In the last several decades, the incidence of prematurity in the United States has risen to 11.5%. Maternal risk factors for prematurity include absence of prenatal care, low socioeconomic status, tobacco abuse, poor nutrition and genitourinary tract infections, to name only a few. Despite a relative increase in prematurity, perinatal mortality rates have decreased to approximately 6 in every 1000 live births. Late-preterm births, defined as delivery at 34 to 36 weeks’ gestation, have significantly increased over the last 15 years. This may partly explain both the rise in the incidence of prematurity and the decrease in perinatal mortality.
Despite improvements, prematurity remains an independent risk factor for increased morbidity and mortality during infancy and childhood. Singleton infants born between 34 and 36 completed weeks’ gestation have a three-fold risk for dying in the first year of life compared with term infants. Those born between 32 and 33 completed weeks of gestation have an almost seven-fold risk for dying in the first year of life. The extremely premature infants remain at high risk for chronic morbidity with a rate of 20% to 50%, which contributes heavily to learning and motor disabilities. Prematurity-related disabilities account for about 50% of all childhood disabilities.
Definitions
It is useful to review some common definitions. The premature infant is often defined as a viable newborn delivered after the 20th completed week of gestation and before full term, with an arbitrary weight of 500 to 2499 g at birth. The preterm infant is born at any time before the 37th completed week (259 days) of gestation (although most clinicians usually consider infants born any time in the 37th week to be full term). Preterm can be further subclassified into late preterm (34–36 weeks’ gestation), moderate preterm (32–34 weeks’ gestation), very preterm (28–32 weeks’ gestation), and extremely preterm (less than 28 weeks’ gestation). Low birth weight (LBW) is defined as less than 2500 g at birth. Very low birth weight (VLBW) is defined as less than 1500 g at birth. Extremely low birth weight (ELBW) is defined as less than 1000 g at birth.
Although the severity of the medical problems described in this chapter is directly correlated with decreasing gestational age, there is a growing recognition that the late preterm (LP) infants have associated risks. LP infants make up 74% of all preterm births and 8% to 9% of total births. The last 6 weeks of gestation are a critical period for neural and respiratory development. LP infants also have an increased risk for the need for resuscitation at birth, feeding difficulty, jaundice, hypoglycemia, temperature instability, apnea and respiratory distress. The mortality rate during infancy is tripled compared with full-term infants. LP infants are more vulnerable to brain injuries and have a tripled risk for developing cerebral palsy, adverse developmental outcomes and academic difficulties up to 7 years of age.
Respiratory Distress Syndrome
Premature infants are born with a deficiency of alveolar type 2 pneumocytes, which are responsible for surfactant production. Surfactant is mainly comprised of phosphatidylcholine, which lowers surface tension inside the alveoli, thus preventing alveolar collapse. Type 2 pneumocytes begin to appear in the fetus by the 22nd week of gestation, and surfactant is primarily produced during the second trimester of pregnancy. Fifty percent of surfactant is produced by the 28th week of gestation, and production is usually complete by 36 weeks.
Surfactant deficiency is associated with a clinical syndrome of pulmonary insufficiency known as respiratory distress syndrome (RDS), formerly termed hyaline membrane disease (HMD). The incidence and severity of RDS is inversely correlated with gestational age; it affects approximately one-half of infants born between 26 to 28 weeks’ gestation and 30% of infants born at 30 to 31 weeks’ gestation, and is infrequent in infants born after the 35th week of gestation. RDS contributes to a large portion of premature deaths. Approximately 50% of premature infant deaths from the age of 12 hours to 14 days can be attributed in part to RDS. Just over 40% of premature deaths in the first month of life can be attributed to complications of RDS. Conditions that decrease surfactant production and increase the incidence of RDS include perinatal asphyxia, maternal diabetes, multiple pregnancies, cesarean section delivery, precipitous delivery, cold stress and a history of affected siblings. Prenatal factors that increase fetal stress and, therefore, increase surfactant production and lower the risk for RDS include pregnancy-associated hypertension, maternal opiate addiction, prolonged rupture of the membranes and antenatal administration of corticosteroids.
Absence or deficiency of surfactant leads to widespread atelectasis, decreased lung compliance, and loss of functional residual capacity (FRC). This correlates with the clinical manifestations of RDS that usually appear shortly after birth and include tachypnea, nasal flaring, audible grunting, chest wall retractions, and use of accessory muscles of respiration. Severely affected infants with substantial ventilation-to-perfusion mismatch will demonstrate cyanosis and respiratory failure. Blood gas analysis will usually reveal hypoxemia, hypercarbia, and metabolic acidosis. The classic finding on chest radiography in infants with RDS is a bilateral diffuse ground-glass appearance and multiple air bronchograms. On occasion, these radiographic findings may not develop until the second day of life.
Treatment of RDS initially includes supplemental oxygen to achieve a target PaO 2 between 55 and 70 mm Hg. Ideal oxygen targets are still unknown, but an oxygen saturation of 90% to 94% is typically the goal in most institutions. Oxygen therapy is a balance between too much (hyperoxia can lead to increase incidence of retinopathy of prematurity) or not quite enough (hypoxia can lead to increased incidence of necrotizing enterocolitis and higher mortality risk). The optimal first mode of respiratory support for suspected RDS is continuous positive-pressure support, often delivered as nasal CPAP. Ideally, the oxygen should be heated and humidified and the pressures delivered, measured, and controlled. CPAP, between 6 to 9 cm H 2 O, with early administration of surfactant is considered optimal management of RDS. In prematurely born infants at risk for developing RDS, artificial surfactant is administered into the lungs via an endotracheal tube shortly after delivery. More recently, less invasive means of delivery have made it possible to avoid intubation up front and potentially altogether. A small catheter advanced into the trachea while the child spontaneously ventilates, with CPAP support, is used to deliver surfactant directly into the trachea. Studies have shown that this less invasive method is just as beneficial as endotracheal administration but may have an indirect benefit considering intubation can potentially be avoided. Nebulized surfactant and pharyngeal deposition of surfactant are even less invasive means of administration which are currently under investigation.
If RDS is suspected at birth, the child is placed initially on CPAP. A high-flow nasal cannula has been shown to be inferior to CPAP because most infants often require escalation to CPAP as a rescue therapy. Any sign of worsening oxygen requirements is indication for artificial surfactant therapy. Early administration of surfactant using a low treatment threshold (Fio 2 <0.45) is preferable to selective surfactant therapy at a higher threshold (Fio 2 >0.45) and results in less pulmonary air leak, chronic lung disease, and decreased need for mechanical ventilation in the first week of life. Instituting mechanical ventilation is indicated if the infant on CPAP cannot maintain an arterial oxygen tension above 50 mm Hg while breathing inspired concentrations of oxygen up to 100%. Additional indications for mechanical ventilation include persistent pH less than 7.2, and central apnea that is unresponsive to pharmacologic therapy.
Because oxygen toxicity and pulmonary barotrauma/volutrauma are thought to be responsible for the development of neonatal chronic lung disease, the goals of mechanical ventilation in the infant with RDS are to achieve relative normoxemia (PaO 2 >50 mm Hg), mild (permissive) hypercapnia (PaCO 2 in the range 40–65 mm Hg), and a normal pH (>7.2), depending on the infant’s clinical status, while minimizing the concentration of inspired oxygen and the level of artificially maintained lung pressures. A modest amount of positive end-expiratory pressure (PEEP) may be used (3–5 cm H 2 O) and ventilatory settings are weaned aggressively as the infant improves.
The majority of infants with RDS who require mechanical ventilation are placed on conventional ventilators that deliver continuous breathing cycles, usually at a rate between 30 and 50 breaths/min. Some studies suggest synchronous intermittent mandatory ventilation may shorten the duration of intubation and decrease oxygen requirements compared with conventional ventilation. Infants who are unresponsive to conventional ventilation may be switched to high frequency jet ventilation (HFJV), which can attain respiratory rates of 150 to 600 breaths/min, or an oscillating type ventilator that can deliver 300 to 1800 breaths/min. The main advantage of these unconventional ventilators is the ability to decrease mean airway pressure and tidal volumes while maintaining the ability to oxygenate and eliminate carbon dioxide.
Some methods used to decrease duration of mechanical ventilation include caffeine therapy and postnatal steroids in the form or systemic or inhaled corticosteroids. Additional doses of surfactant can be administered at regular intervals if respiratory distress persists and may also result in less RDS-related morbidity and mortality. Extremely premature neonates administered surfactant in the delivery room may have improvement in short-term outcomes and milder bronchopulmonary dysplasia (BPD). Some have recommended the prophylactic use of surfactant after resuscitation in extremely premature neonates to further protect the immature lung (<27 weeks’ gestation).
Intraoperative Ventilator Management
In infants with RDS, intraoperative ventilator management using the anesthesia machine can be challenging. Attempts to duplicate preoperative settings often result in hypoxemia and/or hypercarbia. This is partly because of differences in ventilatory equipment, anesthetic-related changes in chest wall and lung compliance, and surgical conditions that affect the efficiency of ventilation. The primary goal of intraoperative ventilation in premature infants is avoidance of hypoxemia (PaO 2 <60 mm Hg, or SpO 2 <90%). Secondary goals include avoidance of a high inspired oxygen concentration and high mean airway pressures.
Volume targeted ventilation (VTV), starting at volumes of 5 mL/kg, prevents lung overdistension and ensures less variable tidal volumes. Traditionally, pressure-limited ventilation has been used in neonates because it is protective against higher peak inspiratory pressures (PIP) and complications such as pneumothorax. However, VTV allows for automatic weaning of PIP in real time as compliance improves and compared with pressure limited ventilation, benefits of VTV include less mechanical ventilation time, less incidence of BPD, and fewer air leaks. During abdominal or thoracic surgery, where lung and chest wall compliance are changing minute by minute, experienced pediatric anesthesiologists with an “educated hand” will manually ventilate the infant and constantly adjust inspiratory pressures while maintaining adequate volumes, viewing the operative field and “feeling” changes in compliance.
PEEP is often used in infants with RDS to maintain alveolar patency, increase and stabilize FRC, and decrease ventilation-perfusion mismatch. Preoperative levels of PEEP should be maintained intraoperatively. Increasing PEEP may increase PaO 2 but may also increase PaCO 2 (secondary to decreased tidal volume) and interfere with venous return, which affects cardiac output in very small infants. In infants with RDS, excess PEEP may also have a deleterious effect on lung compliance. The optimal PEEP is that at which FiO 2 is low with acceptable blood gases and hemodynamic stability.
In general, respiratory rates between 30 and 50 breaths/min are adequate for small infants with RDS. Increasing the respiratory rate will increase alveolar ventilation and decrease PaCO 2 without affecting PaO 2 if the inspiratory/expiratory ratio remains the same.
Inspiratory-to-expiratory (I/E) ratios in infants with RDS range from 1:1 to 1:3. Increasing the inspiratory component will facilitate opening of atelectatic areas, with a resultant increase in PaO 2 . However, increasing the inspiratory time may substantially increase mean airway pressure, with the potential for barotrauma. Furthermore, a shortened expiratory time may cause air trapping and predispose to interstitial emphysema and pneumothorax. Carbon dioxide elimination is not usually affected by changing the I/E ratio.
Outcome of RDS
In most cases, the severity of RDS reaches a peak in 3 to 5 days and is followed by a gradual improvement, provided the infant is not burdened by additional medical problems. In severe cases, ventilatory therapy may be associated with the development of interstitial emphysema, pneumothorax, pulmonary hemorrhage and death. Infants who survive severe RDS are likely to develop neonatal chronic lung disease or bronchopulmonary dysplasia.
Apnea of Prematurity
Apnea is commonly defined as a cessation of breathing for greater than 20 seconds or less if accompanied by bradycardia (heart rate 30 beats/min less than baseline) or hypoxemia (SpO2<90%), cyanosis or pallor. Apnea is extremely common in premature infants, with an incidence that increases with decreasing gestational age. Essentially, all extremely premature infants have apnea of prematurity. Up to 25% of neonates with birth weights of less than 2500 g and up to 84% of infants with birth weights less than 1000 g exhibit some form of apnea. Approximately 50% of infants with birth weights less than 1500 g experience apnea that must be managed pharmacologically or by ventilatory support. Apnea of prematurity usually resolves by the 52nd week after conception. The correlation between apnea and gestational age has implications for both the NICU and postanesthesia care. Generally, all premature infants born less than 35 weeks gestational age will require monitoring in the NICU because of their increased risk for having apneic events, potentially associated with bradycardia. Similarly, because formerly premature infants may develop apnea after stressful events such as general anesthesia, most hospitals and institutions have a policy for admission for cardiorespiratory monitoring of formerly premature infants postanesthesia depending on their gestational age.
Apnea is classified as central (lack of respiratory effort) or obstructive (lack of airflow in the presence of respiratory effort). Most apneic events in prematurely born infants are mixed (some combination of central and obstructive apnea).
Apnea of prematurity is likely caused by neuronal immaturity of the respiratory control center in the brainstem and the peripheral chemoreceptors. Vital organ blood flow decreases significantly during bradycardic events in these infants. However, the association of apnea of prematurity with long-term neurodevelopmental outcomes is not clearly defined. Limited studies indicate that persistent apnea resolving up to or after 36 weeks postmenstrual age may be associated with higher rate of worse neurodevelopmental outcomes; however, it is difficult to distinguish whether the outcomes are caused by apnea or other prematurity-related comorbidities.
Acute episodes of apnea are treated initially with tactile stimulation and simple airway maneuvers to relieve upper airway obstruction (e.g., chin lift or jaw thrust). Bag-mask positive pressure breathing is required if breathing does not resume spontaneously or if hypoxemia continues. Infants with recurrent apneic episodes are placed on prophylactic stimulant therapy consisting of methylxanthines (i.e., caffeine and aminophylline). Nasal CPAP is often used in combination with methylxanthines and is effective in decreasing the severity and number of apneic episodes. It works by maintaining airway patency and decreasing risk for obstruction. Mechanical ventilation is used as a last resort in infants who continue to demonstrate life-threatening apneic events despite pharmacologic therapy. Anemia has been thought to contribute to apnea of prematurity based on a decreased oxygen carrying capacity in anemic infants. Blood transfusions have shown to decrease the number of apneic episodes; however, only short-term effects have been noted, and further studies for long term effects are required.
Patent Ductus Arteriosus
A patent ductus arteriosus (PDA) is a common finding in preterm infants with respiratory disease. In normal newborns, the ductus arteriosus closes within the first few days of life and is functionally closed within the first 72 hours of life. This process is initiated by the normal increase in blood–oxygen tension and decreased levels of circulating maternal prostaglandins. The incidence of a PDA in premature infants is inversely related to birth weight and gestational age. Virtually all shunting through a PDA in a preterm infant is left to right, and only in larger infants is persistent pulmonary hypertension with right-to-left shunting across a PDA an issue. In premature infants, a PDA is associated with exacerbation of respiratory distress syndrome, increased oxygen requirements or prolonged need for mechanical ventilation, increased risk for developing bronchopulmonary dysplasia, cardiovascular instability, the development of intraventricular hemorrhage, renal dysfunction and oliguria, necrotizing enterocolitis, cerebral palsy and mortality .
A symptomatic PDA may be closed in the early newborn period by pharmacologic therapy using indomethacin, transcatheter occlusion or surgical ligation. Side effects of indomethacin include platelet and renal dysfunction. The American Heart Association recommends that infants with congenital heart disease repaired with prosthetic material or device should receive procedure-associated subacute bacterial endocarditis (SBE) prophylaxis for 6 months after artificial closure.
Assessing hemodynamic significance of a PDA is accomplished by physical exam, echocardiography, and serum biomarkers such as b-type natriuretic peptide (BNP) or N-terminal pro-BNP (pro-BNP). Some physical exam findings for patients with PDA include a classic, coarse systolic murmur heard at the left sternal border, prominent arterial pulses, an increased precordial impulse, decreased diastolic pressure with wide pulse pressure and/or decrease in systolic and diastolic blood pressure. Pulmonary congestion may be seen on chest x-ray. A patient with a hemodynamically significant PDA may have trouble weaning oxygen requirements or weaning from ventilator support. Hemodynamically significant PDA has been associated with lower cerebral oxygen saturation, though the long-term clinical ramifications are unclear. A more comprehensive definition of “hemodynamically significant” PDA needs to be identified.
There is ample evidence to show that routine, early assisted closure of PDA, whether medical or surgical in all preterm infants, does not necessarily improve outcomes in the long term. Whether to selectively assist closure in infants deemed high risk for development of complications is still unclear and requires more study. Knowing that prolonged patency of PDA in premature infants is a major cause of morbidity and mortality, having a way to identify those infants at risk for persistent PDA and associated complications, could potentially facilitate early treatment and prevent future morbidity.
Anemia of Prematurity
Anemia in premature infants is often more severe and protracted than the physiologic anemia of infancy. This “anemia of prematurity” refers to anemia associated with low reticulocyte count and low erythropoietin concentration in preterm infants, usually those born at less than 32 weeks gestational age. It occurs usually in the first month of life and is most commonly attributed to decreased production of erythropoietin, decreased erythrocyte production, decreased erythrocyte lifespan, and frequent blood sampling. Its incidence increases with decreasing gestational age. Up to 75% of infants weighing less than 1000 g receive a red cell transfusion at some time during their hospitalization. Anemia of prematurity has been implicated as a cause of apnea of prematurity, poor feeding, inadequate weight gain, persistent tachycardia and unexplained persistent metabolic acidosis. There has been shown to be a correlation between anemia, blood transfusions and necrotizing enterocolitis, retinopathy of prematurity and bronchopulmonary dysplasia.
Treatment options for anemia of prematurity may include transfusion of red cells, recombinant erythropoietin (EPO) and observation. Asymptomatic infants with adequate nutrition and who are not acutely ill may be followed with serial hematocrit measurements. Multiple studies have established premature infants’ response to recombinant human EPO after exogenous administration. However, there is no universal agreement regarding its safety and dosing. Additionally the question remains whether EPO therapy will eliminate the need for transfusion completely or decrease the amount of donor exposures.
Blood transfusion is the mainstay for the treatment of anemia of prematurity. Debate still exists regarding the indications for treatment. Triggering hemoglobin levels vary between centers and range between 7 and 12 g/dL, depending on the concurrent illness of the infant. Some centers administer EPO and iron to these infants. Most centers agree that the infant’s hemoglobin level should be greater than 10 g/dL before any surgical procedure. In older infants recovering from prematurity, lower hemoglobin levels (7–10 g/dL) are tolerated in the absence of symptoms and a reticulocyte count that demonstrates active production of red blood cells. In general, neonatologists tend to keep infants’ hemoglobin levels in direct relationship to their concomitant comorbidities.
Intraventricular Hemorrhage
Intraventricular hemorrhage (IVH) describes a serious condition almost exclusively seen in premature infants that involves spontaneous bleeding into and around the lateral ventricles of the brain. The bleeding originates in the subependymal germinal matrix, an area surrounding the lateral ventricles that contains fragile blood vessels in the premature brain. This fragility is no longer seen in most infants born at term.
The incidence of IVH increases with decreasing birth weight and decreasing gestational age; it occurs in up to 70% of infants with a birth weight less than 750 g, and most cases occur between birth and the third day of life. Additional predisposing factors include trauma, acidosis, anemia, RDS, hypoxic-ischemic injury, seizures, hypocarbia and use of vasopressors. Episodes of acute blood pressure fluctuation accompanied by rapid increases or decreases in cerebral blood flow, cerebral blood volume or cerebral pressure, such as might be observed during endotracheal intubation without administration of a sedative or anesthetic agent, can lead to development of IVH. Rapid infusion of a hyperosmolar solution, such as sodium bicarbonate, has also been shown experimentally to induce IVH in the premature brain. Decreased incidence or severity of IVH has been correlated with administration of antenatal glucocorticoids.
IVH is typically classified into four stages of relative severity, based on ultrasound examination of the brain. Higher grades of bleed correlate with worse clinical symptoms and neurodevelopmental outcome. Grading of IVH is shown in Table 11.1 .
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