The primary function of the lung is gas exchange (i.e., they inhale oxygen and exhale carbon dioxide). Fetal breathing movements begin as early as 10 weeks of gestation, and the breathing of amniotic fluid in and out is essential for the stimulation of lung development. Fetal breathing movements tend to be erratic and occur only 30 to 40 percent of the time up to 30 weeks of gestation. The failure of fetal breathing movements or a lack of amniotic fluid that can be breathed in and out results in underdeveloped lungs (i.e., pulmonary hypoplasia), which can be incompatible with extrauterine life. By approximately 30 to 32 weeks of gestation, the lungs make surfactant, a soap-like substance that helps keep the air sacs (alveoli) open. Infants born before 28 to 30 of weeks gestation lack alveoli and breath with their terminal bronchioles and primitive air sacs. After delivery, the breathing pattern generally becomes more regular and continuous, but immature regulatory systems can lead to brief episodes of not breathing (apnea) (see Chapter 6 for discussion of normal lung development and respiratory distress syndrome).
About 24,000 infants a year and 80 percent of infants born before 27 weeks of gestation will develop respiratory distress syndrome (RDS). RDS is associated with surfactant deficiency. The incidence of RDS increases with decreasing gestational age and is higher among white infants than African-American infants at each week of gestation (Hulsey et al., 1993). Although respiratory distress is less common in infants born at 33 to 36 weeks of gestation and is rare in full-term infants, it can be severe, with a 5 percent mortality rate (Clark et al., 2004; Lewis et al., 1996). Antenatal administration of glucocorticoids to women at risk for preterm delivery reduces the incidence and severity of RDS as well as the rate of mortality (NIH, 1994) (see Chapter 9). Soon after birth, preterm infants with RDS develop rapid breathing, grunting, poor color, and crackling or diminished breath sounds breathing requires increased work. Respiratory failure because of fatigue, apnea, hypoxia, or an air leak (from alveolar injury) results from stiff lungs that need high pressures for ventilation.
RDS is an acute illness treated with respiratory support (oxygen, positive airway pressure, ventilator, or surfactant) as needed and improves in 2 to 4 days and resolves in 7 to 14 days. The optimal methods of providing respiratory support and even the safe and optimal blood levels of oxygen and carbon dioxide in very preterm infants remain quite controversial (Cochrane issue 2; Collins et al., 2001; Phelps, 2000; Saugstad, 2005; Thome and Carlo, 2002; Tin, 2002; Tin and Wariyar, 2002; Woodgate and Davies, 2001). The provision of exogenous surfactant through an endotracheal tube improves pulmonary gas exchange and reduces mortality (by 40 percent), air leak (by 30 to 65 percent), and chronic lung disease but does not influence neurodevelopmental or long-term pulmonary outcomes (Courtney et al., 1995; Dunn et al., 1988; Gappa et al., 1999; Ho et al., 2002a,b; Morley, 1991; Soll, 2002a,b,c; Stevens et al., 2002; Ware et al., 1990). A few randomized controlled trials have addressed the effectiveness of high-frequency ventilation or the use of an inhaled gas (nitric oxide) on survival and the severity of lung injury in severely ill preterm infants (Bhutta and Henderson-Smart, 2002; Henderson-Smart and Osborn, 2002; Mestan et al., 2005; Van Meurs et al., 2005).
Not all acute respiratory illnesses in preterm neonates are RDS. Because congenital pneumonia is difficult to distinguish from RDS, infants with respiratory distress are generally treated with antibiotics. Some infants also have difficulty transitioning from the type of circulation that they have in utero, where gas exchange occurs in the placenta. When they breathe at birth, their circulatory pattern should change to send blood through their lungs. The retention of fetal lung fluid can also cause respiratory distress, but the condition improves as the fluid is reabsorbed.
The chronic lung disease (CLD) that sometimes follows RDS in preterm infants is also called bronchopulmonary dysplasia (BPD). BPD/CLD is a chronic disorder that results from inflammation, injury, and scarring of the airways and the alveoli. It is associated with growth, health, and neurodevelopmental problems during childhood (see Chapter 11). Positive-pressure ventilation, high oxygen concentrations, infection, and other inflammatory triggers all contribute to lung injury; but the primary cause of BPD/CLD is lung immaturity. Especially for infants born at less than 28 to 30 weeks of gestation, the lung tissue is very fragile and the injured lung tissue tends to trap air, collapse, or fill with mucous and other fluids, which further compromise lung growth and development.
Various definitions of BPD/CLD have been used and are based on the respiratory support that an infant requires, but the most commonly used definition is a requirement for oxygen at 36 weeks of postmenstrual age (gestational age plus chronological age). Its incidence varies with gestational age at birth: in a study of infants born in 2002, 28 percent of infants born before 29 weeks of gestation and 5 percent of infants born 29 to 32 weeks gestation required oxygen at 36 weeks of postmenstrual age (Smith et al., 2005). By using this same definition, the incidence of BPD/CLD varies widely among centers:, from 3 to 43 percent among infants with birth weights of less than 1,500 grams (Lee et al., 2000; Lemons et al., 2001).
Infants with BPD/CLD have nutritional and fluid problems because of fluid sensitivity and increased metabolic needs, have difficulties with reactive airways (wheezing), and are quite vulnerable to infections, especially respiratory infections (Vaucher, 2002). Surprisingly few studies of the standard medications used to treat infants with BPD/CLD have been conducted, including diuretics and bronchodilators (Walsh et al., 2006). Modest improvements in survival and BPD/CLD rates have been reported with intramuscular injections of vitamin A (Darlow and Graham, 2002).
The most controversial treatment for preterm infants with BPD/CLD is systemic postnatal corticosteroids (especially dexamethasone), which arrest alveolar and lung growth but allow the pulmonary system to mature (see Chapter 6). Two studies in the 1980s reported that long courses of relatively high doses of corticosteroids reduced the duration of time that oxygen and mechanical ventilation were needed in preterm infants (Avery et al., 1985; Mammel et al., 1983). More than 40 randomized controlled trials of postnatal systemic steroids have been published, with most reporting improved gas exchange, fewer days of mechanical ventilation, and a lower incidence of BPD/CLD; but side effects, including glucose problems, high blood pressure, and growth failure were reported (Bhutta and Ohlsson, 1998; Halliday, 1999; Halliday and Ehrenkranz, 2001a,b,c).
Years after systemic steroids were widely adopted for the treatment of BPD/CLD, follow-up studies reported higher rates of cerebral palsy and cognitive impairment in infants randomly assigned to steroids than in those assigned to placebo, and systematic reviews of the available data have expressed similar concerns (Barrington et al., 2001a,b; Bhutta and Ohlsson, 1998; Halliday, 2004; Kamlin and Davis, 2004; O'Shea et al., 1999; Shinwell et al., 2000; Yeh et al., 1998). Two large trials of lower doses of hydrocortisone for the prevention of BPD/CLD were stopped because of adverse side effects (including gastrointestinal perforation) (Stark et al., 2001; Watterberg et al., 1999). One review calculated that for every 100 neonates given steroids within 96 hours of birth, BPD/CLD would be prevented in 9, while 6 would develop gastrointestinal hemorrhage and 6 would develop cerebral palsy.
Inhaled steroids are also frequently used, despite trials that show that they provide no significant benefits (Shah et al., 2004). Whether corticosteroids should be used to treat the sickest infants with severe BPD/CLD (many of whom may die) remains controversial, especially if lower doses and much shorter courses are used (Doyle et al., 2005; Jones et al., 2005). Whether a drug that provides a short-term gain (and sometimes dramatic results) but increases the likelihood of serious long-term consequences should be used and how one decides between benefit to one organ system (the lungs) but adverse effects on another organ system (the brain) are serious dilemmas.
The likelihood of persistent respiratory problems during infancy is higher in preterm infants with BPD/CLD than in those without BPD/CLD. They may develop significant wheezing with respiratory infections (viral broncholitis) and may need to be rehospitalized, placed back on a ventilator, or even given exogenous surfactant (Kneyber et al., 2005). Preterm infants are especially vulnerable to respiratory syncytial virus (RSV) infection. The American Academy of Pediatrics recommends RSV prophylaxis for 6 months for infants born at 29 to 32 weeks of gestation and for 12 months for infants born at less than 28 weeks of gestation (AAP, 2006). BPD/CLD often results in residual effects on pulmonary function later in life: children who had had BPD/CLD as infants are particularly vulnerable to the effects of secondhand smoke and have higher rates of asthma, persistent growth problems, and neurodevelopmental disabilities (Hack et al., 2000; Jacob et al., 1998; Jones et al., 2005; Thomas et al., 2002; Vohr et al., 2005).
Another complication of preterm birth is apnea, in which infants may stop breathing for 20 seconds or more, sometimes accompanied by a slow heart rate (bradycardia). Immaturity of the control of breathing is the major cause of apnea and bradycardia, although sometimes pre-term infants have obstructive apnea (an obstruction to the movement of air in their airways). They require constant monitoring but generally respond quickly to stimulation (or in the case of obstructive apnea, repositioning). They may occasionally need to be given some positive-pressure breaths to get them breathing again. There is no agreement as to what constitutes pathologic apnea or the threshold of apnea that requires treatment (Finer et al., 2006).
A number of strategies have been used to treat preterm apnea. The primary drugs used to treat apnea are the methylxanthines. Both theophylline and caffeine are effective, but caffeine has less toxicity (Henderson-Smart and Steer, 2004). Another drug, doxapram, has been associated with increases in cognitive delay (Henderson-Smart and Steer, 2002; Sreenan et al., 2001). The provision of vestibular stimulation is not as effective as treatment with methylxanthines for the prevention or treatment of apnea (Henderson-Smart and Osborn, 2002). There is no evidence that treatment of gastroesophageal reflux decreases the frequency or severity of apnea (Finer et al., 2006). Frequent apnea unresponsive to medications is treated with nasal positive airway pressure or mechanical ventilation.
Apnea generally resolves as the preterm infant matures. Occasionally, preterm infants continue to have apnea beyond term, and some are discharged on home apnea monitors. The long-term beneficial effects of the treatment of apnea in preterm infants in a NICU have not been demonstrated (Finer et al., 2006). Acute respiratory infections (especially RSV infections) may cause a recurrence of apnea. Although there is relationship between preterm birth and sudden infant death syndrome, the mechanisms are poorly understood and probably do not include apnea of prematurity (Baird, 2004).
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If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.