83: Apnea

Apnea is common in preterm neonates and is a significant clinical problem. It is manifested by an unstable respiratory rhythm, reflecting the immaturity of the respiratory control system. Apnea can also be secondary to other pathological conditions, which need to be excluded before the diagnosis of apnea of prematurity is assumed. In contrast, periodic breathing is a benign condition and does not merit any treatment. Apnea is defined as cessation of breathing that lasts for at least 20 seconds and is accompanied by bradycardia, oxygen desaturation, or cyanosis.

1. Central apnea. Characterized by total cessation of inspiratory effort with no evidence of obstruction.

2. Obstructive apnea. Infant tries to breathe against an obstructed airway resulting in chest wall motion without air flow throughout the entire apneic episode.

3. Mixed apnea. Consists of obstructed respiratory efforts usually followed by central apnea. Purely obstructive apnea in the absence of a positional problem is probably uncommon.

4. Periodic breathing. Periodic breathing is a normal breathing pattern followed by apnea for 5 to 10 seconds without change in heart rate or skin color. Periodic breathing consists of breathing for 10 to 15 seconds followed by apnea for 5 or 10 seconds, without change in heart rate or skin color, and the net effect may be hypoventilation. It is due to an imbalance between the effect of peripheral and central chemoreceptors on ventilatory drive. Periodic breathing in premature infants is often due to excessive stimulation by the chemoreceptors, thus promoting an imbalance. Prevalence of periodic breathing approaches 100% in preterm infants <1000 g. It is more frequent during active sleep. The prognosis is good, and it is controversial whether periodic breathing is associated with an increased risk for apnea of prematurity.

The incidence of apnea and periodic breathing in the term infant has not been adequately determined. More than 50% of infants weighing <1500 g and 90% of infants weighing <1000 g have apnea. Mixed apnea is the most common type (50%), followed by central (40%), and then obstructive (10%).

Apnea of prematurity is a developmental disorder and reflects a “physiological” rather than “pathological” immature state of respiratory control.

1. Fetal to neonatal transition. The postnatal rise in Pao₂ somewhat diminishes the response of peripheral chemoreceptors, resulting in a brief delay in the onset of spontaneous breathing. This effect is increased when neonates are exposed to 100% oxygen during resuscitation. The immature respiratory pattern and chemoreceptor function in premature infants may delay this postnatal adjustment, given fewer synaptic connections and less myelination of the immature brainstem.

2. Ventilatory response to hypoxia. A transient increase in respiratory rate and tidal volume that lasts for 1–2 minutes followed by a late sustained decrease in spontaneous breathing. This unique response to hypoxia may last for several weeks in response to hypoxic episodes after birth. This late hypoventilatory depression associated with delayed postnatal respiratory adjustment occurs in premature infants. Peripheral chemoreceptor stimulation secondary to hypocapnia after hyperventilation may also contribute to apnea.

3. Ventilatory response to laryngeal chemoreflex. The laryngeal chemoreflex is mediated through the superior laryngeal nerve afferents and is assumed to be a protective reflex. An exaggerated response brought about during feedings may also contribute to apneic episodes.

4. Neurotransmitters and apnea. Increased sensitivity to inhibitory neurotransmitters such as GABA (γ-aminobutyric acid), adenosine, serotonin, and prostaglandins may be related to apnea.

5. Genetic variability and apnea. Genetic and environmental factors may lead to apnea. Heritability of apnea of prematurity was 87% among same-gender twins. The congenital hypoventilation syndrome, defined by a lack of CO₂ responsiveness during sleep, is thought to occur due to the mutation of developmental transcription factor Phox2b. Severe depletion of neurons of the respiratory group of muscles was observed in experimentation animals due to the above mutation.

6. Sleep-related apnea. Most apnea occurs during active sleep. Preterm infants are asleep 80% of time, and 50% of sleep is active. This relationship lasts until 6 months of age. During active sleep there is a low-voltage electrocortical state, decreased arousal from sleep, decreased muscular tone, absence of upper airway adductor activity, and decreased respiratory drive. Irregular breathing and inspiratory chest wall distortion associated with decreased ventilatory drive causes slight elevation in arterial Pco₂. The ventilatory response to hypoxia and ventilatory sensitivity to CO₂ is more depressed during active sleep. Activation of serotonin-containing neurons that are part of the arousal system of the brainstem decreases by nearly half during slow-wave sleep and become nearly silent during rapid eye movement (REM) sleep via activation of GABAergic inputs.

7. Siblings with sudden infant death syndrome (SIDS). The collaborative home monitoring evaluation (CHIME) study showed that the incidence of apnea was the same in siblings of SIDS and normal term infants.

8. Gastroesophageal reflux (GER) and apnea. Studies have shown no temporal relation between GER and apnea. A decreased lower esophageal sphincter tone and increased GER following apnea have been documented, but apnea also occurs before reflux events. Apnea with desaturation events can lead to relaxation of the gastroesophageal junction and may explain the presence of formula often found in the pharynx of infants suctioned during an apneic event. Studies have shown that anti-reflux medications do not reduce apnea and bradycardia.

1. Physiologic immaturity of the respiratory center. This condition is usually present after 1–2 days of life, and is often referred to as apnea of prematurity (AOP).

2. Secondary causes

   1. Neurologic. Birth trauma, meningitis, intracranial hemorrhage, seizures, perinatal asphyxia, congenital myopathies or neuropathies, placental transfer of narcotics, magnesium sulfate (MgSO₄), or general anesthetics.

   2. Pulmonary. Surfactant deficiency, pneumonia, pulmonary hemorrhage, obstructive airway lesions, pneumothorax, hypoxemia, and hypercarbia.

   3. Cardiac. Cyanotic congenital heart disease, hyper- or hypotension, congestive heart failure, patent ductus arteriosis, increased vagal tone, and prostaglandin therapy.

   4. Gastrointestinal. GER and necrotizing enterocolitis (NEC).

   5. Hematologic. Anemia.

   6. Hypothermia or hyperthermia.

   7. Metabolic. Acidosis, hypoglycemia, hypocalcemia, and hypo- or hypernatremia.

   8. Inborn errors of metabolism.

   9. Sepsis.

It is difficult to separate clinical manifestations of apnea from consequences of apnea. Symptoms and signs depend on the duration and frequency of apnea and most are related to hypoxia. Other clinical manifestations depend on the etiology of apnea such as feeding intolerance, lethargy, temperature instability, jitteriness, poor feeding, central nervous system (CNS) depression, irritability, desaturation, tachypnea, tachycardia, bradycardia, hypotonia, and seizures.

1. History and physical examination must include a review of maternal risk factors, medications, birth history, and feeding intolerance. Physical examination should include a search for abnormal neurological signs and signs of sepsis.

2. Laboratory studies

   1. Complete septic workup (eg, complete blood count [CBC], appropriate cultures)

   2. Screening for metabolic disorders

3. Imaging and other studies

   1. Imaging to evaluate for atelectasis, pneumonia, air leak, and NEC, and cranial ultrasound to detect intracranial hemorrhage or congenital abnormalities.

   2. Electroencephalogram (EEG) to rule out seizures, as apnea may be the sole presentation of seizures.

   3. Polysomnography determines the type of apnea in relation to sleep cycles of the infant.

Treatment strategies of apnea of prematurity should be based on modulating an unstable respiratory rhythm into a more stable one. (See Chapter 47.)

1. Pharmacologic management

   1. Methylxanthine therapy. Caffeine, theophylline, and aminophylline have been used as respiratory stimulants to decrease apnea of prematurity. Both caffeine and theophylline are an effective treatment for AOP. Initially, theophylline was the standard of treatment and required close monitoring of serum levels. Since the U.S. Food and Drug Administration (FDA) approval of caffeine for infant use, it has largely replaced theophylline as the first drug for AOP management. Methylxanthines increase minute ventilation, improve CO₂ sensitivity, decrease hypoxic depression, enhance diaphragmatic activity, and decrease periodic breathing. Enhancing the CO₂ sensitivity may be an important component of its effectiveness. Common side effects include tachycardia, feeding intolerance, emesis, jitteriness, restlessness, and irritability. Toxic effects may produce arrhythmias and seizures. Methylxanthines increase metabolic rate and oxygen consumption and have a mild diuretic effect. Caffeine has substantially fewer side effects, is better tolerated, and has a high therapeutic index when compared to theophylline. Caffeine has a long half-life, which makes for a convenient once-a-day dosing regimen, and monitoring of caffeine levels at the recommended dosing is seldom necessary. See Chapter 148 for dosage regimens.

   2. Doxapram. Doxapram is a potent nonspecific respiratory stimulant. It stimulates peripheral chemoreceptors at low dose and central chemoreceptors at high dose. Small doses are used for the treatment of AOP. Doxapram increases tidal volume and minute ventilation. Studies have shown the effectiveness of doxapram in reducing apnea when refractory to methylxanthines. As a result of poor absorption, it is used as a continuous intravenous infusion. Side effects include an increase in blood pressure, abdominal distension, irritability, jitteriness, increased gastric residuals, and emesis. See Chapter 148 for dosage regimens.

   3. Nonpharmacologic management

      1. Evidence based

         1. Prone, head elevated positioning. The chest wall is stabilized and thoracoabdominal asynchrony is reduced in prone position. Prone position along with head elevated tilt position showed reduction in apnea and bradycardia. The effect of head position on bradycardia and intermittent hypoxia is less pronounced in infants already receiving other treatment for apnea of prematurity.

         2. Continuous positive airway pressure (CPAP). CPAP at 4–6 cm H₂O has proven to be a safe and effective therapy of apnea of prematurity. It is effective in obstructive apnea rather than central apnea. Effectiveness of CPAP is related to maintaining airway patency and its splinting effects. CPAP delivers a continuous distending pressure via the infant's pharynx to the airway to prevent both pharyngeal collapse and alveolar atelectasis, thereby enhancing functional residual capacity, reducing work of breathing, improving oxygenation, and decreasing bradycardia. CPAP decreases periodic breathing and apnea.

         3. Flow through nasal cannula. Both high and low flow through nasal cannula can be a useful adjunct therapy in some infants with apnea who are already receiving methylxanthines. High flow produces a distending pressure, especially in very low birthweight infants. It is a variable form of treatment and depends on factors such as flow rate, nasal leak, and mouth closure. Airway pressure cannot be readily monitored while on nasal cannula.

         4. Synchronized nasal ventilation. An extension of CPAP is administration of nasal intermittent positive pressure ventilation (N-IPPV). It has been suggested to be more effective over CPAP in preventing extubation failure.

      2. Other interventions with unclear efficacy

         1. Orogastric versus nasogastric feeding tube placement. A nasogastric tube increases nasal resistance by 50%; therefore, orogastric feeding tubes are sometimes preferred in preterm infants with apnea.

         2. Kangaroo mother care (KMC). Studies have shown that infants receiving KMC had decreased episodes of apnea and bradycardia. The effect of KMC in improvement of apnea and bradycardia is the same as that seen with prone positioning.

         3. Keeping environmental temperature at the lower end of the thermoneutral range. Increase in body temperature in infants enhances the instability of the breathing pattern. Overheating should be avoided, but there is no significant data to recommend a specific environmental temperature that may be used to reduce the incidence of AOP.

         4. Oscillating waterbed and tactile stimulation. Synchronization of respiration may be achieved between the infant's own breathing rhythm and an external rhythm generator (eg, an inflatable mattress connected to a respirator). This synchronization is better beyond 35 weeks gestational age (GA) when AOP is no longer a major issue, so this intervention was largely abandoned. Recently stochastic mechanosensory stimulation using actuators embedded in a specially designed mattress for subcutaneous stimulation have been shown to decrease in the duration of oxygen desaturation.

         5. Olfactory stimulation. Olfactory stimulation modulates the infant's respiratory pattern, particularly during active sleep when apnea is more common. Introduction of a pleasant odor into the incubator reduces the incidence of apnea and bradycardia. A study was done in smaller group for a period of 24 hours.

         6. Red blood cell transfusion. An increase in respiratory drive resulting from increased tissue oxygenation is one of the proposed mechanisms for red cell transfusion to ameliorate AOP. There is insignificant evidence to recommend transfusion to treat AOP in anemic infants. Data on the effect of blood transfusion in treating AOP is conflicting, though it was not associated with apnea frequency, but it was associated with increased risk of bronchopulmonary dysplasia/chronic lung disease (BPD/CLD) and NEC.

         7. Oxygen administration. Application of low flow oxygen results in reduced rate of intermittent hypoxia and apnea. Oxygen toxicity should be considered while using this modality of treatment.

1. Consider stopping caffeine at 34 weeks postmenstrual age.

2. More aggressive approach is to stop when infant is apnea-free for a period of 7 days irrespective of age.

3. If asymptomatic for 5 days after stopping methylxanthines, the child may be discharged without further therapy.

4. Considerations for home apnea monitoring

   1. Persistent, symptomatic apnea at >36 weeks postmenstrual age

   2. History of a severe, apparently life-threatening event and abnormal polysomnography

   3. Technology-dependent infant (eg, home mechanical ventilation)

   4. Home oxygen administration

   5. Central hypoventilation syndromes

Apnea of prematurity resolves with maturation. The physiological basis for resolution of apnea is believed to be myelination of the brainstem. Poor neurodevelopmental outcome is associated with a delay in myelination in infants with apnea of prematurity. Otherwise, in most infants apnea resolves without the occurrence of long-term deficiencies.