks after birth.

Cardiac diseases associated with diminished pulmonary blood flow (and therefore diminished pulmonary markings on the chest X-ray) include tricuspid atresia, pulmonary atresia, pulmonary stenosis, tetralogy of Fallot (TOF), and Ebstein’s anomaly. TOF is one of the most common cyanotic congenital heart diseases presenting in the newborn period, and the degree of cyanosis depends on the severity of pulmonary stenosis. These five cardiac lesions are among the most common cardiac lesions that depend on the presence of a patent ductus arteriosus for communication of the pulmonary and systemic circulations.

Lesions associated with increased pulmonary blood flow and therefore increased pulmonary markings on the chest X-ray include (persistent) truncus arteriosus (fails to divide properly into pulmonary artery and aorta) and total anomalous venous return.

In patients with truncus arteriosus, the cyanosis may not be clinically apparent. A clue to a condition associated with increased pulmonary blood flow is that cyanosis does not respond to prostaglandin administration, which maintains patency of the ductus arteriosus. These two lesions require surgical correction soon after birth.

Cardiac conditions that present with severe heart failure and cyanosis in the neonatal period include hypoplastic left heart syndrome, critical aortic stenosis, interrupted aortic arch, and transposition of the great arteries. These lesions are ductal dependent, so infants may present with cyanosis and shock when the ductus arteriosus closes. Infants with ductal-dependent lesions may be asymptomatic at birth and present to the ED with shock and/or cyanosis in the first 2-3 weeks of life.

Respiratory Disorders

Respiratory disorders (including both upper and lower airway disorders) should be considered in the evaluation of any infant presenting with cyanosis. Disorders that occlude the upper airway such as choanal atresia, Pierre Robin Sequence, airway hemangioma, vascular rings/slings, cystic hygroma, and micrognathia may cause respiratory distress, stridor, and cyanosis. For example, choanal atresia, although usually diagnosed at birth, may include respiratory distress that improves with crying. Newborns as obligate nasal breathers normally breathe through the nose at rest but through the mouth when crying. Because these infants have an obstructed nasal passage, they will have respiratory distress when attempting to breathe through the nose. It is often diagnosed when the physician is unable to pass a catheter through the nares.

The most common lower airway disorders that cause cyanosis are pneumonia and atelectasis, which result in a ventilation-perfusion mismatch. Neonatal pneumonia typically presents with diffuse infiltrates on the chest X-ray. Most common pathogens include Escherichia coli and group B streptococci. Consider Chlamydia in neonates with a history of apnea and cough.

Less common pulmonary disorders include persistent pulmonary hypertension of the newborn (often associated with a diaphragmatic hernia), interstitial lung disease (diffusion abnormality), arteriovenous malformations (extracardiac shunt), congenital cystic adenomatoid malformation, pulmonary sequestration, and congenital lobar emphysema.

Hemoglobinopathies

Any hemoglobin disorder that interferes with transport of oxygen will result in cyanosis. Polycythemia and anemia can both result in cyanosis. Polycythemia may cause pulmonary hypertension secondary to increased viscosity of the blood. Severe anemia, in contrast, may result in cyanosis due to lack of oxygen delivery to vital tissues. A structurally abnormal hemoglobin molecule can have an impaired ability to carry oxygen.

Methemoglobinemia is a disorder in which there is a structurally abnormal hemoglobin molecule and most commonly results from exposures to an oxidizing chemical (see Table 2) but may also arise from genetic or dietary etiologies or may be idiopathic.

In this disorder, the ferrous (Fe2+) irons of heme are oxidized to ferric (Fe3+) state. Hemoglobin can transport oxygen only when iron is in the ferrous form, and so this oxidation shifts the oxygen dissociation curve to the left. Infants younger than 3 months are particularly susceptible to methemoglobinemia for several reasons: 1) they have lower amounts and activity of NADH-cytochrome b5 reductase; 2) they have lower gastric pH resulting in the proliferation of intestinal flora that reduces ingested nitrates to nitrites; and 3) fetal hemoglobin is more easily oxidized to methemoglobin than adult hemoglobin is. Infants with methemoglobinemia usually present with central cyanosis and no respiratory distress.

Infections

It is always important to consider sepsis in the evaluation of a neonate with cyanosis. Sepsis results in cyanosis secondary to increased oxygen utilization. Patients at highest risk for sepsis are those born to group B streptococcus (GBS)–positive mothers, those with a history of maternal infection/chorioamniotitis, prolonged rupture of membranes for more than 18 hours, and those born prematurely. The most common pathogens in neonatal sepsis include E. coli, GBS, and Listeria monocytogenes.

History

A cyanotic infant presenting to the emergency department can have a life-threatening condition. The history should focus on the risk factors for congenital heart disease, respiratory disorders, hemoglobinopathies, and infectious diseases. Address prenatal risk factors, such as family history, maternal medications (e.g., lithium), maternal GBS status, maternal medical conditions (e.g., systemic lupus erythematosis), and ultrasound findings of congenital anomalies. Perinatal risk factors, such as maternal infection, should also be considered. Address postnatal issues, such as feeding intolerance, poor weight gain/excess weight gain, sweating/tiring with feeds, respiratory distress, NICU stay, prematurity, hypothermia, and hyperthermia. If the physician suspects methemoglobinemia, explore risk factors by asking about potential exposures to oxidizing substances.

Evaluation

Based on the initial visual assessment of appearance, work of breathing, and circulation (often referred to as the Pediatric Assessment Triangle), one can often quickly categorize the severity of illness. Infants with cyanotic CHD may appear to have decreased tone and alertness, increased irritability, and/or a weak cry. They may exhibit an increased work of breathing, abnormal airway sounds, retractions, and/or head bobbing.

Evaluating the infant’s work of breathing can be extremely helpful, as infants with respiratory disorders typically present with cyanosis in respiratory distress (associated with retractions), whereas infants with cardiac disorders and methemoglobinimia may present with cyanosis without significant distress. On skin exam, the infant may exhibit pallor, mottling, and/or cyanosis.

Although every workup should be tailored to the specific differential diagnosis being considered, it is a good idea to start any neonatal cyanosis workup by obtaining the following:

• Vital signs, including a rectal temperature and four-limb blood pressures.
• Baseline pulse oximetry reading (pre- and postductal) on room air (and on 100% oxygen, if low on room air).
• EKG.
• Bedside glucose reading.
• Intravenous access.
• CBC.
• Complete metabolic panel.
• Arterial blood gas.
• Chest radiograph.

The physician should note the heart rate, heart sounds, and breath sounds; palpate the precordium for thrills; palpate the peripheral pulses; note the skin quality and capillary refill; evaluate for surgical scars; auscultate the head, chest, and abdomen for bruits, murmurs, and gallops; and assess for hepatomegaly. Of note, murmurs are not present in all clinically significant cardiac lesions. For example, transposition of the great arteries will often not present with a murmur.

The hyperoxia test is the gold standard for differentiating pulmonary disorders and hemoglobinopathies from cardiac disorders. The practitioner must first obtain an arterial blood gas from the right radial artery when the infant is breathing room air (FiO2 0.21) and then again after the infant is placed on 100% oxygen (FiO2 1) for 10-15 minutes.

If unable to obtain arterial blood gas, the physician can compare the pulse oximetry findings of the patient breathing room air vs. the patient breathing 100% oxygen. In infants with cyanotic congenital heart disease, the PaO2 will not be greater than 150 mm Hg (or the pulse oximetry will not significantly rise) with administration of 100% oxygen.

In comparison, patients with a respiratory disorder will have a PaO2 greater than 150 mm Hg after administration of 100% oxygen, indicating that the cyanosis is not the result of a significant shunt.

If after administering 100% oxygen the PaO2 increases to greater than 200 mm Hg but the pulse oximetry remains low, then the patient may have a hemoglobinopathy, such as methemoglobinemia.

In addition to these tests, when there are concerns about an infectious process, the workup should also include a blood culture, urinalysis, urine culture, and cerebrospinal fluid analysis. Hypoglycemia, hyperglycemia, metabolic acidosis, and jaundice all are metabolic findings that commonly accompany neonatal sepsis.

Suspected pulmonary or cardiac disease warrants a chest radiograph to evaluate cardiac silhouette, pulmonary markings, or presence of an infiltrate. With any suspicion for cardiac disease, the workup should also include an echocardiogram and pediatric cardiology consultation.

Treatment

Treatment of the cyanotic neonate depends on the underlying etiology of the cyanosis. All patients should be immediately placed on oxygen via a non-rebreather mask until the airway is secured. Place the patient on a cardiorespiratory monitor and monitor any changes in vital signs.

Strongly consider treating any neonate with cyanosis secondary to suspected congenital heart disease with prostaglandin E1 (PGE1) at 0.05-0.1 microg/kg per minute to keep the ductus arteriosus patent. It is imperative to prepare for endotracheal intubation as PGE1 may cause apnea. Expert pediatric cardiology consultation should be sought early in the course, as echocardiography is essential for further diagnosis and management of the patient.

If a respiratory disorder is suspected, administer oxygen as outlined and treat the underlying disorder. Prepare for endotracheal intubation, as neonates can rapidly progress to respiratory arrest.

The treatment of choice for methemoglobinemia is methylene blue, which acts as an oxidizing agent that is reduced to leukomethylene blue, which in turn reduces methemoglobin to hemoglobin. Methylene blue is indicated if methemoglobin exceeds 25% or if the patient has clinical signs of hypoxia (e.g., lethargy, respiratory distress). In neonates, the dose is 0.3-1 mg/kg as a 1% solution, given intravenously over 3-5 minutes; effects usually are apparent within 30 minutes.

Finally, because sepsis frequently presents with cyanosis and shock in the neonate, a sepsis workup including blood, urine, and cerebrospinal fluid cultures should be obtained and intravenous antibiotics administered as soon as possible.

Of note, broad-spectrum antibiotics (e.g., vancomycin and cefotaxime) should be administered as soon as possible and should not be delayed pending lumbar puncture.

Summary

The evaluation of the cyanotic neonate should be done in an algorithmic manner that focuses on evaluation and management of the most life-threatening disease processes first.The hyperoxia test should be utilized early in the evaluation of these patients to assist in the differentiation and categorization of the cyanotic event. Be careful to obtain a detailed history of the prenatal, birth, and postnatal periods, as physicians will often be able to narrow the differential by the history alone. Neonates may decompensate very quickly, and preparations for a life-saving emergency using the PALS and NRP/NALS guidelines should be made as soon as possible.

Resources

• Avarello JT. Cardiac emergencies. In: Neonatal Emergencies. New York: McGraw-Hill Medical; 2009.
• Bernstein D. Acyanotic congenital heart disease: The left-to-right shunt lesions. In: Nelson’s Textbook of Pediatrics. 18th ed. Philadelphia: Saunders; 2003.
• Bernstein D. Cyanotic congenital heart disease: Evaluation of the critically ill neonate with cyanosis and respiratory distress. In: Nelson’s Textbook of Pediatrics. 18th ed. Philadelphia: Saunders; 2003.
• DeBaun M, Vichinsky E. Hemoglobinopathies. In: Nelson’s Textbook of Pediatrics. 18th ed. Philadelphia: Saunders; 2003.
• Marino BS, Bird GL, Wernovsky G. Diagnosis and management of the newborn with suspected congenital heart disease. Clin Perinatol. 2001;28(1):91-136.
• Steinhorn R. Evaluation and management of the cyanotic neonate. Clin Ped Emerg Med. 2008;9:169-175.