Apnea of Prematurity Clinical Presentation
- Author: Dharmendra J Nimavat, MD, FAAP; Chief Editor: Ted Rosenkrantz, MD more...
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.
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. This classification for apnea of prematurity uses the terms spontaneous, mild, moderate, or severe.
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 O 2 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 O 2 desaturation (ie, central cyanosis). A severe event requires vigorous stimulation, administration of an increased concentration of inspired O 2, 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. Caregivers should familiarize themselves with the advantages and disadvantages of cardiorespiratory monitoring and pulse oximetry in neonates.
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 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 includes the elements described below:
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.
- 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. 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.
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.  )
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 CO 2 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.
- 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.  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.  Some authors have not related the use of methylxanthine to severe GER disease. 
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