Practice Essentials
Apnea is defined by the cessation of respiratory airflow. The length of time necessary to be qualified as a true apneic event has changed dramatically over the last several decades: 2 minutes in 1956, [1] 1 minute in 1959, [2] 30 seconds in 1970, [3] and then 20 seconds or shorter if associated with bradycardia or cyanosis in 1978. [4] The reduction of the duration in the definition of apnea reveals doctors’ desire to intervene early enough to avoid systemic consequences.
The 3 main categories of apnea are central, obstructive, and mixed. Central apnea is a result of inadequate medullary responsiveness and thus results in no or poor muscle coordination for breathing. Obstructive apnea is when there is an obstruction of the airway passages and therefore poor to no air exchange. Often times with obstructive apnea, there is a vigorous inspiratory effort but it is ineffective against the obstruction. Mixed apnea refers to an episode where combinations of both central and obstructive forces are involved.
Background
Infant apnea is defined by the American Academy of Pediatrics 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." [5] Apnea is more common in preterm infants. Apnea of prematurity requires a specific assessment and treatment and is not discussed in full in this article. True apnea is rare among full-term healthy infants and, if present, may indicate an underlying pathology.
The ED physician may not experience many patients with pure apneic events but more likely will have an infant's caregiver come in and report that his or her child appeared to stop breathing, changed color, or became limp. This is a brief resolved unexplained event (BRUE), previously referred to as an apparent life threatening event (ALTE).
Previously, ALTE was defined as: "An episode that is frightening to the observer and is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking or gagging. In some cases, the observer fears that the infant has died. ALTE was meant to replace previous terminology, such as “near miss SIDS.”
ALTE was used as the description of an event or a presenting complaint. The potential underlying diagnoses were broad, and ranged from benign to extremely serious. The challenge with the assessment of the patient who experienced an ALTE often was determining via history if the event was in fact a true episode of apnea, cyanosis, or tone change, and to then use the physical examination findings and various diagnostic studies, if needed, to deduce the reason the event took place.
The American Academy of Pediatrics published a clinical practice guideline in 2016 recommending replacing the term apparent life threatening event (ALTE) with the new term brief resolved unexplained event (BRUE). [6] The goal of this new guideline was to refine the diagnosis to better assess the risk of an underlying serious disorder, and to provide evidence based recommendations on the management of lower risk infants. In an infant who presented with an ALTE, clinicians often times felt compelled to perform tests and hospitalize the patient even though this may have subjected him to unnecessary risk and was unlikely to lead to a treatable diagnosis or prevent future events. A study conducted in 200 analyzed 243 patients diagnosed with an ALTE on whom 3776 tests were performed. Only 5.9% of these tests contributed to reaching a diagnosis. [7]
According to the clinical practice guidelines on BRUE, the term should be used when describing an event that occurs in an infant younger than 1 year, when the caregiver reports a sudden, brief, and now resolved (meaning that the patient has returned to it’s baseline state of health) episode of 1 or more of the following:
-
Cyanosis or pallor
-
Absent, decreased or irregular breathing
-
Marked change in tone
-
Altered level of consciousness
Where as previously, GERD and feeding issues were the most diagnosed cause for ALTE second to idiopathic, this is no longer the case. If the event is thought to be feeding related (with choking, gagging, or vomiting) the diagnosis should be specific to the feeding issue alone despite the apparent serious reaction it caused in the child. Therefore, there is no indication for a BRUE diagnosis. [8]
The term BRUE is intended to better reflect the transient nature and lack of clear cause, and removes the “life threatening” label.
Apnea is a symptom that has large possibility of etiologies. In this article, some of the major etiologies of apneic events that an ED physician or primary care physician will encounter are discussed, namely, apnea of prematurity, BRUE, obstructive sleep apnea, and miscellaneous forms of apnea that are toxin mediated, secondary to head trauma, or caused by infections.
Pathophysiology
Apnea refers to a cessation of respiratory airflow and has 3 major types.
Central apnea
Central apnea occurs when there is a lack of respiratory effort due to either a cessation of output from the central respiratory centers or the inability of the efferent peripheral nerves and respiratory muscles required for oxygenation and ventilation to receive or process the signals from the brain. This can be due to immaturity of the system, as seen in certain premature infants, who have a decreased response to hypercapnia (increased carbon dioxide levels). Patients with central apnea have no respiratory effort. This can be seen by a lack of chest wall movement and no breath sounds will be appreciated on auscultation. [9]
Another cause of central apnea is head trauma, as it may interfere with the afferent and efferent signals of the central respiratory center. Head trauma may be the result of abuse and must always be considered in the apneic pediatric patient without an obvious cause. Toxin-mediated apnea is another form of central apnea, as it may cause central nervous system depression and decrease the respiratory drive.
Obstructive apnea
Obstructive apnea, as the name suggests, results from attempts to breathe through an occluded airway. Obstructive sleep apnea (OSA) is the most common form of obstructive apnea in children. Obstructive sleep apnea is on the sleep-disordered breathing (SDB) spectrum. The sleep-disordered breathing spectrum includes snoring, upper airway resistance syndrome, obstructive hypoventilation and, at its extreme, obstructive sleep apnea.
Mixed apnea
Mixed apnea has characteristics of both central apnea and obstructive apnea. Examples can include a patient with a partial obstructive apnea (due to adenotonsillar hypertrophy) who has undergone sedation (causing central apnea), or a premature infant with central apnea who has an obstruction due to nasal congestion brought on by a viral illness. Gastroesophageal reflux is thought to cause this mixed picture as regurgitated gastric contents may occlude the airway and block laryngeal chemoreceptors to send signals for dilation to the brain.
Etiology
Gastrointestinal causes
Apnea due to reflux often may be a mixed apnea with both central and obstructive tendencies. In older patients with gastroesophageal reflux (GER), apnea is most likely a result of laryngospasm. GER occurs in more than two-thirds of all infants. [10] It has been noted to cause apnea and hypoxia related to obstruction, laryngospasm, and aspiration. Before BRUE, GER was considered to be the most common identifiable etiology of ALTE second only to idiopathic, attributed in 20% to 54% of all patients. [11]
A choking episode is another possibility.
Neurological causes
Neurological causes of apnea include the following
-
Increased intracranial pressure: Such as occurs in congenital hydrocephalus. Examination reveals a large head circumference, as well as a fixed downward gaze (sundowning) of the eyes.
-
Idiopathic apnea (previously the leading cause of ALTE): The usual cause of apnea is unknown but is often presumed to be immaturity of the respiratory center, with a weak respiratory response to hypercapnia.
-
Seizure: Neonatal seizures are often different from those observed in older children, thought to be due to the lack of full myelinization of the peripheral nerves. Although apnea may result from seizures, it is usually not the only symptom. Most patients with seizures also have abnormal movements or posturing, and lateralizing eye movements. In past studies, 10-11% of patients with recurrent ALTE were found to have epilepsy. [12]
-
Head injury causing central apnea
-
Toxin-related central apnea: Certain drugs are known to cause respiratory depression (opiates, benzodiazepines, and barbiturates) and thus place the patient at risk for central apnea; however, in most pediatric apnea cases, the patient has no history of drug exposure. The examining physician should ask about the mother's use of medications, particularly if the infant is being breastfed. Carbon monoxide poisoning must also be considered because it is more likely to affect young infants (because of the greater affinity of CO for fetal hemoglobin) more than adults.
-
Secondhand smoke exposure: One study showed that in utero exposure to nicotine smoke has a negative effect on the chemoreceptors responsible for respiratory drive and may increase the risk of insufficient response to respiratory challenges during sleep. [13] This was confirmed when patients with suspected apnea were found to have less spontaneous arousals during sleep, especially when exposed to second-hand smoke. [13]
-
Breath-holding spells: In older infants, breath-holding spells may cause apnea. A breath-holding spell is usually triggered by an inciting event, namely frustration, surprise, anger, or fear. The infant usually cries, followed by a pause, and then becomes pale or blue. Occasionally, a breath-holding spell can lead to loss of consciousness and the infant will become limp. Breath-holding spells are self-limiting and do not put the infant in danger. There is no treatment for a breath-holding spell, because it is self-limited and benign. Supportive care is all that is needed. However, there needs to be significant education and reassurance given to the family. Breath-holding spells can begin as early as 6 months of age and are usually outgrown by mid-childhood. [11]
Respiratory causes
Upper/lower respiratory tract infection, either due to RSV or other infections (pertussis, influenza, human metapneumovirus, rhinovirus, or other respiratory pathogens), is the second most used discharge diagnosis for patients who initially present with apnea or suspected BRUE. [11]
Aspiration pneumonia may cause apnea of a mixed or obstructive picture and may have a GI, neurological, or a respiratory etiology.
Infectious causes
Upper/lower apnea may be the presenting symptom for sepsis or a serious bacterial infection (SBI). Previous studies have shown that the incidence of SBI presenting with ALTE is approximately 0-3%. [14, 15]
Cardiac causes
Cardiac arrhythmias can cause central apnea by disrupting the perfusion of the brain and lungs. Infants with previous cardiac surgery or known congenital defects near the conducting system may have an arrhythmia. In most cases, the cause is obscure. The infant presenting with BRUE, who ultimately has a cardiac cause, is less likely than others to present with primary apnea alone.
Congenital heart disease may present with cyanosis, hypoxia, and/or seizure.
The 5 T s of pediatric cardiac congenital malformations are as follows:
-
Tetralogy of Fallot
-
Transposition of the great vessels
-
Truncus arteriosus
-
Total anomalous pulmonary venous return
-
Tricuspid atresia
Other potential causes
In an ill-appearing infant, apnea may have many potential causes, including the following:
-
Infection (eg, sepsis, meningitis, bronchiolitis, infant botulism)
-
Dehydration or renal tubular acidosis
-
Child abuse, including physical abuse, Munchausen syndrome by proxy, and aborted infanticide.
-
Abuse should be considered when infants do not appear well on arrival. Careful physical examination should be performed to look for physical signs of abuse. Some of these physical exam findings include but are not limited to: retinal or subconjunctival hemorrhages, unexplained facial injuries such as a torn frenulum in the non ambulatory child, bruising in non ambulatory infants or bruising in unusual locations such as behind the ear or neck, under the chin, on the torso or buttocks, unexplained human bite marks, or unexplained burns.
-
Munchausen syndrome by proxy may be suspected in the infant who has an atypical history relating to the apnea, particularly when the family has been to several EDs and/or physicians with the same complaint and when "no one can find the cause." A previous SIDS death in the family also increases the risk of Munchausen by proxy. Although not found in all cases, family dynamics may include a father who is somewhat distant or uninvolved and a mother (usually the perpetrator) who has a healthcare background and who seems to identify with members of the healthcare team.
-
Home monitor alarm: Causes may include true apnea, but more commonly technical errors such as worn or faulty leads, improper placement of leads, a damaged monitor, failure to adjust the limits of the alarm to account for a decreasing normal pulse and respiratory rate as the infant ages, or noncompliance with monitoring. [16]
Epidemiology
United States statistics
An inverse relationship is found with apnea of prematurity for both birth weight and gestational age. Because advances in NICU care are steadily improving, the number of infants who are surviving ultra-premature births has expanded and therefore the number of children experiencing apnea of prematurity is also growing. Approximately 70% of babies born before 34 weeks gestation have clinically significant apnea, bradycardia, or oxygen desaturation during their hospital stay.
Prior to the new classification of BRUE, the true incidence of apparent life-threatening event (ALTE) was unknown but was thought to account for 2.3% of hospitalized children, and to occur in between 0.5% and 0.6% of all newborns. [17]
Since brief resolved unexplained event (BRUE) is a fairly new term having only been described since 2016, there are no reports to describe its epidemiology. In one recent study, BRUEs accounted for approximately 0.6% to 1.7% of all emergency department visits and 7.5% of calls to the emergency medical services system for infants younger than one year of age. [6]
Obstructive sleep apnea (OSA) has been previously shown to occur in almost 2% of the pediatric population, but that number is rapidly increasing secondary to the explosive incidence of obesity in the United States. In older pediatric textbooks, the classic picture of a patient with obstructive sleep apnea was of a patient who was thin and may have even been considered to have failure to thrive. However, currently, the typical patient with obstructive sleep apnea is significantly overweight. Recent evidence now suggests that sleep disordered breathing, which ranges from primary snoring to OSA, is more common among boys than girls, and among children who are heavier than others, with emerging data to suggest a higher prevalence among African Americans. [18]
There are certain conditions that classically have a high rate of OSA. These conditions include mucopolysaccharidosis, Trisomy 21, craniofacial anomalies, and obesity. Other causes of obstructive apnea are an aspirated foreign body and vocal cord paralysis.
Rosen et al ascertained the prevalence of and risk factors for obstructive sleep apnea syndrome in children with sickle cell anemia. The study concluded that the prevalence of obstructive sleep apnea syndrome in children with sickle cell anemia is higher than in the general pediatric population. [19]
One study has shown that the incidence of apnea can range from 1.2-23.8% in hospitalized infants with respiratory syncytial virus (RSV) bronchiolitis; however, the populations in the studies included premature and neuromuscularly impaired infants. [20]
When assessing apnea in non-RSV viral infections, one study showed that out of 51 apneic infants admitted with bronchiolitis, 13.7% had rhinovirus, while 23.5% had more than one viral infection. Another study analyzed 108 infants with apnea hospitalized at 16 sites spanning 3 winters, and found that apnea risk was similar across the major viral pathogens. [21] Still, RSV was the predominant virus in 33.3% of infants. [22]
International statistics
Prior to the new BRUE classification, the worldwide incidence of ALTE was unknown. One report from Sweden places the incidence of apnea during the first 4 days of life at 0.35 case per 1,000 population. [23] Another study from Italy suggests a cumulative incidence of 4.1 per 1,000 live births in the study area.
A Taiwanese population-based cohort study by Chen et al reported that children who are hospitalized due to enterovirus infection were at increased risk for obstructive sleep apnea (adjusted hazard ratio = 1.62, 95% CI: 1.18-2.21, P = 0.003). Allergic rhinitis was an additional factor that increased the risk. [24]
Sex- and age-related demographics
Most studies do not show a gender difference in the incidence of apnea of prematurity.
For BRUEs the male-to-female ratio is variable, but, in some studies, it has been as high as 2:1.
Sleep-disordered breathing continuum, of which OSA is on, appears to have a male predilection. The male to female ratio is estimated to range anywhere from 3:1 to 5:1 in the general population. [25]
The risk for apnea of prematurity is clearly linked to a younger gestational age at birth as well as lower birth weights. Almost all infants born less than 28 weeks’ gestation suffer from apnea. For infants born at 30-31 weeks, the risk is approximately 50%, and, for those born at 32-33 weeks, the risk is about 14%. The risk for those born at 34-35 weeks is 7%. [26]
The typical infant presenting after a BRUE is 8-14 weeks. Approximately 7% of these infants were born prematurely.
OSA can occur at any age; however, its incidence is bimodal. It has its first peak at age 2-6 years and then again later in adulthood.
Infections such as bronchiolitis, classically caused by RSV but also influenza, rhinovirus, human metapneumovirus, or any other viral pathogen can cause apnea. Acquiring the respiratory illness at a younger age puts the patient at much higher risk for apnea. [27]
A bimodal distribution exists for apnea caused by ingestions. Accidental ingestions most commonly occur after children are capable of a pincer grasp, approximately 9 months, until early childhood, whereas both non-accidental ingestions and illicit drug behavior occurs during adolescence.
Prognosis
The prognosis is case specific. In general, as the child matures, the cause of the suspected brief resolved unexplained event (BRUE) is diagnosed and treated or spontaneously resolves. If the apnea is determined to be idiopathic, the prognosis is generally excellent.
Morbidity/mortality
As previously discussed, there are different types of apnea, and each has its own unique set of possible causes. The outcome may vary significantly from one cause to another.
Apnea of prematurity frequently persists beyond term gestation in infants delivered at prior to 28 weeks' gestational age. These persistent apnea events may contribute to prolonged hospitalization and mortality. Clearly, if a premature infant with apnea is not taken care of in an appropriate medical setting, the morbidity and mortality can be significant.
The morbidity and mortality rates for the patient who has had a BRUE is difficult to assess. A meta-analysis by Brand et al determined that the risk of death after a BRUE is about the same as the baseline risk of death during the first year of life. [7]
Untreated obstructive sleep apnea can result in failure to thrive, cor pulmonale, and loss of intellectual quotient points. In a study performed in first grade children, OSA was found to be disproportionally high in children whose school performance was in the lowest 10% of their class. When children were treated for OSA, they showed significant academic improvement, whereas children who did not receive treatment did not improve academically. [28]
Apnea from miscellaneous sources, such an overwhelming sepsis, various infectious agents (RSV, influenza, pertussis, human metapneumovirus), toxic agents, or trauma, all carry very significant morbidity and mortality rates.
Complications
Because the etiologies are so variable, the complications relate to the specific cause of the apnea.
One complication that is often ignored is the psychological impact of home monitoring on the family. Monitoring places a tremendous amount of pressure on the caretakers. Families deal with these pressures in many ways. Some parents eventually stop using the monitor, whereas others become dependent on it. Some families experience renewed fears when they are told that their child no longer requires home monitoring.
Many of these stressors may be manifested in the ED. Parents of a child for whom home monitor is being discontinued may present to the ED with a complaint of frequent alarms to try to continue monitoring.
Patient Education
Parents of infants who are discharged should be instructed to return if more episodes occur, if episodes become associated with color change, or if new and/or worrisome findings (eg, fever, lethargy, frequent vomiting) develop. Infants who have had a choking episode should receive feeding instructions. Families of monitored infants should be reminded to maintain current CPR training.
For patient education resources, see the following from WebMD:
