Apnea of Prematurity 

Updated: Nov 06, 2016
Author: Dharmendra J Nimavat, MD, FAAP; Chief Editor: Ted Rosenkrantz, MD 

Overview

Background

Our understanding of the anatomy, physiology, biochemistry, and molecular biology of neonatal breathing has increased in recent years.[1, 2, 3, 4] For instance, emerging data are elucidating the genes involved in the embryonic development of central respiratory centers and their neural networks.[5] The central respiratory generator is essential for fetal breathing movements. It appears early in pregnancy and importantly contributes to pulmonary development.[6]

In the fetus, breathing is intermittent and occurs during the low-voltage electrocortical state (analogous to rapid eye movement [REM] sleep) and becomes continuous immediately after birth. The regulatory neurologic mechanisms that cause the transition from intermittent fetal breathing to continuous neonatal breathing are incompletely appreciated.[7, 8]

After birth, apnea of prematurity (AOP) is a major concern for caregivers in intensive care nurseries. The magnitude of this problem resulted in the National Institutes of Child Health and Human Development (NICHD) convening a workshop on apnea of prematurity. Summary Proceedings from the Apnea-of-Prematurity Group have been published.

The NICHD review group emphasized the following conclusions:

  • No consensus has been reached regarding the definition, diagnosis, or treatment of apnea of prematurity.

  • Systematic research has not been conducted to investigate the value of different interventions for apnea of prematurity.

  • Available technology is not routinely used to document real-time events associated with apnea.

  • The time required to demonstrate an improvement in apnea of prematurity with a specific treatment has not been established.

  • The observational period needed after therapy for apnea of prematurity is unknown, and an appropriate duration of surveillance off therapy is needed to reasonably prevent acute life-threatening events.

  • Important confounding conditions that influence the occurrence of apnea of prematurity are poorly recognized and/or integrated into care.

  • The relationship between gastroesophageal reflux (GER) and apnea of prematurity requires additional investigation because current knowledge suggests an infrequent association.

  • Improved characterization of the effects of apnea of prematurity on neurodevelopment during infancy and childhood is needed.

  • Other confounders associated with brain injury in preterm infants are difficult to separate from apnea of prematurity as meaningful causes of abnormal child development.

The NICHD review group also made recommendations about what issues associated with apnea of prematurity that need urgent attention, what research methods might be best for future studies, what outcomes are essential to our understanding of apnea of prematurity, and what ethical principles should govern future investigations of apnea of prematurity.

Given this discussion from the NICHD review group, the present article provides state-of-the-art information regarding what is and what is not known about apnea of prematurity.

Definitions

Apnea is defined as the cessation of breathing for more than 20 seconds or apnea or the cessation of breathing for less than 20 seconds if it is accompanied by bradycardia or oxygen (O2) desaturation.[9] Note the following:

  • Bradycardia in a premature neonate is considered clinically significant when the heart rate slows by least 30 bpm from the resting heart rate.

  • An O2 saturation level of less than 85% is considered pathologic in this age group, as is a decrease in O2 saturation should it persist for 5 seconds or longer.

These definitions represent clinically significant changes in apnea, bradycardia, and O2 saturation changes and rarely occur in healthy preterm neonates older than 36 weeks after conception.

Apnea is classified as central, obstructive, or mixed. Note the following:

  • Central apnea is defined as complete cessation of respiration, which can be differentiated from obstructive apnea through a pneumogram, with cessation of airflow and respiratory effort (see the image below).

    Central apnea is defined as the cessation of both Central apnea is defined as the cessation of both airflow and respiratory effort. ECG = electrocardiogram; HR = heart rate; THO = thoracic impedance; FLOW = air flow; ACT = ; SpO2 = peripheral oxygen saturation; STAGE = sleep stage.
  • Obstructive apnea is the cessation of airflow in the presence of continued respiratory effort.

  • Mixed apnea contains elements of both central and obstructive apnea (see the image below), either within the same apneic pause or at different times during a period of respiratory recording.

    Polysomnogram. Mixed apnea contains elements of bo Polysomnogram. Mixed apnea contains elements of both central and obstructive apnea. ECG = electrocardiogram; HR = heart rate (bpm); THO = thoracic movement; FLOW = flow the from nose and mouth; ACT = gross body movement; SpO2 = peripheral oxygen saturation (%); STAGE = sleep stage, where AT = active sleep.

Apnea of infancy

Apnea of infancy (AOI) occurs when apnea persists in a neonate older than 37 weeks after conception. The physiologic aspects of apnea of prematurity and AOI coincide, though further studies are needed to determine their exact relationship.

Periodic breathing

Periodic breathing is defined as periods of regular respiration for as long as 20 seconds followed by apneic periods of 10 seconds or less that occur at least 3 times in succession (see the image below).

Polysomnogram. Periodic breathing is defined as pe Polysomnogram. Periodic breathing is defined as periods of regular respiration for as long as 20 seconds followed by apneic periods no longer than 10 seconds that occur at least 3 times in succession. ECG = electrocardiogram; HR = heart rate (bpm); THO = thoracic movement; FLOW = flow the from nose and mouth; ACT = gross body movement.

Periodic breathing may be observed for 2-6% of the breathing time in healthy term neonates and as much as 25% of the breathing time in preterm neonates. The occurrence of periodic breathing is directly proportional to the degree of prematurity.

Kelly and coworkers observed periodic breathing in 78% of neonates examined at 0-2 weeks of age.[10] The incidence substantially declined to 29% at the postconceptual ages of 39-52 weeks.

Periodic breathing typically does not occur in neonates during their first 2 days of life.

Periodic breathing most frequently occurs during active sleep, but it can also happen when neonates are awake or quietly sleeping. This pattern, commonly observed in patients at high altitudes, is eliminated with supplemental oxygenation and/or with the use of continuous positive airway pressure (CPAP). Because the prognosis is excellent and because the infant is not compromised, no treatment is usually required.

Pathophysiology

Central respiratory regulation

Immaturity and/or depression of the central respiratory drive to the muscles of respiration have been accepted as key factors in the pathogenesis of apnea of prematurity.[1] Vulnerability of the ventral surface of the medulla and adjacent areas in the brainstem to inhibitory mechanisms is the likely explanation for why apneic episodes occur in prematurely born infants. This vulnerability involves diverse clinicopathologic events.[4, 11] Inhibitory events that affect the central respiratory generator and initiate apnea include hypoxia, hyperthermia and adenosine secretion.[12] Studies of preterm infants and in animals (especially genetically altered mice) have enhanced our understanding of the molecular and biochemical events leading to maturation of the central respiratory generator in preterm infants.[2, 3, 13, 14]

Using noninvasive techniques, Henderson-Smart and coworkers documented that brainstem conduction times of auditory-evoked responses were longer in infants with apnea than in matched premature infants without apnea.[15] This study elucidated apnea in preterm infants by indirectly showing that infants with apnea had greater-than-expected immaturity of brainstem function, which was based on postconceptional age. This finding supports the concept than an immature brainstem eventually develops control of breathing as dendritic spines and synaptic connections mature. An observation that emphasizes the importance of the central respiratory generator is the finding of increased apnea among preterm infants with bilirubin-encephalopathy diagnosed by using abnormal auditory brainstem-evoked responses.[16]

The absence of respiratory muscle activity during central apnea unequivocally implicates depression of respiratory center output. In support of this concept, Gauda and associates (1989) documented reduced electromyographic activity in the diaphragm during spontaneous obstructed inspiratory efforts.[17] Such efforts characterize combined central and obstructive apnea.[18] Therefore, episodes of both central and mixed apneic share an element of decreased respiratory center output to the respiratory muscles.

Sleep state and apnea

Apnea during infancy occurs most frequently during active or REM sleep.[19, 20] Apnea occurs relatively infrequently during quiet sleep, when respiration is characteristically regular, with little breath-to-breath variation in tidal volume and respiratory rate. However, periodic breathing may predominantly occur during non-REM sleep. During active sleep, respiration is mostly paradoxical due to spinal motoneural inhibition of the activity of intercostal muscles.[21]

In extremely preterm infants, the paucity of quiet sleep, together with an extremely compliant rib cage, makes paradoxical chest-wall movements almost a constant phenomenon. Paradoxical chest movement may predispose the baby to apnea by decreasing functional residual capacity (FRC) and limiting oxygenation.[22]

Chemoreceptors and mechanoreceptors

Complex relationships exist between respiratory control; several sites of central chemosensitivity to carbon dioxide (CO2) during sleep; and various neuromechanical factors originating in the lungs, chest wall, and upper airway that modify respiratory function during sleep.[23]

Responses of chemoreceptors in preterm and term neonates were recently reviewed.[24, 25, 26] The response to elevated CO2 concentrations was blunted in prematurely born infants. This diminished response may partly be due to decreased central chemosensitivity or mechanical factors that prevent an adequate ventilatory response.[27, 28]

The slope of the response curve for CO2 is decreased for preterm infants who have apnea.[29] However, a cause-and-effect relationship between decreased CO2 responsiveness and apnea of prematurity has not been clearly established. Administration of CO2 ameliorates periodic breathing, but inhalation of CO2 is not a therapeutic option for human infants.

For many years, scientists have known that preterm infants respond to a decrease in inspired O2 concentration with a transient increase in ventilatory response, followed by return to baseline or even depression of ventilation.[30] This response to low O2 in infants appears to result from initial stimulation of peripheral chemoreceptors then overriding depression of the respiratory center as a result of hypoxemia.[31] Consistent with these findings is the observation that a progressive decrease in inspired O2 concentrations causes a significant flattening of CO2 responsiveness in preterm infants.[32]

This unstable response to low inspired O2 levels may play an important role in the origin of neonatal apnea. It offers a physiologic rationale for the decrease in incidence of apnea observed when a slightly increased concentration of inspired O2 is administered to infants with apnea.[33]

The Hering-Breuer reflex also plays an important role in modulating respiratory timing in human neonates. Pulmonary stretch receptors send an afferent neural input to brain and mediate the Hering-Breuer reflex by means of the vagus nerve. Thereafter, they inhibit inspiration, prolong expiration, or both, while increasing lung volume.[22] Active shortening of expiratory duration with decreased lung volume may provide a breathing strategy for preserving FRC in a neonate with a highly compliant chest wall.

Upper airway obstruction substantially contributes to apneic episodes in preterm infants, and upper airway muscles show preferential reflex activation in response to airway obstruction in infants.[34]

Gerhardt and Bancalari compared the ability of preterm infants with and those without apnea to respond to end-expiratory airway occlusion.[29, 35] Prolongation of the occluded inspiratory effort was significantly prolonged in the group without apnea. This finding suggested that this group had a relatively mature respiratory reflex response that improved their ability to respond to airway obstruction.

In premature infants, complex changes in pulmonary mechanics and ventilatory timing accompany apnea.[36] Before apnea occurs, total pulmonary resistance may increase in association with a decrease in tidal volume and prolongation of the expiratory time. Such changes have been noted before episodes of mixed, obstructive, and central apnea.

In 1982, Waggener and coworkers showed that a diminution in respiratory drive precedes apnea, a finding reminiscent of the cyclic alterations in respiratory drive.[37] After apnea resolves and respiration resumes, the respiratory drive in premature infants initially increases, possibly because of a cumulative effect of hypoxia and hypercapnia. Total pulmonary and supraglottic resistance also increases, perhaps in response to a decrease in lung volume and collapse of the upper airway when respiratory drive declines during the apnea.

Of note, within 2 or 3 breaths after apnea, pulmonary resistance and respiratory drive is restored to normal pre-apnea values in premature infants. Therefore, the neural systems that restore respiratory homeostasis appear to be capable of mounting an adequate response, even in premature infants with apnea.

Upper airway instability and muscles of the chest wall

Premature infants have pharyngeal or laryngeal obstruction during spontaneous apnea.

Thach (1983) proposed a model in which the negative luminal pressures generated during inspiration in the upper airway predispose a compliant pharynx to collapse.[38]

Many muscles of the upper airway, especially the genioglossus muscles, have been widely implicated in mixed and obstructive apnea affecting both infants and adults. Carlo, Martin, and Difiore compared the activity of the genioglossus muscles with that of the diaphragm in response to hypercapnic stimulation.[39] In preterm infants, genioglossus activation was delayed for about one minute after CO2 rebreathing was begun, and it occurred only after a CO2 threshold of approximately 45 mm Hg was reached.

In neonates inspiratory time is often modestly prolonged when end-expiratory airway occlusion prevents lung inflation. As indicated earlier, this effect is a manifestation of the Hering-Breuer reflex.

Studies in animals demonstrated that this vagally mediated inhibition of normal lung inflation has more influence on the upper airway muscles than on the diaphragm.[40]

Upper airway reflexes

The upper airway contains many sensory nerve endings that may respond to various chemical and mechanical stimuli. Sensory input from these upper airway receptors travels to the CNS by means of cranial nerves V, VI, IX, X, XI, and XII. They may strongly affect respiratory rate and rhythm, heart rate, and vascular resistance.[41]

The chemoreceptor drive may augment the ability of the upper airway muscles to respond to increasing negative pressure, whereas input from pulmonary stretch receptors inhibits it.[42]

Swallowing during the respiratory pause is unique to apnea and does not occur during periodic breathing.[43]

Effects of adenosine

Adenosine and its analogs cause respiratory depression.[44] Adenosine antagonism is proposed as a mechanism to explain the therapeutic effect of aminophylline.[45]

Gastroesophageal reflux

GER and apnea are common in preterm infants. Because they often coexist, a lively and ongoing debate persists among healthcare professionals about the role of GER in apnea of prematurity.

An extensive literature review was undertaken to justify arguments about the role of GER in apnea of prematurity. Monitoring studies demonstrated that, when a relationship between reflux and apnea is observed, apnea may precede rather than follow reflux.[46, 47] During an apneic episode, loss of respiratory neural output may be accompanied by a decrease in lower esophageal tone, and GER occurs.

This phenomenon is supported by data from a newborn piglet model, which showed that hypoxia and apnea were accompanied by a reduction in lower esophageal sphincter pressure, which was a predisposing factor for GER.[48]

GER and apnea are also discussed in Differentials and in Special Concerns.

Etiology

The physiology related to apnea of prematurity is reviewed in Pathophysiology. Aspects of causation are briefly reemphasized here.

A premature neonate in whom all other causes of apnea have been excluded may be considered to have apnea of prematurity. Although the etiology of apnea of prematurity is not fully understood, several mechanisms have been proposed to explain this condition, including those described below.

  • 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. (For an excellent review of this topic, see the article by Darnall et al.[1] )

  • 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 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.[49]

  • Findings from several studies have not demonstrated a relationship between episodes of apnea and episodes of acid reflux into the esophagus (see Pathophysiology and Differentials).

  • Menon, Schefft, and Thach observed that regurgitation of formula into the pharynx after feeding was associated with an increased incidence of apnea in premature infants.[50] 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 GER to methylxanthines is based on the literature about asthma, and limited studies in neonatal only suggest its occurrence.[51] Some authors have not related the use of methylxanthine to severe GER disease.[52]

Epidemiology

United States data

Although not always apparent, apnea of prematurity is the most common problem in premature neonates. Approximately 70% of babies born before 34 weeks of gestation have clinically significant apnea, bradycardia, or O2 desaturation during their hospital stay. The more immature the infant, the higher his or her risk of apnea of prematurity. Apnea may occur during the postnatal period in 25% of neonates who weighed less than 2500 g at birth and in 84% of neonates who weigh less than 1000 g.

Carlo and Barrington showed that apnea may begin on the first day of life in neonates without respiratory distress syndrome.[53, 54] However, apnea of prematurity is always a diagnosis of exclusion. Many diseases manifest with apnea on the day of birth; examples are intrapartum magnesium exposure, systemic infections or the fetal inflammatory response syndrome, pneumonia, intracranial pathology, seizures, hypoglycemia, and other metabolic disturbances.

Approximately 50% or more of surviving infants who weighed less than 1500 g at birth have episodes of apnea that must be managed with pharmacologic intervention or ventilatory support. Mixed apnea accounts for about 50% of all cases of apnea in premature neonates; about 40% are central apneas, and 10% are obstructive apneas.[55] These percentages vary in different reports. In 50% of all apneic episodes, an obstructive component precedes or follows central apnea, which leads to mixed apnea.

International data

To the authors' knowledge, no investigators have compared the incidence of apnea of prematurity in the United States with those of other countries.

Race-, sex-, and age-related demographics

The authors know of no systematic, prospective clinical study that has been conducted to evaluate the role of a person's race/ethnic background or sex on the incidence of apnea of prematurity.

A young gestational age at birth is associated with an increased incidence of apnea of prematurity. The age at which apnea of prematurity resolves depends on several factors. The mean time for severe apnea of prematurity to resolve is approximately 43 weeks after conception, but a prolonged duration of risk is not uncommon.[9]

In one report, about 6-22% of babies with a very low birth weight had apnea at term.[56] Approximately 91% of premature neonates had apnea of longer than 12 seconds at the time of hospital discharge. Of these babies, 31% also had bradycardia, and 6.5% required prolonged hospitalization because of the severity of their apnea and bradycardia.

These findings show that apnea of prematurity does not resolve at term in many low birth weight infants and that it may persist for some time after hospital discharge.

Prognosis

Mortality/morbidity

Butcher-Puech and coworkers 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.[57]

In 1985, Perlman and Volpe described a decrease in the cerebral blood flow velocity that accompanies severe bradycardia (heart rate < 80 bpm).[58] Infants with clinically significant apnea of prematurity do not perform as well as prematurely born infants without recurrent apneas during neurodevelopmental follow-up testing.[59, 60]

Patient Education

Family members and others involved in the care of an infant with apnea of prematurity should be well trained in cardiopulmonary resuscitation (CPR).

Many of the pitfalls of home monitoring can be avoided by providing 24-hour telephone access (the ideal level of service) to a designated physician or nurse who is involved in the infant's care. In addition to this access, families should receive frequent, regularly scheduled telephone calls from healthcare providers, as well as home visits by a nurse or respiratory technician or follow-up appointments in a clinic familiar with this field of care.

For patient education resources, see Children's Health Center, as well as Sudden Infant Death Syndrome (SIDS).

 

Presentation

History

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 (AOP) 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.[61]

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.

Classification of the severity of apnea

Criteria to classify the severity of apnea 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.[62] 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 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).

Exclusion of other causes of apnea

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

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.[63] 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.[64]

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.[65]

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.[66] 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.

 

DDx

Diagnostic Considerations

Apnea of prematurity (AOP) is a diagnosis of exclusion. For many diseases in preterm infants, apnea is a presenting symptom. The causes of these diseases are different when the differential diagnosis occurs shortly after birth compared with later in the patient's hospital stay. Other etiologies must be sought before drug and/or ventilatory therapies for apnea of prematurity are started.

Conditions associated with apnea

Shortly after birth, apnea can be a manifestation of several types of conditions. Consider the following:

  • Respiratory distress syndrome and other pulmonary conditions

  • Infections (eg, congenital pneumonia, bacteremia, meningitis, fetal or neonatal inflammatory response syndrome)

  • Hypoglycemia and other metabolic diseases

  • CNS pathology (eg, trauma, intracranial hemorrhage, anoxia and/or ischemia, stroke)

The aforementioned brain insults may be noticed because patients may have seizures and/or associated apnea.[58, 67] Some of the diseases cited above also occur relatively late during the hospitalization of prematurely born infants, but the signs and symptoms may or may not include apnea.

Intraventricular hemorrhage and posthemorrhagic hydrocephalus without seizures increases the frequency of apnea in preterm infants.[57, 68]

Other conditions associated with apnea in preterm infants during their hospitalization

Nosocomial bacterial or fungal infection

Apnea, bradycardia, and desaturations are presenting symptoms of nosocomial infections caused by bacteria and fungi or viral agents.[69, 70]

In a study of 9 infants in an NICU who had respiratory syncytial viral infection, 8 had apnea as a manifestation of disease.[71]

Apnea is also common in preterm infants with Ureaplasma urealyticum infection.[72]

Necrotizing enterocolitis

In addition, apnea is one of several signs and symptoms associated with the onset of necrotizing enterocolitis.[73]

Systemic inflammation

It is well known to the caregivers in the NICU that premature infants who present with a cluster of multiple episodes of apnea, bradycardia, and desaturations could be showing signs of developing sepsis. During the sepsis, the inflammatory mediators and cytokines play a major role in the development of apnea bradycardia and desaturations. Lipopolysaccharide (LPS) attenuates the sensitivity of the carotid body, which leads to the development of apnea, bradycardia, and desaturations.[74]

Exposure to magnesium

The administration of magnesium to prevent seizures in preeclampsia and tocolysis of preterm labor has been associated with hypoventilation, apnea, and other adverse effects in preterm infants.[75] Hypermagnesemia during parenteral nutrition has also been a cause of apnea.[76]

Anemia

Disagreement exists regarding the role of clinically significant anemia in the development of apnea among convalescing preterm infants. Westkamp and colleagues reported that blood transfusions lowered heart and respiratory rates but had little effect on apnea of prematurity.[77] Bell and associates conversely found that liberal versus restrictive blood transfusion significantly reduced apnea.[78] The recent interest in the adverse neurodevelopmental outcomes observed in preterm infants with anemia and low iron status emphasizes neonatology-related awareness of the problem.[79]

Anemia, apnea of prematurity, and blood transfusion

The etiology of apnea in a premature infant is a multifactorial; however, it is a common practice to transfuse packed red blood cells in an infant who is anemic and having multiple episodes of apnea and bradycardia. Many studies have shown conflicting results, as many variables play a role in the pathogenesis of apnea of prematurity. One retrospective study found that packed red blood cell transfusion reduces the number of apneic events in premature infants, with many limitations.[80] When anemia of prematurity and apnea of prematurity occur in conjunction, clinicians are more inclined to transfuse at higher hematocrit levels in affected infants than in infants without apnea of prematurity. Zagol et al observed more cardiopulmonary events during the 72 hours period prior to the blood transfusion compared to 72 hours after the transfusion.[81] Clinicians should judge the merits of transfusion.

Surgery

Postoperative apnea occurs in preterm infants, particularly those whose intraoperative pain relief involved general anesthesia.[82, 83]

Additional research is required to determine whether spinal anesthesia, different analgesic agents, or caffeine can mitigate morbidity associated with apnea after surgery in prematurely born infants.[84, 85]

Immunization

Apnea transiently increases or recurs in hospitalized preterm infants after immunization. The increase in apnea has been attributed to the whole-cell pertussis component.[86] Investigators have observed reduced morbidity with newer vaccines that contain acellular pertussis.[87, 88] Some recent reports still identified clinically significant apnea and other adverse events.[89, 90]

Eye examination

Premature infants routinely undergo screening eye evaluations for retinopathy of prematurity in the NICU. Note that approximately 19% to 25% of infants experience an increased number of apneic spells after these routine eye examinations.[91]

Gastroesophageal reflux

As stated earlier, controversy exists regarding the role of gastroesophageal reflux (GER) as a causative factor in apnea of prematurity. One perspective is that the 2 conditions are related.[51, 92] Laryngeal edema identified during fiberoptic laryngeal endoscopy has been associated with GER, and antireflux surgery has dramatically reduced apnea in preterm infants at highest risk.[93, 94, 95]

Past and recent research failed to reveal a temporal relationship between GER and apnea of prematurity.[46, 47, 96, 97, 98]

Therefore, the NICHD Review Group on Apnea of Prematurity has called for additional investigations with rigorous research designs.

Skin-to-skin contact, or kangaroo care

Skin-to-skin contact, or kangaroo care, for preterm infants has been associated with an increased occurrence of apnea, bradycardia, and desaturation; this appears to be unrelated to hyperthermia.[99, 100] The observation suggests that obstructive events may occur during skin-to-skin contact. These findings call attention to the importance of environmental hyperthermia as a cause of apnea in preterm infants.[101, 102]

No adverse events appear to occur during kangaroo care.[103]

The disparity among the reported studies may be related to the specific practice of skin-to-skin care in a particular NICU or the validity of monitoring during skin-to-skin contact.[104]

Differential Diagnoses

 

Workup

Laboratory Studies

A CBC 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 (AOP). 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 (see Maternal Chorioamnionitis).

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.[105]

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).[106]

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).[107]

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

Several studies may reveal diagnostic findings in selected infants. These 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.[108, 109]

 

Treatment

Medical Care

Goal of medical therapy

The principal goals of treating apnea of prematurity (AOP) 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 O2 desaturation can be life saving, and assisted ventilation and O2 may be required to prevent injury to the 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 O2 desaturation. For example, an infant who has an inadequate response to tactile stimulation and O2 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 O2 desaturation, common treatments include stimulation (usually tactile), methylxanthine, or assisted ventilation (eg, nasal continuous positive airway pressure [CPAP], mechanical ventilation).[110]

Pantalitschka et al 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.[111] 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.

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.[112]

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

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.[113] Infants with long intervals between apneic event often have risk factors other than apnea of prematurity (AOP).

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.

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.[114]

Long-Term Monitoring

Home monitoring

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.[9]  There is no data to suggest that home monitoring can prevent SIDS in preterm infants with the diagnosis of apnea of prematurity.[65]

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 (see Special Concerns).

The National Institutes of Health (NIH) 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.[9]

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 (NRP) 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[25, 115] :

  • 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 AAP offered positioning recommendations in its Back to Sleep campaign.[116] 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.[117, 118] 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.

 

Medication

Medication Summary

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.

Questions have been raised regarding short- and long-term adverse effects in preterm infants.[119] 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 (AOP) is in progress.[120]

For the purpose of this review, pharmacotherapy is based on the 2006 NeoFax.[110] This is the source for information regarding the administration, adverse effects, and interactions of methylxanthines (eg, drug and solution compatibility).

Caffeine

Caffeine is the preferred drug for treating apnea of prematurity.[85] Caffeine is also the most acceptable prophylactic agent to facilitate successful extubation in preterm infants.[121] Caffeine therapy may reduce the rate of bronchopulmonary dysplasia in very low-birth-weight infants.[122]

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.[123] They also suggest starting caffeine early in the high-risk premature neonate, since caffeine has been associated with better long-term outcome.[124] 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.[125]

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.[126]

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.[127]

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.[128, 129] This latter effect may be desired in infants with bronchopulmonary dysplasia.

One concern is that aminophylline may decrease cerebral blood flow.[130, 131, 132, 133, 134]

Early reports in the literature also indicate a concern about the role that aminophylline may play in the occurrence or severity of necrotizing enterocolitis.[135, 136, 137]

Doxapram

Doxapram is excluded as a therapy for apnea of prematurity because it is associated with reduced cerebral blood flow.[138, 139] Use of doxapram was not strongly recommended in a Cochrane Review.[140] 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.

Home Monitoring

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.

For more information about follow-up care, see Follow-up.

Methylxanthines

Class Summary

Aminophylline appears to stimulate skeletal and diaphragmatic muscle contraction, increase the sensitivity of the ventilatory center to CO2, and stimulate the central respiratory drive.

Aminophylline, theophylline, and caffeine act as nonspecific inhibitors of adenosine A1 and adenosine A2a receptors.[119] It is this last effect that raises concerns about the safety of methylxanthine therapy in preterm infants.

Aminophylline (Aminophyllin)

Indications include AOP (eg, apnea after extubation from assisted ventilation, apnea after general anesthesia, apnea during use of prostaglandin E1 to treat ductal-dependent heart defects).

Stimulates central respiratory drive and peripheral chemoreceptor activity; may increase diaphragmatic contractility.

Aminophylline salt is 78.9% theophylline; theophylline PO is 80% bioavailable. May need to adjust dose when changing from IV aminophylline to PO theophylline. In neonates, aminophylline significantly (30-80%) interconverted to caffeine.

IV and PO forms effective in about 80-85% of infants with central apnea.

Caffeine citrate (Cafcit)

Indications include AOP (eg, apnea after extubation from assisted ventilation, apnea after general anesthesia). Therapeutic index more favorable than that of aminophylline.

Increases output of respiratory center, sensitivity of chemoreceptor to CO2, smooth muscle relaxation, and cardiac output.

Serum half-life 40-230 h, which declines until 60-wk postmenstrual age.

 

Follow-up

Complications

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.

Prognosis

Regarding the natural history of apnea in infants born prematurely, the frequencies of all types of apnea gradually decreases during the first months of postnatal life. However, in some infants, apnea may persist until the age of 44 weeks after conception.