Apnea of prematurity

Apnea of prematurity is defined as a sudden cessation of breathing that lasts for at least 20 seconds or is accompanied by bradycardia (decrease in heart rate) or oxygen desaturation (cyanosis) in an infant younger than 37 weeks’ gestational age ¹. The most widely used definition of apnea of prematurity specifies a pause of breathing for more than 15–20 seconds or accompanied by oxygen desaturation (SpO2 ≤ 80% for ≥4 seconds) and bradycardia (heart rate < 2/3 of baseline for ≥4 seconds), in infants born less than 37 weeks of gestation ². Apnea of prematurity is a developmental disorder that self-resolves. In most cases, apnea of prematurity likely reflects a “physiological” rather than a “pathological” immature state of respiratory control.

Apnea of prematurity is generally broken down into three subtypes. Central, obstructive, or mixed ³. Central apnea accounts for approximately 10% to 25% of all cases of apnea, with obstructive apnea accounting for 10% to 25% and mixed for 50% to 75%. In each individual infant, one of these subtypes tends to predominate ³.

1. Central apnea is due to the depressed respiratory center where there is a cessation of output from the central respiratory centers, and there is no respiratory effort.
2. Obstructive apnea occurs when there is an obstruction to the airway, and respiratory efforts are inadequate to maintain ventilation.
3. Mixed apnea (a period of central apnea, typically followed by airway obstruction) is the most frequent type among preterm infants.

Apnea of infancy is defined as “an unexplained episode of cessation of breathing for 20 seconds or longer, or a shorter respiratory pause associated with bradycardia, cyanosis, pallor, and/or marked hypotonia” ¹.

The incidence of apnea of prematurity is inversely correlated with gestational age and birth weight. Seven percent of neonates born at 34 to 35 weeks gestation, 15% at 32 to 33 weeks, 54% at 30 to 31 weeks ⁴ and nearly all infants born at <29 weeks gestation or <1,000 g exhibit apnea of prematurity ⁵.

The incidence of bradycardia is fairly similar across these different groups; however, bradycardia does appear to occur more frequently with longer duration of apnea. Bradycardia occurs in 10% of apneic events with duration of 10–14 s, 34% of apnea lasting 15–20 seconds and 75% of apnea that lasts >20 seconds. Bradycardia usually occurs following oxygen desaturation that is associated with apnea, with a recent study demonstrating an earlier onset of oxygen desaturation than bradycardia (median interval 4.2 seconds) ⁶. However, recovery from bradycardia often precedes the recovery in oxygen saturation after apnea ⁶. Bradycardia may also follow apnea without desaturation, possibly mediated by vagal nerve stimulation and not necessarily by hypoxemia.

Apnea of prematurity is a common problem affecting premature infants, likely secondary to a “physiologic” immaturity of respiratory control that may be exacerbated by neonatal disease ⁷. These include altered ventilatory responses to hypoxia, hypercapnia, and altered sleep states, while the roles of gastroesophageal reflux and anemia remain controversial. Standard clinical management of the obstructive subtype of apnea of prematurity includes prone positioning and and nasal continuous positive airway pressure (NCPAP) or nasal intermittent positive pressure ventilation (NIPPV) to prevent pharyngeal collapse and alveolar atelectasis, while methylxanthine therapy is a mainstay of treatment of central apnea by stimulating the central nervous system and respiratory muscle function. Other therapies, including kangaroo care, red blood cell transfusions, and CO2 inhalation, require further study ⁸.

Most premature babies outgrow apnea as they mature. But sometimes your baby may be sent home with an apnea monitor. It should be used whenever you or your infant is sleeping and when you are busy. The apnea monitor alarms are very loud so don’t place the monitor next to your baby’s head. Check every alarm signal, even if you think it is a false alarm.

Classification of the severity of apnea of prematurity

Criteria to classify the severity of apnea of prematurity have not been well developed in clinical studies.

The University of Washington published indications for different treatments based on the severity of apnea of prematurity ⁹. This classification for apnea of prematurity uses the terms spontaneous, mild, moderate, or severe. Note the following:

• A spontaneous event might be defined by apnea with minimal physiologic changes, an event of brief duration, one associated with self-recovery, or an event only occurring once or twice in 24 hours.
• Mild or moderate events involve apnea, bradycardia, and/or O2 desaturation of intermediate magnitude. These events require therapeutic interventions less rigorous than those needed for severe episodes.
• A severe event entails prolonged apnea associated with clinically significant and persistent bradycardia, as well as O2 desaturation (ie, central cyanosis). A severe event requires vigorous stimulation, administration of an increased concentration of inspired O2, and/or assisted ventilation (eg, bag-mask ventilation).

Clinical centers must develop the classification system they wish to use to measure the severity of apnea. Factors often used to judge the need for future interventions include these:

• Severity of the apnea
• Number of events per day
• Magnitude of the intervention required to alleviate the event

The therapeutic approach used in most neonatal intensive care units (NICUs) involves a progression from tactile stimulation to methylxanthine therapy and then some form of assisted breathing (eg, nasal continuous airway pressure or assisted ventilation).

What is Apgar score?

The Apgar score helps find breathing problems and other health issues. It is part of the special attention given to a baby in the first few minutes after birth. The baby is checked at 1 minute and 5 minutes after birth for heart and respiratory rates, muscle tone, reflexes, and color. A baby who needs help with any of these issues is getting constant attention during those first 5 to 10 minutes. In this case, the actual Apgar score is given after the immediate issues have been taken care of.

Each area can have a score of 0, 1, or 2, with 10 points as the maximum. Most babies score 8 or 9, with 1 or 2 points taken off for blue hands and feet because of immature circulation. If a baby has a difficult time during delivery and needs extra help after birth, this will be shown in a lower Apgar score. Apgar scores of 6 or less usually mean a baby needed immediate attention and care.

Table 1. Apgar score

Sign	Score = 0	Score = 1	Score = 2
Heart rate	Absent	Below 100 per minute	Above 100 per minute
Breathing effort	Absent	Weak, irregular, or gasping	Good, crying
Muscle tone	Flaccid	Some flexing of arms and legs	Well-flexed, or active movements of arms and legs
Reflex or irritability	No response	Grimace or weak cry	Good cry
Color	Blue all over, or pale	Body pink, hands and feet blue	Pink all over

Causes of apnea of prematurity

Although the cause of apnea of prematurity is not fully understood, several mechanisms have been proposed to explain this condition, including those described below.

In premature babies, the part of the brain and spinal cord that controls breathing is not yet mature enough to allow nonstop breathing. Apnea of prematurity can cause babies to have large bursts of breath followed by periods of shallow breathing or stopped breathing. The condition may have other causes. Some of these include:

• Bleeding in or damage to the brain
• Lung problems
• Infections
• Digestive problems such as reflux. Reflux is when the stomach contents move back up into the esophagus.
• Too low or too high levels of chemicals in the body, such as glucose or calcium
• Heart or blood vessel problems
• Triggering reflexes that lead to apnea. This might be from feeding tubes, suctioning, or a baby’s neck position.
• Changes in body temperature

Apnea of prematurity is the clinical phenomenon associated with incompletely organized and interconnected respiratory neurons in the brainstem and their response to a multitude of afferent stimuli. Therefore, the abnormal control of breathing seen in apnea of prematurity represents neuronal immaturity of the brain ¹⁰.

In a premature neonate, protective respiratory reflex activity is decreased, and Hering-Breuer reflex activity is increased.

Dopaminergic receptors may have a role in inhibiting the responses of peripheral chemoreceptor and hypoxia-elicited central neural mechanisms. Evidence from studies of neonatal animals indicates that endogenous endorphin production may depress the central respiratory drive. Although endogenous opiates may modulate the ventilatory response to hypoxia in newborn animals, a competitive opiate receptor antagonist (naloxone) has no therapeutic role in apnea of prematurity.

Negative luminal pressures are generated during inspiration, and the compliant pharynx of the premature neonate is predisposed to collapse. Failure of genioglossus activation is most widely implicated in mixed and obstructive apnea among infants and adults.

The ability of medullary chemoreceptors to sense elevated CO2 levels is impaired. Therefore, an absent, small, or delayed response of the upper airway muscles to hypercapnia might cause upper airway instability when a linear increase in chest-wall activity also occurs. This impairment may predispose the infant to obstructed inspiration after a period of central apnea.

Another important factor to consider is the excitation of chemoreceptors in the larynx due to acid reflux. Laryngeal receptors send afferent fibers to the medulla and can elicit apnea when stimulated.

Swallowing during a respiratory pause is unique to apnea and does not occur during periodic breathing. Accumulation of saliva in the pharynx could hypothetically prolong apnea by means of a chemoreflex mechanism.

Some practicing neonatologists believe that gastroesophageal reflux (GER) is associated with recurrent apnea and have, therefore, treated preterm neonates with antacid and/or antireflux drugs. However, this assumption has been vigorously challenged.

Booth ¹¹ suggested that apneic episodes were reduced when esophagitis resolved because apnea clinically improved 1 or 2 days after the start of antireflux therapy. Therefore, neonatologists have treated xanthine-resistant apnea with H2 blockers, metoclopramide, thickened formula, and/or upright positioning during feeding. No controlled trials have demonstrated that antireflux drugs are effective in preventing apnea; on the contrary, recent data suggest that it may be harmful ¹².

Findings from several studies have not demonstrated a relationship between episodes of apnea and episodes of acid reflux into the esophagus.

Menon, Schefft, and Thach ¹³ observed that regurgitation of formula into the pharynx after feeding was associated with an increased incidence of apnea in premature infants. As stated above, gastric fluids can possibly activate laryngeal chemoreflexes, leading to apnea.

Although well-designed, controlled clinical trials are few, scientists often say that aminophylline exacerbates reflux in infants with apnea. The relationship of gastroesophageal reflux to methylxanthines is based on the literature about asthma, and limited studies in neonatal only suggest its occurrence ¹¹. Some authors have not related the use of methylxanthine to severe gastroesophageal reflux disease ¹⁴.

Fetal to neonatal transition

The fetus moves from an oxygen-poor environment, with PaO2 of 23–27 mmHg, to an oxygen-rich environment after birth that provides a fourfold increase in PaO2 ¹⁵. The postnatal rise in PaO2 effectively silences peripheral chemoreceptors, resulting in delayed onset of spontaneous breathing, especially when neonates are exposed to 100% oxygen during postnatal resuscitation ¹⁶. Therefore, neonates need to quickly adjust their ventilation to adapt to the postnatal environment. The immature respiratory pattern and chemoreceptor function in premature infants may delay this postnatal adjustment, given fewer synaptic connections and poor myelination of the immature brainstem ¹⁷.

Ventilatory response to hypoxia

The ventilatory response to hypoxia after birth in premature infants elicits an initial transient increase in respiratory rate and tidal volume that lasts for 1–2 min, followed by a late, sustained decline in spontaneous breathing that may last for several weeks ¹⁸. This late decline in spontaneous breathing is termed hypoxic ventilatory depression, which may be associated with the delayed postnatal respiratory adjustment that occurs in premature infants.

Peripheral chemoreceptor stimulation may also lead to apnea secondary to hypocapnia seen after hyperventilation ¹⁹. The CO2 level can decrease to a level near the apneic threshold (1–1.3 mmHg below baseline CO2 level) ²⁰. The relative proximity of the apneic threshold of CO2, together with peripheral chemoreceptor activation in response to hyperventilation, may lead to apnea.

Ventilatory response to hypercapnia

In response to hypercapnia, premature infants increase ventilation by prolonging the period of expiration, but not increasing breath frequency or overall tidal volume, leading to less minute ventilation than that seen in term infants. This poor hypercapnic ventilatory response is more pronounced in premature infants with apnea than without apnea ²¹. Contradictory movements of respiratory muscles in response to hypercapnia may also play a role in apnea of prematurity. In a study of piglets exposed to hypercapnia, researchers found that resultant diaphragm activation prior to upper airway muscles activity results in obstructed inspiratory efforts and prolonged apneic events ²².

Ventilatory responses to laryngeal chemoreflex

Activation of the laryngeal mucosa in premature infants can lead to apnea, bradycardia, and hypotension ²³. While this response is assumed to be a protective reflex, an exaggerated response may cause apnea of prematurity. This reflex-induced apnea is termed the laryngeal chemoreflex and is mediated through superior laryngeal nerve afferents ²⁴.

Neurotransmitters and apnea

Enhanced sensitivity to inhibitory neurotransmitters, such as gamma-aminobutyric acid (GABA), adenosine, serotonin, and prostaglandin, is another feature of the premature infant’s respiratory control system ⁴. GABA is the major inhibitory neurotransmitter in the central nervous system. In piglets, GABAergic neurons were activated during hypercapnia ²⁵. Blocking of GABAA receptors prevented ventilatory depression and increased respiratory rate in response to hypercapnia ²⁶.

Adenosine is a product of adenosine triphosphate and is formed as a consequence of metabolic and neural activity in the brain, especially during hypoxia. Recent reports have found an interaction between adenosine and GABA in the regulation of breathing ²⁷. This association is further strengthened by the observations that adenosine receptors are expressed in GABA-containing neurons. The binding of adenosine to its receptor may be involved with the release of GABA and thus inhibit respiration leading to apnea ²⁷.

Genetic variability and apnea

Recently, researchers found that the heritability of apnea of prematurity was 87% among same-gender twins ²⁸. These findings raise the possibility that apnea of prematurity has an important genetic basis. Tamim et al. ²⁹ first reported a higher proportion of first-degree mating for infants with apnea of prematurity compared with those without apnea of prematurity. Genomic studies may provide further information on the pathogenesis that underlies apnea of prematurity.

Apnea of prematurity symptoms

Apnea of prematurity is when a baby’s breathing has stopped for 20 seconds or more. Other signs and symptoms that may happen with apnea include:

• Bluish color to the skin (cyanosis)
• Decrease in heart rate (bradycardia)
• Low oxygen levels (hypoxia)

The symptoms of apnea of prematurity may look like other health conditions. Make sure your child sees his or her healthcare provider for a diagnosis.

Apnea of prematurity complications

Premature babies may have many problems. They often have to stay in the hospital for long periods of time. Apnea of prematurity is one of the problems of babies born too early. A slow heart rate and decreased oxygen levels in the blood may happen with apnea of prematurity. These babies are at risk for respiratory failure and death. They may also have long-term lung problems.

Infants born prematurely are at increased risk for apnea and bradycardia after undergoing general anesthesia or sedation with ketamine, regardless of their history of apnea. Because of this increased risk, defer elective surgery, if possible, until approximately 52-60 weeks after conception to allow the infant’s respiratory control mechanism to mature.

Apnea of prematurity diagnosis

It’s important to find out if the apnea is caused by prematurity or if it is caused by another problem. Your baby’s healthcare provider will examine your baby. He or she will check many of your baby’s body systems to find out what might be causing the apnea. Your baby’s breathing rate, heart rate, temperature, and blood pressure will be continuously checked. Tests used to diagnose the problem may include:

• Blood oxygen levels. Babies have their oxygen levels continuously checked.
• Blood tests. These check blood counts, blood sugar levels, and electrolyte levels. They also check for signs of infection.
• Lab tests. The fluid around the brain and spinal cord, urine, and stool may be checked for infection and other problems.
• X-ray, ultrasound, or other imaging studies. The healthcare provider may order X-rays or other pictures of the upper airways and lungs, brain, heart, or digestive system.
• Sleep studies. Vital signs and oxygen levels are checked.

Initial identification and assessment of apnea

The bedside caregivers—namely, the nurse in the neonatal intensive care unit (NICU) the respiratory care practitioner—identify the problem for the physician. Apnea should be distinguished from periodic breathing and documented. Use of a cardiorespiratory monitor is essential for identifying apnea of prematurity and for monitoring the patient’s blood pressure. Events associated with apnea, such as bradycardia and cyanosis, must be quantified. For bradycardia, the magnitude of reduction in heart rate from baseline and the duration of the event should be recorded. The presence and duration of central cyanosis should also be noted.

Pulse oximetry may be helpful for measuring the severity and duration of central O2 desaturation. Caregivers should be aware of the problems associated with the use of pulse oximetry to evaluate O2 saturation ³⁰.

When apnea is observed, its duration must be established. Cardiorespiratory monitors can be used to quantify the duration. Caregivers should attempt to define the type and severity of the patient’s apnea. The type of apnea is identified as central, obstructive, or mixed. A nasal thermistor may be needed in conjunction with pneumography to differentiate the type of apnea.

Exclusion of other causes of apnea

Before a diagnosis of apnea of prematurity is made, other causes of apnea in neonates must be excluded.

All forms of apnea may be difficult to detect visually, although obstructive apnea is usually most obvious to a trained observer.

Cardiorespiratory monitoring and pulse oximetry have improved bedside detection of apnea of prematurity ³¹. Caregivers should familiarize themselves with the advantages and disadvantages of cardiorespiratory monitoring and pulse oximetry in neonates. Apnea, bradycardia, and desaturation events are very subjective in nature unless the standard definition is strictly followed. Current cardiorespiratory monitors are very sophisticated; however, their use and interpretation are also very subjective. Clinicians heavily rely on nursing documentation to make decisions. By introducing standard definitions, individual subjectivity may be reduced which, in turn, may lead to fewer interventions and potentially decrease the length of stay ³².

Developing a NICU-specific standardized approach to the apnea of prematurity leads to reduce variations among clinicians. Brief isolated events need not be treated same as apnea of prematurity e.g. spontaneously resolving events and feeding related events which improves with interruption of feeding ³³.

Published findings show that even highly trained observers miss more than 50% of apnea of prematurity episodes.

Precise diagnosis of apnea of prematurity requires multichannel recordings, which are most commonly measurements of nasal airflow, thoracic impedance, heart rate, and O2 saturation. Expanded testing may include electroencephalography and/or use of an esophageal pH probe with a high thoracic Clark electrode. Hydrochloric acid may be added to the feedings to increase the gastric concentration of hydrogen ions.

Physical examination

Physical examination should include observation of the infant’s breathing patterns while he or she is asleep and awake. The prone or supine sleeping positions and other lying postures may be important during this clinical observation.

Important to the assessment of neonatal apnea is the identification of airway abnormalities (eg, choanal obstruction, anomalies of the palate, jaw deformities, neck masses) and conditions in distant organs that influence breathing (eg, brain hemorrhages, seizures, pulmonary disorders, congenital heart disease).

Findings in the head and neck and other obvious major and minor anomalies identified may suggest chromosomal abnormalities or a malformation syndrome. Appropriate work-up must then follow.

Physical examination elements

Monitor the baby’s cardiac, neurologic, and respiratory status.

Observe the infant for any signs of breathing difficulty, desaturation, or bradycardia during feeding.

Reflex effects of apnea include characteristic changes in heart rate, blood pressure, and pulse pressure. Note the following:

• Bradycardia may begin within 1.5-2 seconds of the onset of apnea.
• Apneic episodes associated with bradycardia are characterized by decreases in heart rate of more than 30% below baseline rates.
• This reflex bradycardia is secondary to hypoxic stimulation of the carotid body chemoreceptor or a direct effect of hypoxia on the heart.
• Transient bradycardias also occur relatively often in very low birth weight infants who also have apnea of prematurity ³⁴. These events are not associated with apnea, but they are presumed to be mediated by an increase in vagal tone.

Pulse oximetry may reveal clinically significant desaturation. However, pulse oximeters typically have a delay in recording the event.

Laboratory studies

A CBC (complete blood count) count and cultures of blood, urine, and spinal fluid are necessary if a serious bacterial or fungal infection is suspected in patients with apnea of prematurity. Obtain appropriate viral cultures or collection of body fluid for polymerase chain reaction (PCR) analyses if a viral pathogen is suspected.

A C-reactive protein level measured at 36-48 hours after birth may be useful for excluding infection.

Tests for ammonia, amino acid profiles in blood or urine, and organic acid levels in blood and urine are essential if a metabolic disorder is suspected. Testing of pyruvate and lactate concentrations in the blood and cerebrospinal fluid (CSF) may be diagnostically helpful when inborn errors of metabolism are among the differential diagnosis. The presence of ketones in the urine may indicate organic acidemia.

Serum electrolyte, calcium, magnesium, and glucose levels can be useful for diagnosing a recent stressful condition, a metabolic process, or chronic hypoventilation.

Analysis of the stool for different toxins related to botulism may reveal a cause in an infant with apnea, constipation, clinically significant hypotonia, difficulty swallowing or crying, or absent eye movements ³⁵.

Imaging studies

Chest radiography and/or a nuclear medicine milk scanning can be helpful if the child has persistent but unexplained lower airway symptoms (eg, wheezing and/or repetitive regurgitation after feeding, rumination) ³⁶.

In cases of airway obstruction, stridor, or unexplained pathologic obstructive apnea, helpful upper airway evaluations include lateral neck radiography, head and neck 3-dimensional tomography, and otolaryngologic evaluation (eg, fiberoptic assessment of the larynx through the nose during spontaneous breathing) ³⁷.

Imaging studies of intracranial pathology are necessary when hemorrhage is suspected or when findings include dysmorphic facial and somatic features, abnormal neurologic results, disordered hair whorls, and/or mental status changes.

A barium swallow study is useful if the infant has signs of swallowing dysfunction or anatomic anomalies (eg, an esophageal web, tracheoesophageal fistula).

A gastric-emptying study and abdominal sonography are useful in patients whose clinical picture includes a generalized gastrointestinal motility disorder or pyloric stenosis.

Other tests

Obtain a polysomnographic, or continuous multichannel, recording to measure the chest-wall movement, nasal and/or oral airflow (or change in air temperature), O2 saturation, and heart rate trend. A 2-channel pneumogram that is used to measure only chest-wall excursion and trends in heart rate provides insufficient information. The following results are diagnostic:

• Central apnea – Absence of nasal airflow and wall movement (this diagnostic finding on polysomnography recording may be used in lieu of pneumogram)
• Obstructive apnea – Lack of airflow despite chest-wall movement
• Mixed apnea – Combined results of central and obstructive apnea

If gastroesophageal reflux (GER) is suspected, note the intraesophageal pH as part of the multichannel recording.

Consider obtaining an electroencephalogram (EEG) in infants who have suspected apneic seizures or who have persistent pathologic central apnea without an identifiable cause.

Obtain an echocardiogram and consult a cardiologist if the patient’s history or physical findings (eg, feeding difficulties, heart murmur, cyanosis) suggest cardiac disease.

ECG results are useful in patients with severe unexplained tachycardia or bradycardia. Abnormalities in cardiac conduction (eg, prolonged-QT syndrome) are infrequent but important causes of apnea during infancy.

Evaluate patients for unilateral choanal stenosis and choanal atresia by passing a small-diameter feeding tube through both nares. Three-dimensional tomography is probably the method of choice for definitively diagnosing upper airway malformations.

Procedures

Procedures may include fiberoptic examination of the larynx through the nose during spontaneous breathing, direct laryngoscopy, and bronchoscopy which is usually performed with the patient under anesthesia.

Emergency or scheduled tracheostomy may be used to manage severe airway obstruction caused by a number of conditions. Tracheostomy might occur after the airway is stabilized by using endotracheal intubation. Jaw-distraction surgery has been used to avoid tracheostomy in neonatal conditions (eg, Robin sequence) that involve severe micrognathia as a component of malformation ³⁸.

Apnea of prematurity treatment

Many premature babies will “outgrow” apnea of prematurity by the time they reach the date that would have been the 36th week of pregnancy. If treatment is needed, it may include:

• General care. This includes control of body temperature, proper body position, and extra oxygen.
• Nasal continuous positive airway pressure (CPAP). A steady flow of air is delivered through the nose into the airways and lungs. Nasal intermittent positive pressure ventilation may be added to CPAP.
• Medicines. Methylxanthine is used to stimulate breathing.

Your baby may also need blood transfusions, depending on the cause of apnea.

Medical therapy

The principal goals of treating apnea of prematurity are to address its cause and to provide appropriate medical management. For example, bacterial sepsis that causes apnea is treated with antibiotics and other supportive therapies, whereas seizures require anticonvulsants. The use of assisted ventilation to manage severe apnea, bradycardia, and oxygen (O2) desaturation can be life saving, and assisted ventilation and oxygen (O2) may be required to prevent injury to the central nervous system (CNS). The primary disease process must be identified and treated.

When all causes of apnea other than prematurity are excluded during the diagnostic work-up, apnea of prematurity is the presumptive etiology. Caregivers must decide which intervention is appropriate given the severity of the patient’s apnea, bradycardia, and oxygen desaturation. For example, an infant who has an inadequate response to tactile stimulation and oxygen administration and who requires airway suctioning and bag-mask ventilation to recover suggests a serious problem.

A useful strategy is to have a protocol that defines escalating treatments for apnea of prematurity. Depending on the frequency and the severity of apnea, bradycardia, and oxygen desaturation, common treatments include stimulation (usually tactile), methylxanthine, or assisted ventilation (eg, nasal continuous positive airway pressure [CPAP], mechanical ventilation) ³⁹.

Pantalitschka et al ⁴⁰ compared 4 modes of nasal respiratory support for apnea of prematurity in very low birthweight infants: intermittent positive pressure ventilation (IPPV) via a conventional ventilator or a variable flow device and CPAP via a variable flow device or a constant flow underwater bubble system. In their randomized controlled trial with a crossover design, episodes of bradycardia or desaturation occurred at a rate of 6.7 per hour with the conventional ventilator in IPPV mode and at a rate of 2.8 and 4.4 per hour with the variable flow device in CPAP and IPPV mode, respectively (P < 0.03 for both compared with IPPV/conventional ventilator). Pantalitschka et al concluded that a variable flow nasal CPAP may be more effective than a conventional ventilator in nasal IPPV mode for treating apnea of prematurity.

Prone position

Prone positioning can improve thoracoabdominal synchrony and stabilize the chest wall without affecting breathing pattern or SpO2 ⁴¹. Several studies have demonstrated that prone position reduces apnea of prematurity ⁴². Extension of the neck 15 degrees from the prone position is referred to as the head elevated tilt position, which has been found to decrease episodes of oxygen desaturation by 48.5% ⁴³. A more comfortable three-stair-position that maintains the head and abdomen in a horizontal position was reported to improve apnea, bradycardia, and desaturation ⁴⁴. However, head elevated tilt position has not been shown to work in combination with pharmacologic therapy. Recently, two randomized controlled trials investigated the effect of three different postural interventions on the incidence of bradycardia and desaturation. The researchers found that the effect of head elevated tilt position and three-stair-position interventions following aminophylline treatment was similar to standard prone positioning and only decreased the rate of desaturation by 12% ⁴⁴. Thus, in infants receiving other effective treatment, neither head elevated tilt position nor three-stair-position resulted in a further improvement in apnea of prematurity. Since head elevated tilt position and three-stair-position are easy to provide, it should be considered as a first-line intervention in infants with apnea of prematurity.

Stimulation

Tactile stimulation is usually sufficient to terminate an isolated apneic event caused by central apnea. Stimulation akin to that used during neonatal resuscitation (eg, a gentle tap to the sole of the foot or rubbing the back) is often enough to terminate a central apnea. However, other measures may be required to treat an obstructive event or an episode of airway obstruction followed by central apnea.

If the upper airway is obstructed, repositioning the patient’s head and neck or gently elevating the infant’s jaw may alleviate the occlusion.

Use of a high-flow nasal cannula may open the airway enough to reduce obstructive apnea. As an alternative, high-flow oxygenation through a nasal cannula may be an agonist for receptors in the airway. Nasal irritation due to the cannula may prevent central apnea by causing arousal. Additional research is needed to ascertain the usefulness of high-flow nasal cannulas for treating apnea of prematurity.

Administration of oxygen

Supplemental oxygenation or bag-mask ventilation is indicated in infants with signs of bradycardia or desaturation.

Medical treatment is indicated when apneic episodes number 6-10 or more per day; when the infant does not respond to tactile stimulation; or when an event requires O2 and/or bag-mask ventilation to terminate apnea, bradycardia, and/or desaturation.

Avoid hyperoxia, which may increase the risk of retinopathy of prematurity (ROP).

Administration of carbon dioxide

Carbon dioxide is known to be the natural stimulator of breathing, and a study has shown that if the baseline PCO2 is increased in a premature infant, facilitated by providing a low concentration of inhaled carbon dioxide, this abolishes the apneic events in the premature infants; however, it is not as effective as theophylline and is not practical to deliver constant concentration of carbon dioxide, and, therefore, it should not be done ⁴⁵.

Use of CPAP

CPAP has been used to treat apnea in preterm neonates, and it is indicated when the infant continues to have apneic episodes despite achieving a therapeutic serum level of methylxanthine.

CPAP at 3–6 cm H2O (water pressure) has proven a safe and effective therapy for apnea of prematurity over the past 35 years. CPAP delivers a continuous distending pressure via the infant’s pharynx to the airways to prevent both pharyngeal collapse and alveolar atelectasis. Therefore, CPAP can enhance functional residual capacity and reduce the work of breathing, improving oxygenation and decreasing bradycardia ⁴⁶. CPAP works effectively to reduce the incidence of obstruction, but it has no clear efficacy in central apnea of prematurity ⁴⁷.

CPAP is delivered with nasal prongs, a nasal mask, or a face mask with 3-6 cm of water pressure.

An extension of CPAP is the administration of nasal intermittent positive pressure ventilation (NIPPV). Systematic meta-analysis has shown it to be effective in preventing extubation failure and for the treatment of apnea of prematurity ⁴⁸. A randomized crossover trial ⁴⁹ found that variable-flow nasal continuous positive airway pressure (NCPAP) is more effective in treating apnea of prematurity than a conventional ventilator using NIPPV mode. In a word, reduced work of breathing may be the key to improving apnea of prematurity, which can be achieved via either synchronized NIPPV ⁵⁰ or variable-flow NCPAP devices ⁴⁹.

CPAP effectively treats mixed and obstructive apnea, but it has little or no effect on central apnea. This limitation suggests that CPAP may reduce the frequency of apnea by means of several mechanisms, including stabilization of the partial pressure of O2 (PaO2) by increasing the functional residual capacity (FRC), by altering the influence of stretch receptors on respiratory timing, or by splinting the upper airway in an open position.

Discharge considerations

Apnea-free interval before discharge

Most neonatologists agree that babies should be apnea-free for 2-10 days before discharge. However, the interval between the last apneic event and a safe time for discharge is not clearly established. The minimum apnea-free period is debated among clinicians. Darnall et al concluded that otherwise healthy preterm neonates continue to have periods of apnea separated by as many as 8 days before the last episode of apnea before discharge ⁵¹. Infants with long intervals between apneic event often have risk factors other than apnea of prematurity.

Home monitoring

Home monitoring after discharge is necessary for infants whose apneic episodes continue despite the administration of methylxanthine. Infants undergoing methylxanthine therapy rarely are sent home without a monitor because apnea may recur after they outgrow their therapeutic level. Without a monitor, caregivers may not know when apnea reappears.

Some families cannot manage monitoring in the home. In these cases, the administration of caffeine may be the only possible therapy. Infants in this situation need frequent follow-up visits, and they should be readmitted for further evaluation when their blood levels approach the subtherapeutic range.

Various agencies and organizations have stated that home monitoring cannot prevent sudden infant death syndrome (SIDS), also called crib death or cot death, in preterm infants who have apnea of prematurity during their hospitalization ⁵². There is no data to suggest that home monitoring can prevent SIDS in preterm infants with the diagnosis of apnea of prematurity ³³.

Indications for home monitoring

Home monitoring may be indicated in the situations described below.

• Historical evidence suggests the occurrence of clinically significant apnea or an apparent life-threatening event (ALTE).
• Recording monitoring or multichannel evaluation documents apnea.
• The patient has gastroesophageal reflux (GER) with apnea.
• A sibling or twin of the patient died from SIDS or another postneonatal cause of death

The National Institutes of Health consensus conference recommends monitoring for the siblings of infants with SIDS, but only after 2 SIDS-related deaths occur in a family. Physicians often begin monitoring after one sibling dies from SIDS; this practice may be related to a fear of litigation should another child in the family die from SIDS. Siblings of patients who died from SIDS are routinely monitored until one month past the patient’s age at death.

Monitoring is not indicated to prevent SIDS in infants older than one year, though proponents believe that such monitoring reduces anxiety in the parents of high-risk infants. Opponents of monitoring cite a lack of evidence to show that monitoring reduces the rate of SIDS. They argue that monitors intrude on the family’s life and that they are poorly tolerated by the family ⁵².

Types of monitors

Several types of cardiorespiratory monitors are available for home use in the United States. The most common type combines impedance pneumography with an assessment of the patient’s mean heart rate. The most notable drawback of impedance monitors is their inability to detect obstructive apnea. Newer monitors can minimize false alarms caused by motion artifact.

Standard home monitors detect respiratory signals and heart rates. Electrodes are placed directly on the infant’s chest or inside an adjustable belt secured around his or her chest.

Monitoring units should be capable of recording cardiac and respiratory data because this information can help the physician in evaluating the need to stop medication or monitoring. These devices also record compliance with monitor use. The event recorder contains a computer chip that continuously records respiratory and cardiac signals. Normal signals are erased, but any event that deviates from preset parameters activates the monitor to save records of that event, as well as data 15-75 before and 15-75 seconds it. Additional channels are available to record pulse oximetry readings, nasal airflow, and body position (eg, prone vs supine). The records are downloaded within 24 hours after a parent reports an event or after excessive alarms occur.

Many units now have computer modems that instantly transmit data to the physician’s office for evaluation. These easily installed devices are especially useful for families who have had problems with events or alarms.

Some devices, such as pulse oximeters, piezo belts, and pressure capsules, have been impractical to use or have had limited applications. Newer technologies and software programs may soon make such oximeters and similar devices more practical than they once were.

All monitoring devices are associated with false alarms, which are alerts without in the absent of a true cardiorespiratory event. False alarms worry parents. If they happen often, they may discourage use of the monitor. Excessive false alarms can usually be minimized by adjusting the placement of the electrodes and by educating the parents.

Details of monitoring depend on the frequency of events observed during neonatal hospitalization, the size and stability of the infant at the time of discharge, and the degree of parental anxiety.

Follow-up of home monitoring and patient education

Careful follow-up is needed with all cases of home monitoring in prematurely born neonates. Physicians who have limited experience with home monitoring or who cannot interpret the downloaded recordings should seek assistance from a center or program with expertise in these areas.

The most important issue with monitoring is that Neonatal Resuscitation Program instructors should educate parents, guardians, and other caregivers about neonatal resuscitation by using a mannequin before their child is discharged from the NICU.

Parents should also be educated about prenatal and postnatal factors associated with an increased risk of SIDS, namely, the following ⁵³:

• Prenatal and postnatal tobacco use
• Opiate abuse during pregnancy
• Baby’s prone sleeping position
• Pacifier use
• Use of soft bedding
• Shared sleeping with children and adults
• Illnesses in infants with bronchopulmonary dysplasia
• Genetic factors

Parents must also be aware that postural skull deformities have occurred after the American Academy of Pediatrics offered positioning recommendations in its Back to Sleep campaign ⁵⁴. Prematurely born infants are probably at increased risk. Ways to avoid or minimize skull deformities should be discussed with parents.

Parents of infants with home monitors must have a clearly designated person who they can contact on a regular basis and during emergencies. Many programs or centers provide 24-hour assistance for families of children with home monitors.

The mean duration of home monitoring for prematurely born neonates is often more than 6 weeks. Extended monitoring is reserved for infants whose recordings show notable cardiorespiratory abnormalities. Monitoring beyond age 1 year is uncommon. Most often, children who require such monitoring have other conditions that require the use of additional technology. An example is an infant with bronchopulmonary dysplasia who requires mechanical ventilation at home.

For infants who require therapy with a methylxanthine, drug therapy is typically stopped after 8 weeks without true events, but monitoring is continued for an additional 4 weeks ⁵⁵. If no events are noted in this period, monitoring can be discontinued. These recommendations regarding discontinuing methylxanthines or home monitoring are not based on data from controlled studies; these investigations are badly needed.

Immunization

Premature infants often have apnea and bradycardia events following the first series of immunizations, and neonatologists caring for premature infants prefer to give immunization while the child remains in the NICU, if the infant is near discharge. These events are less likely to recur during subsequent immunizations; however, prospective studies are required in this regard ⁵⁶.

Medications

Methylxanthines

Methylxanthines may help reduce the incidence of events in a neonate with central apnea, though apnea in 15-20% of infants does not respond to methylxanthines.

Home monitoring after discharge is always necessary for infants whose apneic episodes continue despite the administration of methylxanthine. Infants undergoing methylxanthine therapy should rarely be sent home without a monitor because apnea may recur when they outgrow their therapeutic level.

Some families cannot manage monitoring in the home. In these cases, caffeine may be the only possible therapy.

Questions have been raised regarding short- and long-term adverse effects in preterm infants ⁵⁷. The relationship of methylxanthine therapy to neurodevelopmental outcomes over time is especially of concern. For this reason, a clinical trial related to the safety of caffeine in preterm infants with apnea of prematurity is in progress ⁵⁸.

Caffeine

Caffeine is the preferred drug for treating apnea of prematurity ⁵⁹. Caffeine is also the most acceptable prophylactic agent to facilitate successful extubation in preterm infants ⁶⁰. Caffeine therapy may reduce the rate of bronchopulmonary dysplasia in very low-birth-weight infants ⁶¹.

In addition, caffeine has a therapeutic margin wider than that of other methylxanthines, such as theophylline. Therefore, an overdose is less likely to occur with caffeine than with other drugs in its class.

Caffeine has been proposed as an adjunct treatment for successful extubation from the ventilator during first week of life of a very low birth weight premature neonate and the authors support this practice based on their own experience and evidence from the current literature ⁶². They also suggest starting caffeine early in the high-risk premature neonate, since caffeine has been associated with better long-term outcome ⁶³. At this time they do not suggest starting caffeine prophylaxis in a preterm neonate only based on prematurity, and current literature review also supports this ⁶⁴.

The results from one study suggest that while neonatal caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at age 18 months, the improvement was no longer realized at age 5 years ⁶⁵.

The benefits of caffeine therapy during the NICU stay are not controversial for many reasons, although long-term benefits of caffeine have been questioned. Caffeine has been linked with improved rates of survival without neurodevelopmental disability on 18- to 21-month follow-up. However, recently published data suggest that this benefit is no longer associated with a significantly improved rate of survival without disability in children who were of very low birth weight and assessed at age 5 years. That being said, caffeine remains the preferred drug of choice to treat the apnea of prematurity ⁶⁶.

Aminophylline

Aminophylline is the alternative methylxanthine. Aminophylline may be preferred when the physician wants to enhance contractility in the thoracic musculature or if the infant might benefit from the bronchodilator properties of aminophylline ⁶⁷. This latter effect may be desired in infants with bronchopulmonary dysplasia.

One concern is that aminophylline may decrease cerebral blood flow ⁶⁸.

Early reports in the literature also indicate a concern about the role that aminophylline may play in the occurrence or severity of necrotizing enterocolitis ⁶⁹.

Doxapram

Doxapram is excluded as a therapy for apnea of prematurity because it is associated with reduced cerebral blood flow ⁷⁰. Use of doxapram was not strongly recommended in a Cochrane Review ⁷¹. Doxapram should be reserved for infants in whom appropriate methylxanthine therapy and continuous positive airway pressure (CPAP) fail to control severe apneic events. If the caregiver wishes to use this agent, they should consult other resources regarding its administration.

Apnea of prematurity long term effects

Butcher-Puech and coworkers ⁷² found that infants in whom obstructive apnea exceeded 20 seconds had an increased incidence of intraventricular hemorrhage, hydrocephalus, prolonged mechanical ventilation, and abnormal neurologic development after their first year of life.

In 1985, Perlman and Volpe ⁷³ described a decrease in the cerebral blood flow velocity that accompanies severe bradycardia (heart rate < 80 bpm). Infants with clinically significant apnea of prematurity do not perform as well as prematurely born infants without recurrent apneas during neurodevelopmental follow-up testing ⁷⁴.

References

1. Kondamudi NP, Wilt AS. Infant Apnea. [Updated 2020 Jan 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441969
2. Moriette G, Lescure S, El Ayoubi M, Lopez E. Apnea of prematurity: what’s new? Arch Pediatr. 2010;17(2):186–190. doi: 10.1016/j.arcped.2009.09.016
3. Stokowski LA. A primer on Apnea of prematurity. Adv Neonatal Care. 2005;5(3):155–170. doi: 10.1016/j.adnc.2005.02.010
4. Martin RJ, Abu Shaweesh JM, Baird TM. Apnoea of prematurity. Paediatr Respir Rev. 2004;5(Suppl 1):S377–S382. doi: 10.1016/S1526-0542(04)90067-X
5. Robertson CM, Watt MJ, Dinu IA. Outcomes for the extremely premature infant: what is new? And where are we going? Pediatr Neurol. 2009;40(3):189–196. doi: 10.1016/j.pediatrneurol.2008.09.017
6. Poets CF. Apnea of prematurity: what can observational studies tell us about pathophysiology? Sleep Med. 2010;11(7):701–707. doi: 10.1016/j.sleep.2009.11.016
7. Zhao J, Gonzalez F, Mu D. Apnea of prematurity: from cause to treatment. Eur J Pediatr. 2011;170(9):1097‐1105. doi:10.1007/s00431-011-1409-6 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158333
8. Bloch-Salisbury E, Indic P, Bednarek F, Paydarfar D. Stabilizing immature breathing patterns of preterm infants using stochastic mechanosensory stimulation. J Appl Physiol. 2009;107(4):1017–1027. doi: 10.1152/japplphysiol.00058.2009
9. Apnea of Prematurity. http://healthlibrary.uwmedicine.org/Library/DiseasesConditions/Pediatric/HighRiskNewborn/90,P02922
10. Darnall RA, Ariagno RL, Kinney HC. The late preterm infant and the control of breathing, sleep, and brainstem development: a review. Clin Perinatol. 2006 Dec. 33(4):883-914; abstract x
11. Newell SJ, Booth IW, Morgan ME, et al. Gastro-oesophageal reflux in preterm infants. Arch Dis Child. 1989 Jun. 64(6):780-6.
12. Terrin G, Passariello A, De Curtis M, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics. 2012 Jan. 129(1):e40-5.
13. Menon AP, Schefft GL, Thach BT. Apnea associated with regurgitation in infants. J Pediatr. 1985 Apr. 106(4):625-9.
14. Khalaf MN, Porat R, Brodsky NL, Bhandari V. Clinical correlations in infants in the neonatal intensive care unit with varying severity of gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2001 Jan. 32(1):45-9.
15. Mercer JS, Erickson-Owens DA, Graves B, Haley MM. Evidence-based practices for the fetal to newborn transition. J Midwifery Womens Health. 2007;52(3):262–272. doi: 10.1016/j.jmwh.2007.01.005
16. Vento M, Asensi M, Sastre J, et al. Oxidative stress in asphyxiated term infants resuscitated with 100% oxygen. J Pediatr. 2003;142(3):240–246. doi: 10.1067/mpd.2003.91
17. Darnall RA, Ariagno RL, Kinney HC. The late preterm infant and the control of breathing, sleep, and brainstem development: a review. Clin Perinatol. 2006;33(4):883–914. doi: 10.1016/j.clp.2006.10.004
18. Nock ML, Difiore JM, Arko K, Martin RJ. Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants. J Pediatr. 2004;144(3):291–295. doi: 10.1016/j.jpeds.2003.11.035
19. Cardot V, Chardon K, Tourneux P, et al. Ventilatory response to a hyperoxic test is related to the frequency of short apneic episodes in late preterm neonates. Pediatr Res. 2007;62(5):591–596. doi: 10.1203/PDR.0b013e318155868e
20. Khan A, Qurashi M, Kwiatkowski K, et al. Measurement of the CO2 apneic threshold in newborn infants: possible relevance for periodic breathing and apnea. J Appl Physiol. 2005;98(4):1171–1176. doi: 10.1152/japplphysiol.00574.2003
21. Darnall RA. The role of CO2 and central chemoreception in the control of breathing in the fetus and the neonate. Respir Physiol Neurobiol. 2010;173(3):201–212. doi: 10.1016/j.resp.2010.04.009
22. Carlo WA, Martin RJ, Difiore JM. Differences in CO2 threshold of respiratory muscles in preterm infants. J Appl Physiol. 1988;65(6):2434–2439.
23. Praud JP. Upper airway reflexes in response to gastric reflux. Paediatr Respir Rev. 2010;11(4):208–212. doi: 10.1016/j.prrv.2010.07.001
24. Kelly BN, Huckabee ML, Jones RD, Frampton CM. Nutritive and non-nutritive swallowing apnea duration in term infants: implications for neural control mechanisms. Respir Physiol Neurobiol. 2006;154(3):372–378. doi: 10.1016/j.resp.2006.01.009
25. Zhang L, Wilson CG, Liu S, et al. Hypercapnia-induced activation of brainstem GABAergic neurons during early development. Respir Physiol Neurobiol. 2003;136(1):25–37. doi: 10.1016/S1569-9048(03)00041-7
26. Simakajornboon N, Kuptanon T. Maturational changes in neuromodulation of central pathways underlying hypoxic ventilatory response. Respir Physiol Neurobiol. 2005;149(1–3):273–286. doi: 10.1016/j.resp.2005.05.005
27. Zaidi SI, Jafri A, Martin RJ, Haxhiu MA. Adenosine A2A receptors are expressed by GABAergic neurons of medulla oblongata in developing rat. Brain Res. 2006;1071(1):42–53. doi: 10.1016/j.brainres.2005.11.077
28. Bloch-Salisbury E, Hall MH, Sharma P, et al. Heritability of apnea of prematurity: a retrospective twin study. Pediatrics. 2010;126(4):779–787. doi: 10.1542/peds.2010-0084
29. Tamim H, Khogali M, Beydoun H, et al. Consanguinity and apnea of prematurity. Am J Epidemiol. 2003;158(10):942–946. doi: 10.1093/aje/kwg226
30. Sola A, Chow L, Rogido M. Pulse oximetry in neonatal care in 2005. A comprehensive state of the art review [in Spanish]. An Pediatr (Barc). 2005 Mar. 62(3):266-81.
31. Di Fiore JM. Neonatal cardiorespiratory monitoring techniques. Semin Neonatol. 2004 Jun. 9(3):195-203.
32. Powell MB, Ahlers-Schmidt CR, Engel M, Bloom BT. Clinically significant cardiopulmonary events and the effect of definition standardization on apnea of prematurity management. J Perinatol. 2016 Sep 29 [Epub ahead of print].
33. Eichenwald EC, Committee on Fetus and Newborn, American Academy of Pediatrics. Apnea of prematurity. Pediatrics. 2016 Jan. 137(1).
34. Gamble YD, Lutin WP, Mathew OP. Non-sinus bradyarrhythmias in very low birth weight infants. J Perinatol. 2007 Jan. 27(1):65-7.
35. Arnon SS, Midura TF, Clay SA, et al. Infant botulism. Epidemiological, clinical, and laboratory aspects. JAMA. 1977 May 2. 237(18):1946-51.
36. Jeffery HE, Rahilly P, Read DJ. Multiple causes of asphyxia in infants at high risk for sudden infant death. Arch Dis Child. 1983 Feb. 58(2):92-100.
37. Cademartiri F, Luccichenti G, Lagana F, et al. Effective clinical outcome of a mandibular distraction device using three-dimensional CT with volume rendering in Pierre-Robin sequence. Acta Biomed. 2004 Aug. 75(2):122-5.
38. Denny A, Amm C. New technique for airway correction in neonates with severe Pierre Robin sequence. J Pediatr. 2005 Jul. 147(1):97-101.
39. Young TE, Mangum B. Methylxanthines. NeoFax. 19th ed. Raleigh, NC: Acorn; 2006. 200-3.
40. Pantalitschka T, Sievers J, Urschitz MS, et al. Randomised crossover trial of four nasal respiratory support systems for apnoea of prematurity in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2009 Jul. 94(4):F245-8.
41. Oliveira TG, Rego MA, Pereira NC, et al. Prone position and reduced thoracoabdominal asynchrony in preterm newborns. J Pediatr. 2009;85(5):443–448.
42. Poets CF, Bodman A. Sleeping position for preterm infants. Z Geburtshilfe Neonatol. 2008;212(1):27–29. doi: 10.1055/s-2008-1004610
43. Sher TR. Effect of nursing in the head elevated tilt position (15 degrees) on the incidence of bradycardic and hypoxemic episodes in preterm infants. Pediatr Phys Ther. 2002;14(2):112–113. doi: 10.1097/00001577-200214020-00008
44. Bauschatz AS, Kaufmann CM, Haensse D, et al. A preliminary report of nursing in the three-stair-position to prevent apnoea of prematurity. Acta Paediatr. 2008;97(12):1743–1745. doi: 10.1111/j.1651-2227.2008.00989.x
45. Alvaro RE, Khalil M, Qurashi M, et al. CO(2) inhalation as a treatment for apnea of prematurity: a randomized double-blind controlled trial. J Pediatr. 2012 Feb. 160(2):252-257.e1
46. Paoli AG, Davis PG, Faber B, Morley CJ. Devices and pressure sources for administration of nasal continuous positive airway pressure (NCPAP) in preterm neonates. Cochrane Database Syst Rev. 2008;23(1):CD002977b
47. Hoecker C, Nelle M, Poeschl J, et al. Caffeine impairs cerebral and intestinal blood flow velocity in preterm infants. Pediatrics. 2002;109(5):784–787. doi: 10.1542/peds.109.5.784
48. Lemyre B, Davis PG, Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for apnea of prematurity. Cochrane Database Syst Rev. 2002;1:CD002272
49. Pantalitschka T, Sievers J, Urschitz MS, et al. Randomized crossover trial of four nasal respiratory support systems on apnoea of prematurity in very low birth weight infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):245–248. doi: 10.1136/adc.2008.148981
50. Moretti C, Giannini L, Fassi C, et al. Nasal flow-synchronized intermittent positive pressure ventilation to facilitate weaning in very low-birthweight infants: unmasked randomized controlled trial. Pediatr Int. 2008;50(1):85–91. doi: 10.1111/j.1442-200X.2007.02525.x
51. Darnall RA, Kattwinkel J, Nattie C, Robinson M. Margin of safety for discharge after apnea in preterm infants. Pediatrics. 1997 Nov. 100(5):795-801.
52. American Academy of Pediatrics, Committee on Fetus and Newborn. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics. 2003 Apr. 111(4 Pt 1):914-7.
53. Hunt CE, Hauck FR. Sudden infant death syndrome. CMAJ. 2006 Jun 20. 174(13):1861-9.
54. [Guideline] Persing J, James H, Swanson J, Kattwinkel J. Prevention and management of positional skull deformities in infants. American Academy of Pediatrics Committee on Practice and Ambulatory Medicine, Section on Plastic Surgery and Section on Neurological Surgery. Pediatrics. 2003 Jul. 112(1 Pt 1):199-202.
55. Spitzer AR, Gibson E. Home monitoring. Clin Perinatol. 1992 Dec. 19(4):907-26.
56. Anderson J, Noori K, Morris SA. Apnoea after the 2-month immunisation in extremely preterm infants: what happens with the 4-month immunisation?. J Paediatr Child Health. 2013 Mar. 49(3):E217-20.
57. Millar D, Schmidt B. Controversies surrounding xanthine therapy. Semin Neonatol. 2004 Jun. 9(3):239-44.
58. Schmidt B. Methylxanthine therapy for apnea of prematurity: evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial. Biol Neonate. 2005. 88(3):208-13.
59. Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in preterm infants. Cochrane Database Syst Rev. 2001. (3):CD000140
60. Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. Cochrane Database Syst Rev. 2003. (1):CD000139
61. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006 May 18. 354(20):2112-21.
62. Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for endotracheal extubation in preterm infants. Cochrane Database Syst Rev. 2010 Dec 8. CD000139
63. Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for apnoea in preterm infants. Cochrane Database Syst Rev. 2010 Dec 8. CD000140
64. Henderson-Smart DJ, De Paoli AG. Prophylactic methylxanthine for prevention of apnoea in preterm infants. Cochrane Database Syst Rev. 2010 Dec 8. CD000432
65. Schmidt B, Anderson PJ, Doyle LW, et al. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012 Jan 18. 307(3):275-82.
66. Banni S, Evans RW, Salgo MG, Corongiu FP, Lombardi B. Conjugated diene and trans fatty acids in a choline-devoid diet hepatocarcinogenic in the rat. Carcinogenesis. 1990 Nov. 11(11):2047-51.
67. Eichenwald EC, Howell RG 3rd, Kosch PC, et al. Developmental changes in sequential activation of laryngeal abductor muscle and diaphragm in infants. J Appl Physiol. 1992 Oct. 73(4):1425-31.
68. Robel-Tillig E, Vogtmann C. Aminophylline influences cerebral hyperperfusion after severe birth hypoxia. Acta Paediatr. 2000 Aug. 89(8):971-4.
69. Cikrit D, Mastandrea J, Grosfeld JL, et al. Significance of portal vein air in necrotizing entercolitis: analysis of 53 cases. J Pediatr Surg. 1985 Aug. 20(4):425-30.
70. Dani C, Bertini G, Pezzati M, et al. Brain hemodynamic effects of doxapram in preterm infants. Biol Neonate. 2006. 89(2):69-74.
71. Henderson-Smart D, Steer P. Doxapram treatment for apnea in preterm infants. Cochrane Database Syst Rev. 2004. (4):CD000074
72. Butcher-Puech MC, Henderson-Smart DJ, Holley D, et al. Relation between apnoea duration and type and neurological status of preterm infants. Arch Dis Child. 1985 Oct. 60(10):953-8.
73. Perlman JM, Volpe JJ. Episodes of apnea and bradycardia in the preterm newborn: impact on cerebral circulation. Pediatrics. 1985 Sep. 76(3):333-8.
74. Emancipator JL, Storfer-Isser A, Taylor HG, et al. Variation of cognition and achievement with sleep-disordered breathing in full-term and preterm children. Arch Pediatr Adolesc Med. 2006 Feb. 160(2):203-10.