Apnea is a feature of many primary diseases that affect neonates . These disorders produce apnea by direct depression of the central nervous system’s control of respiration (hypoglycemia, meningitis, drugs, hemorrhage, seizures), disturbances in oxygen delivery (shock, sepsis, anemia), or ventilation defects (pneumonia, RDS, persistent pulmonary hypertension of the newborn [PPHN], muscle weakness).
Idiopathic apnea of prematurity occurs in the absence of identifiable predisposing diseases. Apnea is a disorder of respiratory control and may be obstructive, central, or mixed.
Obstructive apnea (pharyngeal instability, neck flexion, nasal occlusion) is characterized by absent airflow but persistent chest wall motion. Pharyngeal collapse may follow the negative airway pressures generated during inspiration, or it may result from incoordination of the tongue and other upper airway muscles involved in maintaining airway patency.
In central apnea, which is caused by decreased central nervous system (CNS) stimuli to respiratory muscles, airflow and chest wall motion are absent. Gestational age is the most important determinant of respiratory control, with the frequency of apnea being inversely related to gestational age. The immaturity of the brainstem respiratory centers is manifested by an attenuated response to carbon dioxide and a paradoxical response to hypoxia that results in apnea rather than hyperventilation. The most common pattern of idiopathic apnea in preterm neonates has a mixed etiology (50–75%), with obstructive apnea preceding (usually) or following central apnea. Short episodes of apnea are usually central, whereas prolonged ones are often mixed.
Pathophysiology
Apnea is sleep state dependent; the frequency increases during active (rapid eye movement) sleep. Paradoxical chest wall movement (inspiratory abdominal expansion and inward chest wall movement) is common during active sleep and may cause a fall in Pao2 because of ventilation-perfusion defects. Furthermore, increased negative pressure during paradoxical breathing and inhibition of pharyngeal muscle tone during active sleep may contribute to upper airway collapse and obstructive apnea.
CLINICAL MANIFESTATIONS.
The incidence of idiopathic apnea of prematurity varies inversely with gestational age. In preterm infants, it is rare on the 1st day of life; apnea immediately after birth signifies another illness. The onset of idiopathic apnea occurs on the 2nd–7th day of life. In preterm infants, serious apnea is defined as cessation of breathing for longer than 20 sec, or any duration if accompanied by cyanosis and bradycardia. The incidence of associated bradycardia increases with the length of the preceding apnea and correlates with the severity of hypoxia. Short apnea episodes (10 sec) are rarely associated with bradycardia, whereas longer ones (>20 sec) have a higher incidence of bradycardia. Bradycardia follows the apnea by 1–2 sec in more than 95% of cases and is most often sinus, but on occasion can be nodal. Vagal responses and, rarely, heart block are causes of bradycardia without apnea.
TREATMENT.
Infants at risk for apnea should be placed on cardiorespiratory monitors. Gentle tactile stimulation is often adequate therapy for mild and intermittent episodes. Infants with recurrent and prolonged apnea may require suctioning, repositioning, and bag and mask ventilation. Oxygen should be administered judiciously to treat hypoxia. The onset of apnea in a previously well premature neonate after the 2nd wk of life or in a term infant at any time is a critical event that warrants immediate investigation. Recurrent apnea of prematurity may be treated with theophylline or caffeine. Methylxanthines increase central respiratory drive by lowering the threshold of response to hypercarbia, as well as enhancing contractility of the diaphragm and preventing diaphragmatic fatigue. The specific effects appear to vary to some degree between theophylline and caffeine. Evidence suggests that caffeine is a more potent centrally acting respiratory agent with fewer side effects than theophylline. Loading doses of 5–7 mg/kg of theophylline (orally) or aminophylline (intravenously) should be followed by doses of 1–2 mg/kg given every 6–12 hr by the oral or intravenous routes. Loading doses of 20 mg/kg of caffeine citrate are followed 24 hr later by maintenance doses of 5 mg/kg/24 hr qd orally or intravenously. These doses should be monitored by observation of vital signs, clinical response, and serum drug levels (therapeutic levels: theophylline, 6–10 ?g/mL; caffeine, 8–20 ?g/mL). Caffeine may reduce the risk of BPD. Doxapram, known to be a potent respiratory stimulant, acts predominantly on peripheral chemoreceptors and has been used in neonates with apnea of prematurity, but has a limited therapeutic role due to side effects. Transfusion of packed red blood cells to reduce the incidence of idiopathic apnea is reserved for severely anemic infants. Gastroesophageal reflux may also occur in infants with apnea of prematurity. Data do not support a causal relationship between gastroesophageal reflux and apneic events or the use of antireflux medications to reduce the frequency of apnea in preterm infants.
Nasal continuous positive airway pressure (CPAP, 2–5 cm H2O) and high-flow humidified nasal cannula (1–2.5 L/min) are effective therapies for mixed or obstructive apnea. The efficacy of CPAP is related to its ability to splint the upper airway and prevent airway obstruction.
CLINICAL MANIFESTATIONS.
The incidence of idiopathic apnea of prematurity varies inversely with gestational age. In preterm infants, it is rare on the 1st day of life; apnea immediately after birth signifies another illness. The onset of idiopathic apnea occurs on the 2nd–7th day of life. In preterm infants, serious apnea is defined as cessation of breathing for longer than 20 sec, or any duration if accompanied by cyanosis and bradycardia. The incidence of associated bradycardia increases with the length of the preceding apnea and correlates with the severity of hypoxia. Short apnea episodes (10 sec) are rarely associated with bradycardia, whereas longer ones (>20 sec) have a higher incidence of bradycardia. Bradycardia follows the apnea by 1–2 sec in more than 95% of cases and is most often sinus, but on occasion can be nodal. Vagal responses and, rarely, heart block are causes of bradycardia without apnea.
TREATMENT.
Infants at risk for apnea should be placed on cardiorespiratory monitors. Gentle tactile stimulation is often adequate therapy for mild and intermittent episodes. Infants with recurrent and prolonged apnea may require suctioning, repositioning, and bag and mask ventilation. Oxygen should be administered judiciously to treat hypoxia. The onset of apnea in a previously well premature neonate after the 2nd wk of life or in a term infant at any time is a critical event that warrants immediate investigation. Recurrent apnea of prematurity may be treated with theophylline or caffeine. Methylxanthines increase central respiratory drive by lowering the threshold of response to hypercarbia, as well as enhancing contractility of the diaphragm and preventing diaphragmatic fatigue. The specific effects appear to vary to some degree between theophylline and caffeine. Evidence suggests that caffeine is a more potent centrally acting respiratory agent with fewer side effects than theophylline. Loading doses of 5–7 mg/kg of theophylline (orally) or aminophylline (intravenously) should be followed by doses of 1–2 mg/kg given every 6–12 hr by the oral or intravenous routes. Loading doses of 20 mg/kg of caffeine citrate are followed 24 hr later by maintenance doses of 5 mg/kg/24 hr qd orally or intravenously. These doses should be monitored by observation of vital signs, clinical response, and serum drug levels (therapeutic levels: theophylline, 6–10 ?g/mL; caffeine, 8–20 ?g/mL). Caffeine may reduce the risk of BPD. Doxapram, known to be a potent respiratory stimulant, acts predominantly on peripheral chemoreceptors and has been used in neonates with apnea of prematurity, but has a limited therapeutic role due to side effects. Transfusion of packed red blood cells to reduce the incidence of idiopathic apnea is reserved for severely anemic infants. Gastroesophageal reflux may also occur in infants with apnea of prematurity. Data do not support a causal relationship between gastroesophageal reflux and apneic events or the use of antireflux medications to reduce the frequency of apnea in preterm infants.
Nasal continuous positive airway pressure (CPAP, 2–5 cm H2O) and high-flow humidified nasal cannula (1–2.5 L/min) are effective therapies for mixed or obstructive apnea. The efficacy of CPAP is related to its ability to splint the upper airway and prevent airway obstruction.
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