Reese H. Clark, MD

Differential Diagnosis of Neonatal Pulmonary Disorders

See Table 18-1.

No. Although apnea is often believed to be a provocative factor for SIDS, this relationship has never been causally established. It appears that premature infants with apnea of prematurity are no more likely to die as a result of SIDS than those of comparable gestational age who do not have apnea of prematurity. Premature infants do, however, have a higher SIDS rate than do term infants, suggesting that immaturity of respiratory control may be a component of SIDS. Furthermore, several studies have indicated that unless respiratory patterns of premature infants are recorded, apnea will not be detected because the respiratory abnormalities in these babies are very difficult to see clinically. ¹

Of infants who die as a result of bacteremia, 90% have evidence of pneumonia on postmortem examination. Many of these infants, however, will not have positive blood cultures during life, making the bacteriologic diagnosis of pneumonia difficult. If pneumonia is suspected on the basis of the clinical examination or chest x-ray, it should be treated aggressively until it has clinically resolved or until the child has been treated for a minimum of 10 days.

In premature infants GBS often mimics respiratory distress syndrome (RDS) with a diffuse reticulogranular pattern and air bronchograms. It is unclear whether this pattern indicates simultaneous disease processes (RDS and GBS) or whether GBS disease causes a secondary surfactant deficiency that produces a radiographic appearance similar to that of RDS when a premature infant is infected.

In term neonates the most common GBS appearance mimics that of transient tachypnea of the newborn, with increased perihilar interstitial markings, hyperexpanded lung fields, and small pleural effusions.

Neonates who have low oxygen saturations or arterial oxygen levels (arterial PO₂), normal carbon dioxide levels (PaCO₂), and no signs of respiratory distress usually have cyanotic congenital heart disease. Low arterial PO₂ and a rising PaCO₂ in a neonate with labored breathing (e.g., grunting, retractions, tachypnea) suggest intrinsic lung disease and its attendant intrapulmonary shunt. A high level of PaCO₂ in association with severe retractions, normal arterial PO₂ in minimal oxygen support, and signs of gas trapping on chest radiograph is most consistent with upper airway obstruction. Therefore if an infant is easy to oxygenate and impossible to ventilate, think airway; if the infant is easy to ventilate and impossible to oxygenate, think heart; and if both oxygenation and ventilation are problems, think lung disease.

Neonatal Resuscitation

Airway, airway, airway: Managing the airway is always the most critical aspect of resuscitation. Most neonates who require support in the delivery room will respond to stimulation, opening of the airway, and gentle ventilation with a bag and mask.

Only about 40% oxygen can be delivered without a reservoir. Each time a self-inflating bag is squeezed, room air is drawn into the bag, diluting any oxygen that is connected. When a reservoir is connected, concentrations up to 90% or more of oxygen may be delivered. One of the limitations of the self-inflating bag is that the desired concentration of oxygen cannot be altered easily.

These sizes are reasonable approximations for most infants, but attention should be paid to the ease of introduction of the ET tube into the airway. A 2.5-mm ET tube may be too small for some babies weighing less than 1000 g, and it may be too large for a few infants with birth weights greater than 1000 gm. The ET tube should slide easily into the airway, and a small leak should be audible around the ET tube when pressures of 25 to 30 cm H₂O are exceeded. An ET tube that is too snug may lead to tracheal inflammation and stenosis, whereas an ET tube that is too small simply may not allow adequate gas delivery to the lungs.

The “tip-to-lip” rule for placement is the distance from the ET tube tip to the centimeter marking on the tube itself ( Fig. 18-1). Good approximations are as follows:

No. Compared with expectant management, intubation and suctioning of the apparently vigorous meconium-stained infant does not result in a decreased incidence of meconium aspiration syndrome (MAS) or other respiratory disorders. In addition, it may provoke airway injury, especially if the child is active and moving after delivery. ³⁴

Only (C), epinephrine for heart rate below 60 bpm is currently recommended by the Neonatal Resuscitation Program. The other therapies have their advocates, but most studies have not shown them to be effective adjuncts for neonatal resuscitation.

Two meta-analyses of several randomized controlled trials comparing neonatal resuscitation initiated with room air versus 100% oxygen showed increased survival when resuscitation was initiated with room air. ⁵⁶⁷

Voltaire, Samuel Johnson, Johann Wolfgang von Goethe, Thomas Hardy, Pablo Picasso, and Franklin D. Roosevelt—the world would have been a very different place had these individuals not had the benefit of resuscitation, rudimentary as it was. Remember, there were no board-certified neonatologists until the mid-1970s.

James Blundell (1790-1878), a Scottish obstetrician, used a “silver tracheal pipe” that had a blunt distal end with two side holes. He would slide his fingers over the tongue to feel the epiglottis and guide the tube into the trachea. Blundell would blow air into the tube approximately 30 times per minute to ventilate the baby.

Term gestation, crying or breathing, and good muscle tone are three useful characteristics identifying infants who do not require resuscitation.

A regular sequence of events occurs when an infant becomes hypoxemic and acidemic. Initially, gasping respiratory efforts increase in depth and frequency for up to 3 minutes, followed by approximately 1 minute of primary apnea ( Fig. 18-2). If oxygen (along with stimulation) is provided during the apneic period, respiratory function spontaneously returns. If asphyxia continues, gasping then resumes for a variable period of time, terminating with the “last gasp” and is followed by secondary apnea. During secondary apnea the only way to restore respiratory function is with positive pressure ventilation and high concentrations of oxygen. Thus a linear relationship exists between the duration of asphyxia and the recovery of respiratory function after resuscitation. The longer that artificial ventilation is delayed after the last gasp, the longer it will take to resuscitate the infant. Clinically, however, the two conditions are indistinguishable, although an infant’s cyanosis will become progressively worse over time.

The first breath of an infant has been measured in the delivery room and is reported to be between −30 and −140 cm H₂O. These pressures are needed to overcome the substantial fluid and elastic forces present in the airway at the time of delivery. As surfactant is deposited, however, subsequent breaths rapidly decrease to −4 to −10 cm H₂O. If surfactant is decreased, as is the case in RDS, the baby must continue to exert the original very high effort to continue to inflate the lung. With limited energy reserves this effort soon deteriorates, and respiratory failure ensues.

Studies support both routes of intubation for newborn infants. The oral intubation school argues that because neonates are obligate nose breathers, they will demonstrate increased work of breathing and atelectasis after removal of nasotracheal tubes. On the other hand, nasal intubation proponents assert that orotracheal intubation results in grooving of the palate with subsequent orthodontic problems. Nasal tubes, however, have been associated with injury to the nasal cartilage. Therefore operator skill and institutional tradition are primary considerations in this clinical decision. After extubation, however, there does appear to be a higher incidence of atelectasis with nasal ET tubes. ⁷³

Transitional Physiology and the Asphyxiated Fetus

The correct answer is (C), metabolic acidosis. “Asphyxia” has become a controversial term because difficult deliveries of babies have resulted in so much litigation. The term asphyxia often is used inappropriately to describe infants who experience transient depression or delayed transition, much to the dismay of obstetricians, because of the medicolegal problems associated with birth asphyxia. In general, it is better not to label infants as “asphyxiated,” but simply to describe numerically the metabolic derangements in the blood gases that are present after birth.

Tricuspid regurgitation is the most likely source of the murmur. Tricuspid regurgitation is due to increased pulmonary pressure and the backflow of blood into the right atrium. Although two fetal channels often remain open in this situation of transitional circulation (i.e., the foramen ovale and the ductus arteriosus), the source of heart murmurs is most likely from the associated tricuspid regurgitation.

A neonate who has had hypoxia proximal to delivery that was sufficiently severe to result in hypoxic-ischemic encephalopathy should show evidence of all of the following:

True. The etiology of mental retardation and seizures is not known in most cases.

Dr. Little was an orthopedic surgeon. He saw children with the spasticity and mobility problems associated with CP. Only in the past two decades has it been recognized that only 4% to 10% of CP can be attributed to intrapartum events. That understanding has not, however, prevented the initiation of litigation in many cases of CP, even when no obstetric or neonatal malpractice exists.

Sigmund Freud. Although he is most famous for his work in psychiatry, Freud was a prominent neurologist who made many astute observations in the field.

False. Electronic fetal monitoring has not been shown to be any better than intermittent auscultation of the fetal heart rate. There are no well-controlled trials that show any decline in deaths or CP rates that can be attributed to electronic fetal heart rate monitoring. Although the use of fetal heart rate monitoring has become a standard practice, its prognostic value is currently unclear.

If arterial blood gases were taken from a fetus, the PaO₂ (arterial PO₂) would be in the range of 25 to 35 mm Hg. Although seemingly low, the strong affinity of fetal hemoglobin for oxygen results in a highly saturated blood that is sufficient to meet the metabolic needs of the fetus. There is, however, little additional room for the PO₂ to decrease, and the fetus whose oxygen level begins to decrease even a small amount may develop problems quickly.

No. Fetal distress often manifests as nonreassuring fetal heart rate patterns, meconium staining of the amniotic fluid, or a low 1-minute Apgar score. None of these has any predictive value for long-term neurologic outcome. However, the presence of signs of fetal distress is a good predictor of the need for resuscitation after delivery.

Shorter and less severe periods of asphyxia often reverse spontaneously and may not lead to any long-term damage unless they occur repeatedly. However, complete failure of gas exchange can cause death in as little as 10 minutes.

The outcome of infants with asphyxia depends on several factors:

The significance of ischemia, in particular, cannot be overstated. Unless circulation is restored, the administration of oxygen will not be effective, and acidemia will increase. The ABCs of resuscitation—airway, breathing, and circulation—remain the key to successful outcome in resuscitation.

Virginia Apgar, an anesthesiologist at Columbia Presbyterian Medical Center in New York City, introduced the Apgar scoring system in 1953 to assess newborn infants’ responses to the stress of labor and delivery.

Apgar scores are useful for assessing and describing the condition of neonates after birth and their subsequent transition to an extrauterine state ( Table 18-2). The Apgar scores are generally obtained and totaled at 1 minute and 5 minutes after birth; however, scores should be recorded for longer periods (at 10, 15, and even 20 minutes) if they are low (until the score is ≥7). Low Apgar scores are useful in identifying neonates who are depressed, and the change in score at 1 minute, 5 minutes, and subsequent time intervals is often helpful in assessing the efficacy of resuscitation. Low Apgar scores (<3) that persist beyond 5 minutes have a better correlation with a poor long-term outcome than Apgar scores at 1 minute. ¹¹

The mortality among severely asphyxiated infants is high and can vary from 50% to 75%. Among survivors, long-term neurodevelopmental sequelae are common and occur in approximately one third of infants. Currently, there are no dependable predictors of long-term outcome. The presence and extent of neurologic abnormalities in the early postasphyxial phase and the persistence of abnormal neurologic findings at the time of discharge are the simplest and most effective predictors of long-term outcome. One measure of the severity of early neurologic dysfunction is the clinical staging system developed by Sarnat. Infants with Sarnat stage I encephalopathy are the ones who have mild asphyxia and recover without any significant neurologic sequelae. However, among infants with Sarnat stages II and III encephalopathy, the incidence of long-term neurodevelopmental handicaps can range anywhere from 50% to 100%. In one study of infants who had no detectable heart rate at birth and at 1 minute of age, two thirds died before discharge and 33% of the survivors had severe neurologic handicaps ( Table 18-3).

Younger animals have been shown to have greater resistance to hypoxic-ischemic injury than older animals. Certain areas of the brain, however, appear to be more vulnerable to injury in neonates than in adults and in preterm compared with term infants. The neonatal brain is often described as having some degree of “plasticity,” in which some areas may assume the function of other areas of the brain after injury. To what degree this phenomenon actually takes place is not known, but it may explain why prediction of outcome after neurologic injury in neonates is so fraught with error.

In preterm infants who survive with hypoxic-ischemic injury, periventricular leukomalacia is the most common (and most devastating) neuropathologic lesion. A large percentage of infants with periventricular leukomalacia develop spastic diplegia later in life. In term infants patterns of neuropathologic injury commonly seen are “watershed infarcts” and diffuse cortical necrosis. These infants are at high risk for developing spastic monoplegia, hemiplegia, or quadriplegia.

In asphyxiated infants who have been successfully resuscitated, the central nervous system (CNS) is the most frequently involved site (72%), followed by the kidneys (62%), heart (29%), intestines (29%), and lungs (26%). Multiple organ involvement occurs even as an asphyxiated fetus or neonate tries to redistribute blood to vital organs as a part of the “diving reflex.” Fortunately, injury to these organs (except the CNS) is not permanent, and complete recovery of function can be expected in most infants who survive. However, the presence of multiorgan failure can seriously jeopardize chances of survival in the immediate postnatal period. ¹²

Oliguria is commonly seen in asphyxiated infants and can result from one or more of the following causes:

Although recovery from acute tubular necrosis is common, acute cortical necrosis is usually fatal. Infants with asphyxiated bladder syndrome, with marked distention, usually recover within a few days, as do most infants with SIADH, unless there has been a pituitary infarct.

Until recently, the presence of hypothermia in resuscitated infants was thought to correlate with poor survival and a higher occurrence of complications. However, recent studies have shown that selective cooling of the brain in infants suspected of having severe hypoxic-ischemic brain damage can improve long-term outcome. Multicenter trials from nurseries around the world have been very promising in this regard. It appears, however, that the primary beneficiary is a child with mild to moderate perinatal asphyxia. Infants with more severe forms of injury do not appear to benefit as much. In addition to improving neurodevelopmental outcomes, cooling reduces mortality risk. Analysis of data from all 10 trials that reported mortality rates showed that infants treated with prolonged moderate hypothermia were less likely to die than those who received normal care. A total of 169 (26%) of the 660 infants treated with therapeutic hypothermia died, compared with 217 (33%) of the 660 infants who received standard care (relative risk 0.78, 95% CI 0.66 to 0.93, P=0.005), with a number needed to treat of 14 (95% CI 8 to 47). ¹³¹⁴

The outcome of depressed infants is usually determined by the degree of resuscitative efforts that are necessary. In one study infants who required chest compressions and epinephrine had the worst outcome, with up to 56% dying in the neonatal period and 21% having an intracranial hemorrhage. Other complications noted in recipients of chest compressions included seizures (18%), respiratory distress (68%), and pneumothorax (24%). ¹⁵

Very-low-birth-weight (VLBW) infants have the greatest need for resuscitation at birth, with up to two thirds of infants weighing less than 1500 g requiring some form of resuscitation. The morbidity and mortality rates in VLBW infants requiring cardiopulmonary resuscitation are inversely related to their birth weight. Recent data indicate that VLBW infants do better if they are delivered and cared for at tertiary care centers. The speed of an in-house response team to the delivery room for resuscitation unquestionably is a great advantage of the tertiary care center compared with a community hospital.

Immediate bag-and-mask ventilation is contraindicated when there is thick meconium in the hypopharynx and trachea or if a congenital diaphragmatic hernia is known or suspected. In all instances, however, the resuscitator must weigh the advantages of bag-and-mask therapy with the risks. At times, immediate intubation for suctioning or to avoid abdominal distention may be required.

Make sure the oxygen source is turned on to the bag apparatus (“The heart and lungs can’t run if there’s no gas”).

In a depressed infant with gasping or absent respirations, 100% oxygen should be given by positive pressure ventilation. Depending on the extent of asphyxia (and depression of heart rate), cardiac compressions are usually initiated within 30 seconds. If there is no response (i.e., increased heart rate) after at least 30 seconds of positive pressure ventilation with 100% oxygen and chest compressions, epinephrine is indicated. As Kattwinkel et al. explain, “The recommended IV dose is 0.01 to 0.03 mg/kg per dose. Higher IV doses are not recommended because animal and pediatric studies show exaggerated hypertension, decreased myocardial function, and worse neurologic function after administration of IV doses in the range of 0.1 mg/kg. If the endotracheal route is used, doses of 0.01 or 0.03 mg/kg will likely be ineffective. Therefore, IV administration of 0.01 to 0.03 mg/kg per dose (0.1-0.3 mL of the 1:10,000 solution), is the preferred route.” ¹⁶

Unless ventilation is adequate, the carbon dioxide produced by the buffering reaction will not be eliminated and will act as a weak acid, further reducing the pH (“closed flask” phenomenon). It is therefore inappropriate and even dangerous to give bicarbonate until ventilation has been established and is found to be adequate.

The relative risks of sodium bicarbonate therapy in infants are related to dosage (higher > lower), rapidity of administration (faster > slower), and osmolality (higher > lower). Physiologic complications include a transient increase in PaCO₂ and fall in arterial PO₂. The sudden expansion of blood volume and increase in cerebral blood flow may increase the risk of periventricular and intraventricular hemorrhage in preterm infants. Other potential complications include the development of hypernatremia and metabolic alkalosis. For these reasons sodium bicarbonate is not recommended as a routine part of the Neonatal Resuscitation Program (NRP).

Generally, it is safest to correct half the base deficit initially and then reassess acid–base status to determine whether further correction is necessary. Administration of bicarbonate to improve acidosis will often expand the circulation and provide additional acid washout, reducing the need for further therapy. Under optimal circumstances, sodium bicarbonate should be infused in small doses over 10 to 20 minutes as a dilute solution (0.5 mEq/mL). It is sometimes not possible to take that much time to administer bicarbonate.

Naloxone has a history of being remarkably free of adverse effects, except for the possible precipitation of sudden drug withdrawal in infants born to drug-addicted mothers. Other reported side effects relate to the sudden release of catecholamines, which can cause hypertension, sudden cardiac arrest, and cardiac dysrhythmias. It is important to remember that the half-life of naloxone is significantly shorter than that of opioids. As a result, new guidelines from NRP are as follows: “Administration of naloxone is not recommended as part of initial resuscitative efforts in the delivery room for newborns with respiratory depression. Heart rate and oxygenation should be restored by supporting ventilation.”

Heart rate is the main variable through which an infant can increase cardiac output. A baby cannot significantly change stroke volume. Bradycardia will therefore significantly reduce a newborn’s cardiac output.

NRP 2010 states that “chest compressions are indicated for a heart rate that is less than 60 per minute despite adequate ventilation with supplementary oxygen for 30 seconds. Because ventilation is the most effective action in neonatal resuscitation and because chest compressions are likely to compete with effective ventilation, rescuers should ensure that assisted ventilation is being delivered optimally before starting chest compressions. Compressions should be delivered on the lower third of the sternum to a depth of approximately one third of the anterior-posterior diameter of the chest. Two techniques have been described: compression with 2 thumbs with fingers encircling the chest and supporting the back (the 2 thumb–encircling hands technique) or compression with 2 fingers with a second hand supporting the back. Because the 2 thumb–encircling hands technique may generate higher peak systolic and coronary perfusion pressure than the 2-finger technique, 76–80, the 2 thumb–encircling hands technique is recommended for performing chest compressions in newly born infants.” ¹⁷

An umbilical venous catheter (UVC) can be placed quickly by trimming the umbilicus to approximately 0.5 to 1 cm in length and inserting the catheter just far enough to obtain blood flow (usually about 3 to 5 cm in term infants). All medications (including vasopressor agents) and fluids can be given through this line. This source of access is often available for many days after birth with appropriate preparation of the cord. The catheter, however, should not be left in this position for a prolonged period of time. If the field has remained sterile (a not terribly common situation in the haste of resuscitation), the catheter should soon be advanced into the inferior vena cava, just below the level of the right atrium. A chest radiograph should be obtained to determine the position. If the catheter has been contaminated, it should be replaced after sterile preparation of the field.

If the heart rate remains below 60 beats per minute despite adequate ventilation with 100% oxygen and chest compressions, administration of epinephrine or volume expansion (or both) may be indicated. Rarely, buffers, narcotic antagonists, or vasopressors may be useful after resuscitation; they are not recommended in the delivery room. The recommended IV dose of epinephrine is 0.01 to 0.03 mg/kg per dose. Higher doses are not recommended.

“Volume expansion should be considered when blood loss is known or suspected (pale skin, poor perfusion, weak pulse) and the baby’s heart rate has not responded adequately to other resuscitative measures. An isotonic crystalloid solution or blood is recommended for volume expansion in the delivery room. The recommended dose is 10 mL/kg, which may need to be repeated. When resuscitating premature infants, care should be taken to avoid giving volume expanders rapidly, because rapid infusions of large volumes have been associated with intraventricular hemorrhage.” ⁷²

Hypoglycemia can be very damaging to the developing nervous system. It can result when hepatic glycogen stores are depleted as a result of stress. A blood glucose level below 40 mg/dL warrants treatment. The clinician should infuse 10% dextrose in water at a dose of 2 mL/kg over 10 to 15 minutes in an attempt to correct hypoglycemia. The target glucose concentration is greater than 45 to 50 mg/dL before each feeding. It is not necessary to use higher concentrations of glucose (e.g., D₂₅W) in such circumstances. After the hypoglycemia has been corrected, normoglycemia can usually be maintained by an infusion rate of 5 to 8 mg/kg/min. In some circumstances hypoglycemia may not be corrected until the infusion rate is 8 to 12 mg/kg/min. Infants receiving levels this high who continue to demonstrate hypoglycemia may have an islet cell adenoma of the pancreas that is producing hyperinsulinemia. ¹⁹

The immediate response to acute blood loss is vasoconstriction to maintain blood pressure. The blood that has been lost contains the same percentage of red blood cells as the blood that is retained. The hematocrit will not drop until fluid repletion of the intravascular volume occurs.

These clinical signs are pulse rate and quality, capillary refill time, and urine output.

No precise answer is possible because clinical circumstances and responses are variable. However, in one study of 58 newborns with an Apgar score of 0 at 10 minutes despite appropriate resuscitative efforts, only 1 of 58 survived, and that infant had profound CP. Studies of therapeutic hypothermia, however, show that initiaton of cooling within 6 hours improves outcomes. According to NRP guidelines (see first reference below), “In a newly born baby with no detectable heart rate, it is appropriate to consider stopping resuscitation if the heart rate remains undetectable for 10 minutes. The decision to continue resuscitation efforts beyond 10 minutes with no heart rate should take into consideration factors such as the presumed etiology of the arrest, the gestation of the baby, the presence or absence of complications, the potential role of therapeutic hypothermia, and the parents’ previously expressed feelings about acceptable risk of morbidity.”

Prolonged resuscitation has a very high risk of ischemic injury to the brain, resulting in cystic encephalomalacia, CP, severe microcephaly, and developmental delay. Failure of response after more than 10 to 15 minutes should prompt the clinician to consider cessation of therapy, as difficult as that always is to do. ²⁰²¹²²

Radiology of Pulmonary Disorders of the Neonate

There are two major schools of thought on this subject. For many years the preferred position was between the third and fourth lumbar vertebrae, as projected on an AP radiograph. The tip lies below the take-off points for the renal and mesenteric arteries, theoretically reducing the risk of injecting fluids or drugs directly into those vessels. With this catheter placement, however, it has been shown that even with relatively low pressure, injectable material can ascend retrograde into the aorta for quite some distance. Other neonatologists prefer a higher placement, in the thoracic aorta at approximately T10 to T12, again avoiding placement of the catheter near the major tributaries off of the descending aorta. Positioning the tip there, however, means that anything injected will flow past major vessels. Several papers have argued for one placement instead of the other, but both are probably safe as long as the clinician takes the following precautions:

Umbilical catheters may be left in place for many days as long as the aforementioned conditions are satisfactorily met. The typical goal is to remove umbilical lines within 7 days of birth. In extreme cases a catheter can be kept in place for 3 weeks without complication. One of the most common errors that is made in neonatal medicine, however, is to leave a catheter in place that is no longer necessary. Because it is not needed, the catheter is often not checked religiously and the risk of complications rises dramatically.

The UVC should be kept at the lower margin of the cardiac silhouette, approximately at the level of the right diaphragm, which would correspond to the junction of the inferior vena cava and right atrium of the heart. UVCs should not be allowed to remain below this level or within any of the branches of the portal system of the liver. Infusion of calcium or hyperalimentation into catheters in these incorrect positions may lead to liver toxicity, portal necrosis, cirrhosis, and cavernous transformation of the portal vein. Umbilical venous lines may also inadvertently cross the foramen ovale and enter the left side of the heart if inserted too far. Catheters in this location occasionally cause rhythm disturbances of the heart. This incorrect placement can be detected by the high levels of PO₂ obtained on a venous sample of blood. A single AP film can be misleading because the left atrium is posterior to the right atrium. Line placement may appear to be appropriate because the AP film does not demostrate how far posterior the line is placed. Lateral films of the chest and abdomen and echocardiograms can be used to confirm appropriate placement.

The optimal position for an ET tube is approximately halfway between the thoracic inlet (look for the medial ends of the baby’s clavicles to get a good approximation) and the carina or level of tracheal bifurcation. In small neonates ET tubes often enter the right mainstem bronchus and produce left-sided atelectasis. They may also exert vagal effects and cause bradycardia or irritation if they strike the carina. Tubes that are excessively high also may produce vagal effects and loss of effective ventilation.

The classic RDS picture in a premature neonate has a diffuse increase in lung density (opacity) with a fine, reticulogranular (grainy) or ground-glass appearance, air bronchograms (a darker appearance to the branching central airway in contrast to the opacity of the lungs), and low lung volumes ( Fig. 18-4).

GBS pneumonia in a premature infant is reported to have an appearance similar to that of RDS. However, premature babies with GBS disease may also have surfactant inactivation or deficiency with true RDS as well as GBS septicemia. Although Sir William Osler might not like the concept of two diagnoses in one little patient, it probably happens more often than not.

Affected babies often have a coarse, irregular increase in lung markings accompanied by hyperinflation of the lungs. The pneumonic process here is one of patchy atelectasis and overdistention ( Fig. 18-5). Pneumomediastinum and pneumothorax are frequent accompanying abnormalities as well.

The textbook description of this clinical condition is a hazy-appearing lung, often with fluid in the right horizontal fissure and increased perihilar markings. The babies have rapid, shallow breathing, in contrast to the retractions of RDS or MAS. It usually is reported to last approximately 24 hours, with 48 to 72 hours considered the maximum. Some infants, however, seem to have this clinical problem for many more days, with subsequent uneventful recovery. What turns off fetal lung fluid production at birth has not been established. One theory is that certain babies may continue to produce a low level of lung fluid for some time after they are born.

A patient with congenital diaphragmatic hernia rarely presents at birth as the diagnostic dilemma in the delivery room, as once was the case. With fetal ultrasound most of these infants are diagnosed before birth. Radiographically, they have a complex pattern of lucency in one hemithorax (usually the left side, and reflecting air-containing loops of intestine), contralateral shift of the heart and other mediastinal structures, and a lack of expected air-containing intestine in the abdomen.

Early air leaks are often difficult to diagnose. The most obvious finding is a separation of the edge or margin of the lung from the inner margin of the chest wall, with no lung markings definable in that space. An AP decubitus view of the chest with the side of suspected pneumothorax to the top (nondependent) is also helpful. For example, if you suspect a left-sided pneumothorax, you should order a “right decubitus AP chest radiograph,” which means the right side of the patient will be dependent and the left side nondependent. If a pneumothorax is present, look for a zone of lucency representing pleural air collecting between the lateral chest margin and the adjacent lung ( Fig. 18-6).

Respiratory Distress Syndrome

The small one collapses more quickly because of surface tension. The LaPlace relationship states P = 2T/R, where P is the pressure across the wall of the sphere, T is surface tension of the substance forming the bubble (i.e., its tendency to collapse), and R is the radius of the sphere. The smaller the radius, the greater the collapsing pressure ( Fig. 18-7).

When the bubbles are alveoli without surfactant, pressure on the alveolar surface is quite high because the surface tension is high. As the alveolus collapses without surfactant during exhalation, pressure increases as the radius of the alveolus decreases.

Avery and Mead described the absence of a surface tension–reducing substance in the alveolar fluid of infants who died of hyaline membrane disease. The substance turned out to be the complex substance known as surfactant, which greatly lowers the alveolar surface tension and therefore the tendency of the alveolus to collapse. Surfactant also lowers surface tension as the diameter of the alveolus decreases, allowing for stable alveoli at end-expiratory volumes.

Within minutes after delivery, pulmonary artery pressure falls, and blood flow increases in response to birth-related stimuli, such as ventilation, increased PO₂, and shear stress. Physical stimuli, including increased shear stress, lung inflation, ventilation, and increased oxygen, cause pulmonary vasodilation in part by increasing production of vasodilators, nitric oxide, and prostacyclin. Pretreatment with the nitric oxide synthase inhibitor, nitro-L-arginine, attenuates pulmonary vasodilation after delivery by 50% in near-term fetal lambs. These findings suggest that a significant part of the rise in pulmonary blood flow at birth may be related directly to the acute release of nitric oxide. Each of the birth-related stimuli can stimulate nitric oxide release independently, followed by vasodilation through cyclic guanosine monophosphate kinase–mediated stimulation of K channels. Although the endothelial isoform of nitric oxide synthase III has been presumed to be the major contributor of nitric oxide at birth, recent studies suggest that other isoforms (neuronal type I and inducible type II) may be important sources of nitric oxide release in utero and at birth. Other vasodilators, especially prostacyclin, also modulate changes in pulmonary vascular tone. Rhythmic lung distention and shear stress stimulate both prostacyclin and nitric oxide production in late gestation. Increasing oxygen tension also triggers nitric oxide activity and overcomes the effects of prostacyclin inhibition at birth. Thus, although nitric oxide does not account for the entire fall in pulmonary vascular resistance at birth, nitric oxide synthase activity appears important in achieving postnatal adaptation of lung circulation.

More recently, vasculoendothelial growth factor (VEGF), which is really a family of growth factors, and angiopoietins 1 through 4 have been also shown to have important angiogenic roles during fetal development of the pulmonary vascular bed. These agents also appear to be closely related to the release and influence of nitric oxide in pulmonary development and vasodilation. Additional proteins have been elaborated that may play critical roles in this entire process, demonstrating the increasing complexity of our understanding of neonatal lung development. ²³

Surfactant, from “surface active material,” is 80% phospholipids and 8% neutral lipids. The phospholipid most responsible for surface tension reduction is dipalmitoylphosphatidylcholine. About 12% of surfactant is protein, half of which most likely comprises serum contaminants. Surfactant proteins A, B, C, and D (SP-A, SP-B, SP-C, SP-D) are active in surfactant’s surface tension reduction, secretion, absorption, and immune function. SP-A works with other proteins and lipids to improve surface actions and regulate secretion and reuptake. It also works with host defense in the alveolus. Lipophilic SP-B and SP-C facilitate adsorption and spread of lipid across the alveolar surface. SP-D is known to be a ligand for pathogens.

Surfactant is made in alveolar type II cells. The endoplasmic reticulum and Golgi apparatus package the lipid and protein precursors. Lamellar bodies are formed, including more protein with increasing gestational age. Catecholamines, corticosteroids, and other hormones stimulate the type II cells to secrete lamellar bodies. These unravel to form tubular myelin. Tubular myelin then adsorbs as a lipid-protein monolayer on the alveolar surface, giving maximum surface support to the alveolus. The interaction between intact protein and phospholipid allows optimal surfactant functioning.

Surfactant is inactivated in the alveolar space without large changes in amounts of its components. The monolayer does break down as protein and lipid dissociate. Surfactant changes to a small aggregate form that minimally reduces surface tension. These aggregates are then absorbed by macrophages and type II cells, which recycle lipid and protein components. ²⁴