The Premature Infant CHAPTER DEFINITIONS RESPIRATORY DISTRESS SYNDROME

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1 4206 Litman-10.qxd 1/19/04 2:33 PM Page 68 CHAPTER 10 The Premature Infant RONALD S. LITMAN, D.O. Definitions Respiratory Distress Syndrome Intraoperative Ventilator Management Outcome of RDS Apnea of Prematurity Patent Ductus Arteriosus Anemia of Prematurity Intraventricular Hemorrhage Retinopathy of Prematurity Hypoglycemia In the last several decades, the incidence of prematurity in the United States has remained relatively constant at approximately 10%. 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 relatively constant rates of prematurity, perinatal mortality rates have decreased to approximately 9 in 1000 live births, due primarily to the advent of surfactant replacement therapy. Despite improvements in morbidity and mortality, prematurity remains an independent risk factor for increased mortality during childhood. Singleton infants born between 34 and 36 completed weeks of gestation have a three-fold risk of dying in the first year of life when compared to term infants. Those born between 32 and 33 completed weeks of gestation have an almost seven-fold risk of dying in the first year of life. This chapter reviews the most common medical problems seen in premature infants.these include respiratory distress syndrome (hyaline membrane disease), apnea of prematurity, anemia of prematurity, patent ductus arteriosus, intraventricular hemorrhage, and hypoglycemia. When appropriate, anesthetic implications of these disorders will be included. DEFINITIONS It is useful to review some common definitions. The premature infant is often defined as a viable newborn delivered after the twentieth completed week of gestation, and before full term, with an arbitrary weight of g at birth. The preterm infant is born at any time before the thirty-seventh completed week (259 days) of gestation (although most clinicians usually consider infants born any time in the thirty-seventh week to be full term). Low birthweight (LBW) is defined as less than 2500 g at birth. Very low birthweight (VLBW) is defined as less than 1500 g at birth. Extremely low birthweight (ELBW) is defined as less than 1000 g at birth. 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 at about 22 weeks gestation, and surfactant is primarily produced during the second trimester of pregnancy. Fifty percent of surfactant is produced by the twenty-eighth 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 are inversely correlated with gestational age; it affects approximately one-half of infants born between 28 and 32 weeks gestation, and is rare in infants born after the 68

2 4206 Litman-10.qxd 1/19/04 2:33 PM Page 69 The Premature Infant 69 thirty-fifth week of gestation. 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 of 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) (Fig. 10-1).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 (Fig. 10-2). 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 mmhg. Although treatment regimens vary by institution, continuous positive airway pressure (CPAP), up to 10 cmh 2 O, is added if this oxygen tension cannot be achieved with inspired oxygen concentrations less than 60%. Institution of mechanical ventilation is indicated if the infant on CPAP cannot maintain an arterial oxygen tension above 50 mmhg while breathing inspired Air volume ml/gm Normal Respiratory distress syndrome Pressure cmh 2 O Figure 10-1 Compliance curves comparing the normal newborn lung with the lung of a prematurely born infant with RDS. The RDS lung requires a much greater amount of pressure per volume to achieve lung expansion. (Redrawn with permission from Klaus MH, Fanaroff AA: Care of the High Risk Neonate, 5th edn, WB Saunders, Philadelphia, 2001.) Figure 10-2 The chest radiograph of an infant with RDS demonstrates a bilateral diffuse ground glass appearance and multiple air bronchograms. 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. Since 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 mmhg) and mild (permissive) hypercapnia (PaCO 2 in the range mmhg) while minimizing the concentration of inspired oxygen and the level of artificially maintained lung pressures. A modest amount of positive end-expiratory pressure (PEEP) is used (3 5 cmh 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 per minute. Infants who are unresponsive to conventional ventilation may be switched to high-frequency jet ventilation (HFJV), which can attain respiratory rates of breaths/min, or an oscillating type ventilator which can deliver 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. In prematurely born infants at risk of developing RDS (<28 weeks gestation), artificial surfactant is administered into the lungs via the trachea shortly after delivery. Additional doses can be administered at regular intervals

3 4206 Litman-10.qxd 1/19/04 2:33 PM Page PEDIATRIC ANESTHESIA: THE REQUISITES IN ANESTHESIOLOGY if respiratory distress persists. Infants born later than 28 weeks of gestation receive surfactant therapy if they develop clinical signs of RDS. Exogenously administered surfactant has been shown to decrease RDS-related morbidity and mortality. 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 due to 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 < 50, or SpO 2 < 87%). Secondary goals include avoidance of high inspired oxygen concentration and high mean airway pressures. Pressure-limited ventilation will assure that airway obstruction does not result in peak airway pressures (PIP) that may cause pneumothorax.the right amount of PIP is that pressure that adequately provides lung expansion as evidenced by the degree of chest wall rise. This can be rapidly achieved by manually ventilating the intubated infant, and noting the PIP that is associated with adequate chest rise and maintenance of normoxemia. Unless chest wall excursions are excessive, increases in PIP can be used to treat intraoperative hypoxemia and/or hypercarbia. During abdominal or thoracic surgery, where lung and chest wall compliance are changing minute-by-minute, experienced pediatric anesthesiologists will manually ventilate the infant, and constantly adjust inspiratory pressures while viewing the operative field and feeling changes in compliance. PEEP is 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. In general, respiratory rates between 30 and 50 breaths per minute 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 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 (see Chapter 11). 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 (SpO 2 < 90%). Apnea is extremely common in premature infants, with an incidence that increases with decreasing gestational age. Up to 90% of infants with birthweights less than 1500 g exhibit some form of apnea.apnea of prematurity usually resolves by the fifty-second week following conception. 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. 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 theophylline or caffeine. Nasal CPAP treatment or mechanical ventilation is used as a last resort in infants who continue to demonstrate life-threatening apneic events despite pharmacologic therapy.

4 4206 Litman-10.qxd 1/19/04 2:33 PM Page 71 The Premature Infant 71 PATENT DUCTUS ARTERIOSUS A patent ductus arteriosus (PDA) is a common finding in preterm infants with respiratory disease (see Chapter 3). In normal newborns, the ductus arteriosus closes within the first few days 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 birthweight 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 the development of intraventricular hemorrhage, necrotizing enterocolitis, oliguria, and increased pulmonary disease. A symptomatic PDA may be closed in the early newborn period by pharmacologic therapy using indomethacin or by surgical ligation. Side-effects of indomethacin include platelet and renal dysfunction. The American Heart Association recommends that infants with a history of a PDA should receive procedure-associated subacute bacterial endocarditis (SBE) prophylaxis for 6 months following artificial closure. ANEMIA OF PREMATURITY Anemia in premature infants is often more severe and protracted than the physiologic anemia of infancy. This anemia of prematurity 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 95% 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. Treatment of anemia of prematurity is transfusion of red cells. However, there is not a universal agreement as to the proper indications for treatment.triggering hemoglobin levels vary between centers and range between 10 and 14 g/dl, depending on the concurrent illness of the infant. Some centers administer recombinant human erythropoietin (EPO) and iron to these infants. Most centers agree that the infant s hemoglobin level should be greater than 10 g/dl prior to any surgical procedure. In older infants recovering from prematurity, lower hemoglobin levels (7 10 g/dl) are tolerated in the absence of symptoms, as well as a reticulocyte count that demonstrates active production of red blood cells. Table 10-1 Grade I II III IV INTRAVENTRICULAR HEMORRHAGE Intraventricular hemorrhage (IVH) describes a 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 birthweight; it occurs in up to 70% of infants with a birthweight less than 750 g, and most cases occur between birth and the third day of life. Additional predisposing factors include RDS, hypoxic ischemic injury, and episodes of acute blood pressure fluctuation accompanied by rapid increases or decreases in cerebral blood flow, such as might be observed during endotracheal intubation without administration of a sedative or anesthetic agent. Rapid infusion of a hyperosmolar solution, such as sodium bicarbonate, has also been shown experimentally to induce IVH in the premature brain. IVH is typically classified into four stages of relative severity, based on ultrasound examination of the brain (Table 10-1). Higher grades of bleed correlate with worse clinical symptoms and neurodevelopmental outcome. Clinical manifestations of IVH include signs of abrupt neurological changes in the first several days of life, such as hypotonia, apnea, seizures, loss of the sucking reflex, and a bulging anterior fontanelle. More severe cases are manifest as unexplained anemia or hypovolemic shock. IVH into or beyond the lateral ventricles may result in an obliterative arachnoiditis that causes blockage of cerebral spinal fluid (CSF) resorption and/or blockage of CSF flow at the Aqueduct of Sylvius.This leads to a communicating hydrocephalus which often necessitates ventriculoperitoneal shunt placement early in life. Grading of IVH Based on Ultrasound Exam Severity Bleeding confined to the periventricular germinal matrix Bleeding into the lateral ventricle without ventricular dilatation A substantial amount of bleeding into the lateral ventricle that causes ventricular dilatation Bleeding that extends into the brain parenchyma

5 4206 Litman-10.qxd 1/19/04 2:33 PM Page PEDIATRIC ANESTHESIA: THE REQUISITES IN ANESTHESIOLOGY Bleeding into the brain parenchyma causes areas of hemorrhagic infarction and leads to the development of periventricular leukomalacia (PVL). PVL, which consists of cavitary cysts in the white matter surrounding the ventricles, is thought to be the single strongest predictor of cerebral palsy later in life. PVL may develop in patients without prior history of IVH or parenchymal hemorrhage. RETINOPATHY OF PREMATURITY Retinopathy of prematurity (ROP), formerly called retrolental fibroplasia (RLF), is a disease of the premature infant that is associated with immature development of the retinal vasculature. ROP occurs when the retinal vessels become vasoconstricted before their full maturation and growth into the periphery of the retina. New abnormal vessels proliferate in the area of devascularization and are characterized by their propensity for abnormal growth, hemorrhage, and edema, all which may lead to retinal scarring and loss of vision. Risk factors for development of ROP include low gestational age, low birthweight, prolonged oxygen exposure, mechanical ventilation, and comorbidities. The precise concentration of inspired oxygen or PaO 2 that results in retinal vessel vasoconstriction is unknown and probably varies between patients.there are even reports of cyanotic infants who have developed ROP! The incidence of ROP has declined in mildly premature infants because of the recognition of hyperoxia as a major contributing factor.however,the overall incidence of ROP has remained steady because of improved care and survival of extremely premature infants. Most infants with mild to moderate disease will attain normal vision without treatment; advanced disease is treated by laser therapy or retinal cryotherapy to prevent retinal detachment and vision loss. Does oxygen administered during general anesthesia cause or exacerbate ROP? Although scattered reports implicate oxygen administration during general anesthesia as a contributing factor, this does not support withholding oxygen in fear of causing or exacerbating ROP. Intraoperatively, the oxygen saturation (SpO 2 ) should be maintained in the low to mid 90 s (%) in extremely premature infants. In the presence of anemia, this concentration should be increased. If unsure, the anesthesiologist should always err on the side of keeping the O 2 saturation too high, rather than too low, because of the known devastating effects of hypoxemia. HYPOGLYCEMIA Glucose is a crucial substrate for proper brain growth and development. In utero, glucose is maternally derived by transfer through the placenta. After birth, the newborn infant brain receives glucose by exogenous sources or endogenous gluconeogenesis from glycogen stores. However, glycogen is accumulated in the fetal liver mostly during the third trimester of pregnancy. Therefore, premature infants are at risk for developing hypoglycemia. This risk is also increased in infants with intrauterine growth retardation, infants of diabetic mothers, and infants suffering from hypothermia, respiratory distress, polycythemia, or perinatal asphyxia. The definition of hypoglycemia has been a subject of debate. Currently, neonatologists advocate treatment of blood glucose levels <50 mg/dl, or more if there are symptoms. Symptoms of hypoglycemia include tremors (or jitteriness), cyanosis, neonatal convulsions (e.g., eyerolling, limpness), apnea, high-pitched or weak cry, or refusal to eat. The major consequence of prolonged hypoglycemia in the newborn period is a severe neurodevelopmental deficit. Therefore, hypoglycemia should be treated aggressively. Premature newborns who are not expected to receive glucose by enteral feedings are administered 10% dextrose intravenously, with a target glucose infusion rate of 8 mg/kg/min by the second day of life. Symptomatic hypoglycemia is treated with intravenous bolus dosing of 10% dextrose (2 4 ml/kg) until the symptoms resolve and the blood glucose has risen above normal levels. Rebound hypoglycemia commonly occurs; therefore, these infants are placed on a continuous glucose infusion, and blood glucose levels are monitored frequently. Premature infants who present for surgical procedures under general anesthesia will be receiving glucose solutions in the immediate preoperative period. Since the stress response that accompanies the onset of surgery usually results in an elevation of blood glucose, many pediatric anesthesiologists will reduce the rate of the maintenance glucose infusion by 50% or more at the beginning of the surgical procedure. Subsequent intraoperative glucose measurements are usually performed on an hourly basis. ARTICLES TO KNOW Flynn JT, Bancalari E, Snyder ES et al: Cohort study of transcutaneous oxygen tension and the incidence and severity of retinopathy of prematurity. N Engl J Med 326: , Fowlie PW, Davis PG: Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Neonatal Group. Cochrane Database of Systematic Reviews 1, Lloyd J, Askie L, Smith J,Tarnow-Mordi W: Supplemental oxygen for the treatment of prethreshold retinopathy of prematurity. Cochrane Neonatal Group. Cochrane Database of Systematic Reviews 1, 2003.

6 4206 Litman-10.qxd 1/19/04 2:33 PM Page 73 The Premature Infant 73 Perlman JM,Volpe JJ: Episodes of apnea and bradycardia in the preterm newborn: impact on cerebral circulation. Pediatrics 76: , Soll RF: Synthetic surfactant for respiratory distress syndrome in preterm infants. Cochrane Neonatal Group. Cochrane Database of Systematic Reviews 1, Steer PA, Henderson-Smart DJ: Caffeine versus theophylline for apnea in preterm infants. Cochrane Neonatal Group. Cochrane Database of Systematic Reviews 1, Wheeler AS, Sadri S, DeVore JS, David-Mian Z, Latyshevsky H: Intracranial hemorrhage following intravenous administration of sodium bicarbonate or saline solution in the newborn lamb asphyxiated in utero. Anesthesiology 51: , Woodgate PG, Davies MW: Permissive hypercapnia for the prevention of morbidity and mortality in mechanically ventilated newborn infants. Cochrane Neonatal Group. Cochrane Database of Systematic Reviews 1, 2003.