A 5 hour old male newborn infant was born at 39 weeks gestation via normal vaginal delivery to a 23 year old G2 P2 O+ mother with unremarkable prenatal serology studies. Apgar scores were 8 and 9 at 1 and 5 minutes. His initial physical exam was normal. He stayed in mother's room and breastfed shortly after delivery. At 5 hours of age, with the second feeding, the baby appears tachypneic and cyanotic, and he is therefore taken to the nursery for further evaluation.

Exam: VS T 37.0, HR 145, RR 78, BP 67/38, oxygen saturation 82% in room air. Length 53 cm (50%ile), weight 3.7 kg (50%ile), HC 34 cm (50%ile). He is an alert active, nondysmorphic and mildly cyanotic term male. Tachypnea and mild nasal flaring are present. His heart is regular with a grade 2/6 systolic ejection murmur at the lower left sternal border. The precordium is quiet. Lungs are clear bilaterally. No hepatosplenomegaly is noted.

He is placed in an oxygen hood with a fraction of inspired oxygen (FiO2) of 0.5 (50%) with no appreciable rise in his oxygen saturation.

A chest radiograph is normal. A radial arterial blood gas shows pH 7.44, pCO2 35, paO2 34, bicarb 22 in FiO2 0.7 (70%) by hood. Echocardiography reveals D-transposition of the great vessels with a 5mm ventricular septal defect and patent ductus arteriosus. A prostaglandin E1 infusion is started. The infant is mechanically ventilated and subsequently transported to a pediatric cardiac surgical specialty center. An arterial switch procedure is performed successfully. He is discharged home 3 weeks later.

The newborn infant with cyanosis challenges the clinician to identify the cause and institute appropriate treatment. Although cardiorespiratory disorders dominate the differential diagnosis, hematologic and metabolic derangements and neuromuscular disorders should also be considered.

As with all neonatal conditions, diagnosis is aided by obtaining a thorough maternal and birth history. Clues to infant problems may be found in pregnancy screening tests such as maternal serum alpha-fetoprotein, a marker for fetal aneuploidy, or knowledge of pre-existing maternal medical conditions such as diabetes. Maternal medications should also be noted. Both diabetes and chromosomal abnormalities increase the likelihood of congenital heart malformations. Although fetal ultrasound may reveal congenital heart, lung, or CNS anomalies, major anomalies frequently escape prenatal detection (1). Maternal serologies and cultures identify newborns at risk for perinatal group B streptococcal pneumonia or intrauterine toxoplasmosis infection.

The progress of labor and delivery, as reflected in Apgar scoring and delivery room resuscitation, also provides valuable information. An intrapartum complication leading to the need for aggressive neonatal resuscitation suggests an acquired perinatal etiology for neonatal cyanosis as opposed to a congenital cardiac malformation. Fetal heart rate pattern abnormalities, meconium staining of the amniotic fluid, maternal fever or bleeding may suggest neonatal pneumonia, hypoxic-ischemic injury, meconium aspiration syndrome or persistent pulmonary hypertension.

Cyanosis is recognized by evaluation of the mucus membranes and tongue. Peripheral cyanosis (acrocyanosis) is a normal finding in newborns and does not indicate systemic desaturation. The nail beds are not the place to look in newborns. Pigmentation of the vermilion border and facial bruising may also masquerade as cyanosis. It is necessary to look in an infant's mouth to get a true assessment of oxygenation.

The prerequisite for recognition of cyanosis is thought to be 5 g/dL or more of desaturated hemoglobin. Infants who are both hypoxic and severely anemic may escape recognition because the amount of desaturated hemoglobin is below the level of detection. Likewise, the polycythemic infant with a normal oxygen saturation may appear cyanotic from peripheral sludging of desaturated red cells despite normal oxygen saturation.

Minor levels of desaturation may also escape visual detection. Infants with oxygen saturation in the mid 80's often appear pink, especially under the bright lights above radiant warmers, and are judged to have normal Apgar scores and transition assessments. Only later is the hypoxia detected with the investigation of ancillary signs such as tachypnea, tachycardia or other signs of distress.

In general, cyanosis associated with respiratory problems is accompanied by dyspnea, retractions and grunting, possibly leading to apnea. The quality and symmetry of breath sounds may suggest focal disorders such as pneumothorax and diaphragmatic hernia or more generalized ones such as respiratory distress syndrome. Cyanotic cardiac disease may produce only tachypnea or a more dramatic picture of respiratory distress if pulmonary circulatory overload is present.

Heart murmurs are common in neonates during perinatal transition. The systolic murmurs of a patent ductus arteriosus and tricuspid regurgitation are heard in normal neonates. More infrequently heard holosystolic or diastolic murmurs require definitive evaluation. Conversely, many serious cyanotic congenital heart malformations are not accompanied by murmurs. The quality of peripheral pulses should be noted. Generally weak pulses denote systemic hypoperfusion as in low volume states and decreased cardiac output. Decreased femoral pulses alone suggest coarctation of the aorta. Bounding pulses suggest a widened pulse pressure.

The association of cyanosis with dysmorphic features may provide diagnostic information. For example, Down syndrome (trisomy 21) as well as trisomy 18, trisomy 13 and Turner (XO) syndrome are associated with specific cardiac malformations. Colobomata (eye defects), choanal atresia, genital and ear anomalies appear with cardiac defects such as tetralogy of Fallot in the CHARGE association (Coloboma, Heart defects, Atresia choanae, Retardation of growth and development, Genitourinary problems, Ear abnormalities). Facial and limb deformation associated with oligohydramnios is associated with hypoplastic lungs and pulmonary hypertension leading to cyanosis (5).

The most common congenital heart lesions presenting with cyanosis in the newborn period are those of the hypoplastic right heart syndrome complex (pulmonary and tricuspid atresia) and transposition of the great vessels. The basic pathophysiologic mechanisms leading to hypoxemia are inadequate perfusion of the lungs or marked right-to-left shunting and admixture of desaturated venous blood in the systemic arterial circulation. The most common cardiac conditions seen in Hawaii are listed in the table below.

Table. Cyanotic Congenital Heart Disease in Hawaii 1986-1998 (2). N=264,833 births

Diagnosis (number)
Pulmonary Artery Atresia/Stenosis (407)
Persistent Pulmonary Hypertension (187)
Tetralogy of Fallot (105)
Transposition of the Great Vessels (104)
Pulmonary Valve Atresia/Stenosis (43)
Tricuspid valve atresia/stenosis (38)
Hypoplastic Left Heart (44)
Truncus arteriosus (26)
Total Anomalous Pulmonary Venous Return (22)
Single Ventricle (17)
Partial Anomalous Pulmonary Venous Return (12)
Ebstein's Anomaly (9)

Persistent pulmonary hypertension (PPHN) of the newborn mimics many signs and symptoms of structural heart disease, and the effort to distinguish the two is a common clinical challenge. PPHN (formerly called persistent fetal circulation) may be a primary problem with little antecedent history or more commonly an associated problem of primary pulmonary diseases such as meconium aspiration syndrome, congenital diaphragmatic hernia, respiratory distress syndrome and congenital heart disease.

The entire gamut of neonatal respiratory disorders may present with cyanosis. The chest x-ray and history in combination often suggest the diagnosis. Some of the more common conditions include respiratory distress syndrome, meconium aspiration syndrome, neonatal pneumonia, and pneumothorax. Less common conditions include congenital anomalies of the lungs such as congenital diaphragmatic hernia, tracheoesophageal fistula and pulmonary hypoplasia. Transient tachypnea of the newborn, a common neonatal respiratory disorder, generally is not accompanied by marked cyanosis.

Central nervous system dysfunction caused by hypoxic ischemic injury, seizures, intracranial hemorrhage, infection, or metabolic derangement such as hypoglycemia may lead to cyanosis. Severe neuromuscular diseases such as phrenic nerve palsy, Werdnig-Hoffmann disease, or neonatal botulism may affect respiratory function and lead to cyanosis (6).

Methemoglobinemia may produce a slate gray hue to the skin generally accompanied by low oxygen saturation and hypoxemia, although an arterial pO2 on a blood gas will be paradoxically normal (similar to carbon monoxide poisoning since methemoglobin similarly does not carry oxygen). Methemoglobinemia is associated with ingestion of toxic agents such as nitrites and congenital absence of methemoglobin reductase. An usual pattern of methemoglobinemia has also been described in infants with diarrheal disease of various etiologies including milk protein intolerance and infectious gastroenteritis accompanied by severe systemic acidosis (3,4).

Echocardiography with color-flow Doppler is the definitive test for cyanotic structural heart disease and PPHN. However, prior to obtaining a cardiology consultation and echocardiogram, the clinician may perform a number of other valuable tests to define the cause or mechanism of cyanosis.

An anteroposterior chest x-ray will identify pneumonia, pneumothorax or the intrathoracic bowel gas patterns characteristic of diaphragmatic hernia. The shape and size of the cardiac silhouette and prominence of the central pulmonary vessel may provide clues to cardiac pathology. The classic cardiac silhouettes of transposition of the great vessels ("egg on side"), total anomalous pulmonary venous return ("snowman" heart) and tetralogy of Fallot (boot-shape) are uncommon in the newborn period. The chest x-ray appearance of PPHN is variable: oligemic (hypoperfused) lung fields in the idiopathic variety, prominent infiltrates (if accompanied by meconium aspiration syndrome), or normal in some cases.

The hyperoxy test is a rapid bedside screen for cyanotic diseases that do not respond to supplemental oxygen. The patient is placed in a high concentration oxygen hood (FiO2 at or near 100%) and the paO2 or oxygen saturation by pulse oximetry is compared to the value in room air. A significant increase in oxygen saturation or paO2 suggests pulmonary pathology, whereas an insignificant change in oxygenation suggests the fixed right-to-left shunting of structural cyanotic congenital heart disease, PPHN or very severe pulmonary disease.

Two pulse oximeter probes placed simultaneously on an upper and lower extremity will give clues to right-to-left shunting across a patent ductus arteriosus. A higher oxygen saturation reading in the hand than the foot is classically seen in PPHN and interrupted aortic arch. Likewise, a marked differential in paO2 between blood drawn from an upper extremity artery and umbilical artery catheter or posterior tibial artery carries the same implication.

Laboratory studies such as arterial blood gases can also supply information on ventilation and acid base status. A methemoglobin level can be ordered if methemoglobinemia is suspected. A rapid bedside screen for methemoglobinemia is arterial blood which has a "chocolate" color which does not turn red after several minutes of exposure to room air or oxygen.

The CBC provides an index of hemoglobin level. Polycythemia may exaggerate or falsely mimic cyanosis, while anemia may mask it. The white count, differential, and platelet count provide clues to disorders associated with inflammation and coagulopathy such as sepsis. Blood glucose should be monitored, as hypoglycemia may be an accompanying factor or the inciting cause of cyanosis. Infants ill enough to be cyanotic may require blood transfusion either for stabilization or surgery.

Echocardiography provides the definitive answer in the majority of common congenital heart lesions and PPHN. Rarely is cardiac catheterization required, except in confusing cases of complex anatomy or instances of uncertainty. The diagnosis of PPHN rests primarily on the finding of normal cardiac anatomy and direct evidence of right-to-left or bidirectional shunting of blood on color-flow Doppler through the foramen ovale or ductus arteriosus. Elevated right ventricular systolic pressures estimated by regurgitant flow through the tricuspid valve, ventricular septal flattening or paradoxical wall motion suggest but do not define PPHN in the absence of demonstrable shunting (7).

Targeted treatment is dependent on accurate diagnosis and understanding of pathophysiology. Respiratory support with oxygen or mechanical ventilation is often required in cyanotic newborns. In most cases, oxygen supplementation is helpful if not vital. An exception to this rule is in functionally univentricular hearts (as in hypoplastic left heart syndrome), in which cardiac output to the systemic versus pulmonary circulation is dependent on a balance of the relative resistance of each vascular bed. Oxygen, a potent pulmonary vasodilator, may increase pulmonary blood flow at the expense of systemic perfusion. In anomalous pulmonary venous return with obstruction, oxygen therapy may be particularly hazardous contributing to increasing pulmonary venous hypertension and clinical deterioration. However, in most pulmonary problems and PPHN, oxygen and ventilation are important aspects of supportive care. When a prostaglandin E1 infusion is used to maintain patency of the ductus arteriosus in ductal dependent lesions, apnea is a common side effect. Anticipation of this common complication and stabilization of the patient's airway and ready availability of ventilatory support can avoid deterioration especially in the transport setting. In transposition of the great vessels, timing and severity of presentation relates to the degree of right/left mixing. If there is a coexisting ventricular septal defect with adequate mixing, recognition may be delayed up to several weeks. However if a VSD is absent or mixing is inadequate, an emergency balloon atrial septostomy (Rashkind procedure) may be necessary prior to definitive repair (8).

Therapeutic use of nitric oxide, an endogenous regulator of vascular tone, has revolutionized the treatment of PPHN. Mortality from this condition, which at one time approached 50%, has improved in recent decades. Strategies for treatment have included aggressive oxygen use and hyperventilation to lower pulmonary vascular tone. When these approaches failed, extracorporeal membrane oxygenation (ECMO) was used as a successful rescue treatment. Multiple ECMO centers were established around the country in the 1980s. However with clinical trials of inhaled nitric oxide (iNO) in the 1990s and FDA approval of iNO in 1999, there has been a steady decrease in the use of ECMO in the United States (9).

Adequate support of cardiac function with inotropic agents such as dopamine, dobutamine, epinephrine, and milrinone infusions is extremely important in both PPHN and other cardiovascular diseases resulting in cyanosis. Red blood cell transfusion is commonly employed to support oxygen carrying and delivery capacity. Metabolic needs are addressed with provision of adequate glucose and nutritional support. Attention to fluid and electrolyte balance includes calcium maintenance for optimal cardiac performance. Acid-base derangement is addressed with attention to treatment of underlying disorders and the judicious use of sodium bicarbonate.

In the unusual event of cyanosis due to methemoglobinemia, methylene blue, an exogenous electron donor for NADPH-methemoglobin reductase, can be used in severe symptomatic cases. Methylene blue will be ineffective in babies with G6PD deficiency, because reduction of methylene blue requires an intact pentose phosphate pathway (10). Although methemoglobin is produced during iNO therapy for PPHN, concentrations are generally clinically insignificant.

Cardiac surgery techniques have improved to the point where palliative procedures such as systemic to pulmonary shunts have been largely replaced when possible by primary definitive repair in the newborn period. Examples are the arterial switch (Jatene) procedure for transposition of the great vessels and primary repair of anomalous pulmonary venous drainage and tetralogy of Fallot. Staged procedures are used for more complex lesions with unfavorable anatomy. Immediate outcome for the arterial switch procedure is 90-95% survival in the newborn period. The best outcomes for neonatal cardiac surgery are seen in pediatric cardiac centers with high volumes and skilled teams (8,11).

Questions

1. What are the 2 most common congenital heart diseases leading to cyanosis in the newborn period?

2. What therapies are used as a bridge to definitive therapy in cyanotic congenital heart disease?
. . . . . a. Prostaglandin E1 infusion
. . . . . b. Mechanical ventilation
. . . . . c. Inotropic agents
. . . . . d. All of the above

3. True/False: The definitive treatment for pulmonary hypertension of the newborn is surgical?

4. A 12 day old infant, exclusively fed cow's milk formula, presents to the ER appearing greyish/cyanotic. With 5L/minute oxygen by mask, his radial artery paO2 is 236 torr. His most likely diagnosis is:
. . . . . a. Tetralogy of Fallot
. . . . . b. Persistent Pulmonary Hypertension
. . . . . c. Methemoglobinemia
. . . . . d. Transposition of the Great Vessels

5. A 2 day old term infant previously thought to be well and about to be discharged from the nursery becomes acutely pale, slightly cyanotic, with weak femoral and brachial pulses. The congenital heart disease most likely to present in this manner is:
. . . . . a. Tetralogy of Fallot
. . . . . b. Hypoplastic Left Heart Syndrome
. . . . . c. Tricuspid Atresia
. . . . . d. Total Anomalous Pulmonary Venous Return

6. Name the four components of Tetralogy of Fallot. Of these four, which one most determines the severity of the cyanosis?

7. True/False: Because cardiac murmurs are uncommon in the newborn period, echocardiography should be performed on all newborns when a murmur is detected.

8. True/False: Cyanosis of the hands and feet of a newborn may be normal if the mucus membranes are pink.

References

1. Simpson L. Structural Cardiac Anomalies. Clinics in Perinatology 2000;27:839-863.

2. Merz RD, Forrester MB. Hawaii Birth Defects Program 1986-1998 Statewide Data, Surveillance Report Number 7 on Birth Defects in Hawaii, January 1,1986-December 31, December 1999, 1-126.

3. Yano SS, Danish EH, Hsia YE. Transient Methemoglobinemia with acidosis in infants. J Pediatr 1982;100:415-418.

4. Murray KF, Christie DL. Dietary protein intolerance in infants with transient methemoglobinemia and diarrhea. J Pediatr 1993;122:90-92

5. Jones KL, et al. Smith's Recognizable Patterns of Human Malformation, 5th edition. 1997, Philadelphia: W.B. Saunders, pp. 8-87, 668-670.

6. Marino BS, Wernovsky G. Chapter 12, Preoperative care. In: Chang AS, et al (eds). Pediatric Cardiac Intensive Care. 1998, Baltimore: Williams and Wilkins, pp. 151-162.

7. Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr 2000:136:717-726.

8. Bernstein D. Chapter 438-Cyanotic Congenital Heart Disease Lesions Associated with increased pulmonary blood flow. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: WB Saunders Co., pp. 1395-1398.

9. Hintz SR, Van Meurs KP et al. Decreased use of Neonatal Extracorporeal Membrane oxygenation (ECMO): How New Treatment Modalities Have Affected ECMO Utilization. Pediatrics 2000;106:1339-1343.

10. Lukens JN. Chapter 13-Methemoglobinemia and other disorders accompanied by cyanosis. In: Lee GR, et al (eds). Wintrobe's Clinical Hematology, 10th ed. 1999, Philadelphia: Lippincott, Williams and Wilkins, pp. 1046-1055.

11. Jenkins KJ, et al. In-hospital mortality for surgical repair of congenital heart defects: preliminary observations of variation by hospital caseload. Pediatrics 1995:953:23-30.

Answers to questions

1. Hypoplastic right heart syndrome/Pulmonary atresia (these two are part of a spectrum) and transposition of the great vessels.

2. d. All of the choices are correct.

3. False

4. c

5. b

6. Ventricular septal defect (VSD), overriding aorta, pulmonic stenosis, right ventricular hypertrophy. The severity of the pulmonic stenosis is the most important factor in determining the degree of cyanosis.

7. False.

8. True.