Infantile Apnea

Infantile apnea is a rare disease that is characterized by cessation of breathing in an infant for at least 20 seconds or a shorter respiratory pause that is associated with a slow heart rate, bluish discoloration of the skin, extreme paleness, gagging, choking, and/or decreased muscle tone. Apnea of prematurity is defined as a sudden cessation of breathing that lasts for at least 20 seconds or is accompanied by bradycardia or oxygen desaturation (cyanosis) in an infant younger than 37 weeks gestational age.

Apnea is a term used to describe the temporary absence of spontaneous breathing defined as an unexplained episode of cessation of breathing lasting 20 seconds or longer, or a shorter respiratory pause associated with bradycardia, cyanosis, pallor, and/or marked hypotonia. Infantile apnea occurs in children under the age of one year. Apnea may occur because of neurological impairment of the respiratory rhythm or obstruction of airflow through the air passages. The symptoms of infantile apnea include the stoppage of breathing during sleep, abnormal bluish discoloration of the skin (cyanosis), and sometimes an unusually slow heartbeat (bradycardia). Infantile apnea may be related to some cases of sudden infant death syndrome. Episodes of apnea may decrease with age. However, several forms of adult sleep apnea also exist.

Classification

There are three major categories of apnea known as central, obstructive, and mixed apnea.^[rx]^[rx]^[rx]

Central Apnea

Central apnea is characterized by insufficient responsiveness from respiratory centers such as the medulla, which results in poor coordination of the body systems that are necessary for breathing.^[rx]^[rx] Respiratory muscles and nerves lose the ability to effectively receive and process signals from the brain causing respiratory efforts to cease.^[rx] Central apnea is quite common and can be found in healthy, full-term infants for short periods before breathing patterns in the infant stabilize.^[rx] In premature infants, central apnea is attributed to an underdeveloped respiratory system which results in decreased response to higher carbon dioxide levels and difficulty breathing.^[rx] Head trauma may also cause central apnea as it interferes with normal signaling of the central respiratory system, this might be present in infants who suffer from abuse so investigating patient background is an important consideration.^[rx]

Obstructive Apnea

Obstructive apnea occurs when the airway passages are obstructed and little to no air exchange occurs, resulting in impaired breathing.^[rx]^[rx] In some cases, it occurs when patients are born with a small airway opening.^[rx] Patients with obstructive apnea often have vigorous inspiratory effort but the efforts are still ineffective.^[rx] Normally, the muscles at the level of the throat relax and dilate while asleep to open up the airway however, patients with obstructive apnea may have decreased neuromuscular tone of the muscles responsible for dilating the pharynx during sleep.^[rx] The inability of the vocal cords to move and the presence of a foreign body may also cause obstructive apnea.^[1]^[rx] Cases of obstructive apnea are rarely found in infants who are healthy.^[rx]

Mixed Apnea

Mixed apnea is a combination of both central and obstructive factors.^[rx] The majority of premature infants with sleep apnea have mixed apnea.^[rx]Mixed apnea occurs predominantly among premature infants but can also be caused by gastroesophageal reflux, pertussis, and bronchiolitis.

Apnea of prematurity

It is defined as a sudden cessation of breathing that lasts for at least 20 seconds or is accompanied by bradycardia or oxygen desaturation (cyanosis) in an infant younger than 37 weeks gestational age.

Apnea of infancy

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

Causes

The exact cause of infantile apnea is not known. It may occur as the result of a combination of environmental and developmental factors (multifactorial). In extremely rare cases, central infantile apnea may be familial and affect more family members than would otherwise be expected.

Causes of Central apnea include central nervous system (CNS) infections (meningitis, encephalitis), head trauma (birth asphyxia or abusive trauma), toxin exposure, pertussis, infant botulism, inborn errors of metabolism (mitochondrial disease, Pompe disease, Leigh syndrome, and the mucopolysaccharidoses), metabolic derangements (hypoglycemia, hypocalcemia, and acidosis) and congenital anomalies (congenital central hypoventilation, Down syndrome and Arnold-Chiari malformation). Obstructive apnea can occur due to obstructive sleep apnea, infections (pneumonia, croup), vocal cord paralysis, and congenital upper airway anomalies (e.g., Pierre-Robin sequence)

Other conditions that predispose individuals to obstructive sleep apnea (OSA) include:

Craniofacial anomalies (Pierre Robin sequence, Beckwith-Wiedemann syndrome, Apert syndrome, Treacher Collins syndrome)
Chronic nasal obstruction (severe septal deviation, allergic rhinitis, nasal polyps)
Down syndrome
Metabolic abnormalities (mucopolysaccharidosis)
Infections (supraglottis, croup, bronchiolitis, pneumonia)
Asthma attacks,
Foreign body in the airway
Congenital chest wall deformities.

Disease condition

Craniofacial

Maxillary hypoplasia

Craniosynostosis

Apert

Crouzon

Pfeiffer

Muenke

Saether-Chotzen

Achondroplasia

Down’s syndrome

Treacher Collins

Micrognathia

Nonsyndromic Robin sequence

Syndromic Robin sequence (Stickler, Treacher Collins)

Nager syndrome

Hemifacial microsomia

Macroglossia

Beckwith-Wiedemann

Down’s syndrome

Hemangioma, lymphangioma

Achondroplasia

Laryngeal

Laryngomalacia

Vocal cord paralysis

Laryngeal edema

Congenital subglottic stenosis

Acquired subglottic stenosis

Laryngeal web/cysts

Hemangiomas

Neurological

Cerebral palsy

Chiari malformation

Spinal muscular atrophy

Mitochondrial disorders

Nasal obstruction

Choanal atresia

Pyriform aperture stenosis

Nasolacrimal duct cysts

Upper respiratory infection

Nasogastric tube

Septal deviation

Allergic rhinitis

Respiratory mechanics/ventilatory control

High chest wall compliance

Rib configuration round/horizontal

Small diaphragmatic zone of apposition

High metabolic rate

NREM apneic threshold close to eupneic CO₂ level

Ventilation–perfusion mismatch

Miscellaneous

Prader-Willi syndrome

Mucopolysaccharidoses

Gastroesophageal reflux

Obesity

Adenotonsillar hypertrophy (generally >6 mo of age)

Maternal smoking during gestation

Increased REM sleep

Neck flexion

Respiratory Infection

Sleep deprivation

Sedatives

Sickle cell anemia has been associated with OSA, but its mechanism is unclear. Predominant central causes of apnea include central nervous system (CNS) infections, raised intracranial pressure (accidental or inflicted head trauma, hydrocephalus, tumors), toxin exposures (CNS depressants, carbon monoxide poisoning), and central idiopathic hypoventilation. Neuromuscular disorders (Guillain-Barré syndrome, Duchenne muscular dystrophy, Werdnig-Hoffman disease) often cause mixed apnea. Morbid obesity itself can cause hypoventilation (Pickwickian syndrome) and predispose to apnea. Laryngospasm can occur as a protective reflex during episodes of gastroesophageal reflux and should be suspected when episodes are associated with feeding.

Related Disorders

Symptoms of the following disorders can be similar to those of infantile apnea. Comparisons may be useful for a differential diagnosis:

Sudden infant death syndrome (SIDS) is the sudden death of an infant or young child that is unexpected, based on their medical history, and for which no adequate cause for death can be found. Infants are not breathing during a time when they are presumed to be sleeping. The exact relationship between sudden infant death syndrome and infantile apnea is not clear. (For more information on this disorder, choose “sudden infant death” as your search term in the Rare Disease Database.)

Apnea in infants may occur for many reasons. Infants who are born prematurely (less than 34 weeks gestation) may experience episodes of apnea. It is also important to rule out other causes of apnea such as Hypoglycemia, Sepsis, Meningitis, Hyaline Membrane Disease, Arnold Chiari Syndrome, Down’s Syndrome, enlarged adenoids, anemia, gastro-esophageal reflux, craniofacial abnormalities, Zellweger Syndrome, Holoprosencephaly, Alpers Syndrome, Schinzel-Giedion Syndrome, chromosomal abnormalities, and intracranial hemorrhage. (For more information on these disorders, choose “Hypoglycemia”, “Meningitis”, “Arnold Chiari”, “Zellwenger”, “Holoprosencephaly”, “Alpers”, “Schinzel-Giedion” and “Chromosomal” as your search terms in the Rare Disease Database.)

Symptoms

The symptoms of infantile apnea include the temporary cessation of breathing; an abnormal bluish discoloration of the skin, lips, and mouth (cyanosis), and/or an unusually slow heartbeat (bradycardia). Serious apnea is defined as the cessation of breathing during sleep for longer than 10 to 15 seconds.

Infantile sleep apnea may occur in several forms. The normal rate of respiration is regulated by groups of nerve cells in the brain. They control the rhythm of breathing in response to changing oxygen levels in the blood (respiratory drive). In central apnea, the respiratory drive is low and, during apneic episodes, there are no chest movements and no air passes through the mouth or nostrils. In this form of the disease, the brain does not send adequate signals to the diaphragm and lungs. Breathing stops and does not resume until the oxygen-starved brain sends impulses to the diaphragm and lungs.

In obstructive apnea (upper airway apnea), the airway is blocked and breathing may become difficult. Blockage may occur for a variety of reasons including the collapse of the soft tissues of the throat. In this form of apnea, chest movements are present, but there is no airflow into the lungs. When breathing resumes, infants may make a loud “snorting noise” and become aroused from sleep. Obstructive apnea does not involve the cessation of breathing; rather, the affected infant struggles to breathe and has increased respiratory effort.

Central apnea followed by or together with obstructive apnea is known as mixed apnea.

Some research indicates that in many cases the symptoms of infantile apnea may decrease with advancing age.

Diagnosis

History and Physical

The initial history should be aimed to differentiate between a true apneic episode and periodic breathing or breath-holding spell. Once deemed as an apneic episode, a thorough review of the antenatal, perinatal, postnatal, and feeding history should be done. History of apneic episodes should be elicited as this indicates a life-threatening underlying cause and a higher probability of recurrence. The family history of seizures, infant deaths, and the presence of serious illnesses in family members should also be ascertained. Social history should ask about potentially toxic exposures, including drugs or medications in the home, tobacco smoke exposure, and potential carbon monoxide exposure. Associated symptoms such as sleep problems, snoring, and mouth breathing should be inquired about. A physical exam often provides valuable clues and aids to identify congenital anomalies, genetic syndromes, or stigmata of inborn errors of metabolism and congenital infections. Fever or hypothermia can raise the suspicion of sepsis or other infectious processes, tachypnea may indicate a lower respiratory tract infection or metabolic acidosis, and stridor indicates upper airway obstruction. Unexplained skin bruises should raise a suspicion of child abuse.

The performance of lab and imaging studies should be guided by the history and physical exam findings. In neonates, complete blood count, serum glucose, calcium, and electrolyte measurement can be considered. If the infant is febrile or hypothermic and a serious infection is suspected, appropriate cultures of blood, urine, and possibly cerebrospinal fluid (CSF) should be obtained. An EKG can be done to rule out cardiac dysrhythmias, especially the Long QT syndrome. Neuroimaging, EEG, and specialist consults are not routinely recommended unless specifically indicated by the clinical picture. If the patient meets low-risk criteria for a Brief Resolved Unexplained Event (BRUE), no lab studies are indicated.[rx][rx]

Treatment

To help prevent the potentially severe complications of infantile apnea, home apnea and cardiac monitors can alert a parent or caregiver to an episode of symptoms. These devices should be purchased only under the advice of a physician who is knowledgeable about the safety and effectiveness of apnea and cardiac monitors. Treatment may sometimes include the administration of drugs that stimulate the respiratory system (i.e., theophylline or caffeine). Parents and caregivers should be knowledgeable in lifesaving techniques such as cardiopulmonary resuscitation (CPR). In some infants, overheating should be avoided to possibly help reduce the frequency of apneic episodes. The infant should sleep in a supine position unless he/she has obstructive sleep apnea or gastroesophageal reflux.

Overall medical therapy has limited value in OSA. Fluticasone administered nasally for six weeks reduced the frequency of obstructive events in children, but the effect is not long-lasting, and it was used in mild OSA. Systemic steroids have no role in treating OSA. In a double-blind, randomized control trial, oral montelukast for six weeks decreased the severity of OSA and adenoidal hypertrophy. Consultation with specialists should be based on the identified cause of apnea.

If the symptoms of infantile apnea are severe, the drug aminophylline or another xanthine medication may be prescribed. Oxygen may be supplied as needed. For those infants with obstructive or mixed apnea, a medical device known as a continuous positive airway pressure (CPAP) may be used to assist with regular breathing. A mask is placed on the infant’s nose and is connected through a tube to the CPAP device. This machine forces air through the tube at low pressure which is sufficient to keep the infant’s upper airway open and to allow air to enter the lungs.

Medical Therapy

Infants with the PRS sequence may experience less airway obstruction in the prone position, but this therapy alone is adequate only in infants with mild obstruction. Infants with PRS should undergo nasopharyngoscopy and bronchoscopy to determine the site of obstruction and to identify any comorbid airway abnormalities. Although prone positioning has been associated with a twofold increase in SIDS, the overall incidence of SIDS in prone-sleeping infants remains less than 2 per 1000 infants. In infants with PRS sequence, the improvement in OSA observed in the prone position may result in a favorable risk-to-benefit ratio for this intervention. We recommend continuous pulse oximetry monitoring of all infants placed pronely. Positional therapy was successful in clinical reporting in improving airway obstruction in 72% of infants with nonsyndromic PRS and 50% of infants with syndromic PRS (rx). However, the observation that micrognathia infants with OSA may be relatively silent during apnea mandates that comprehensive polysomnography is used to verify improvement (rx, rx). Approximately one-third of infants with PRS who fail to respond sufficiently to positional therapy will respond to nasopharyngeal airway intubation (rx). A standard 3.0- or 3.5-sized endotracheal tube placed transnasally to the level of the hypopharynx is used to stent open the airway, thus alleviating OSA. Most infants respond dramatically to the nasopharyngeal tube but they are unable to feed, and the tube must be replaced every 4–6 weeks. Parhizkar and colleagues reported that 75% (26 of 35) of infants with micrognathia treated by nasopharyngeal airway placement did not require any further airway intervention, although objective testing was not performed (RX).

Surgical Therapy

Adenotonsillectomy (T&A) or adenoidectomy is an effective therapy for OSA in infants with adenotonsillar hypertrophy (rx, rx), although residual OSA is common (rx). T&A for OSA in infants has been reported to improve growth and development (rx, rx). However, infants with OSA undergoing T&A have more postoperative respiratory and airway complications than older children (rx). Also, after T&A, 65% of children less than 3 years old with OSA have at least moderate residual OSA (rx) compared with 29% of older children (rx). Infants should be monitored carefully, in the hospital, after T&A for obstruction and hypoxemia that may require CPAP or reintubation (rx, rx).

Surgical management of laryngomalacia in infants with OSA has evolved away from tracheotomy in favor of supraglottoplasty, using endoscopic techniques, resulting in reduced morbidity and resolution of OSA in the majority of infants (rx). A supraglottoplasty includes incising the aryepiglottic folds to release the epiglottis, removing redundant soft tissue overriding the accessory cartilages, and removing the lateral edges of the epiglottis. Before performing the endoscopic operative procedure the airway must be fully evaluated by direct laryngoscopy and bronchoscopy to determine the presence of any synchronous airway lesions. Complications are rare after supraglottoplasty and the infant usually requires 1–2 days of hospitalization.

Infants born with syndromic micrognathia often present with severe OSA that may persist long-term because of poor mandibular growth, and are more likely to benefit from mandibular distraction. The choice and urgency of therapy are predicated on the severity of the airway obstruction, the presence of obstruction when awake, and the adequacy of feeding. These infants often receive temporizing treatments, including prone positioning, oxygen, CPAP, or a nasopharyngeal tube. These therapies are frequently ineffective or are too poorly tolerated to be used long-term. With CPAP, a considerable effort is made at providing a properly fitting mask and facilitate acceptance of this mode of therapy. Cheng and colleagues reported that 6 of 20 infants with the PRS failed a trial of CPAP (rx). Infants with PRS and OSA who are not responsive to medical management are evaluated for surgical intervention, including lip–tongue adhesion, mandibular distraction, and tracheostomy. Our experience over the last decade supports the use of mandibular distraction as the first-line surgical treatment.

Lip–tongue adhesion (LTA) consists of a surgical fixation between the mucosa and muscles of the lip and tongue. LTA is a relatively simple operation with rare serious long-term complications. Bijnen and colleagues reported that LTA resulted in clinical improvement in OSA in 60% of infants with isolated tongue-based obstruction (rx). Sedaghat and colleagues documented at least partial polysomnographic improvement after LTA in eight infants with PRS (rx). Preoperatively, seven of eight infants had severe OSA, and postoperatively, one infant had resolution of OSA, two had mild OSA, and two had moderate OSA. Thus, residual moderate to severe OSA was present in five of eight infants. Similarly, Denny and colleagues performed LTA in 11 infants with PRS (7 syndromic) and reported that 10 of the infants required an additional airway intervention (rx).

Mandibular distraction osteogenesis (MDO) involves bilateral osteotomies of the mandibular rami and the placement of a distraction apparatus bilaterally. The surgery requires approximately 3 hours, results in less than 30 ml of blood loss, and infants are generally extubated within 3–6 days (rx). The device is extended daily 1–2 mm for 3 weeks, left in place for 3 months, and then removed. The goal of distraction is to produce a 23- to 30-mm distraction resulting in a slight overcorrection with a class III malocclusion (rx). Mandibular distraction has been reported to alleviate sleep-disordered breathing in micrognathia infants, as well as to improve feeding and growth (rx, rx). The preponderance of studies has reported both short- and long-term near-normalization of OSA after MDO (rx, rx). However, Cheng and colleagues reported a series of PRS infants with comorbid airway lesions including laryngomalacia, choanal atresia, tracheal stenosis, and epiglottal abnormalities who had moderate or severe residual OSA after MDO and LTA (rx). In infants with syndromic micrognathia, nasopharyngoscopy and/or imaging studies are helpful in clearly determining the site of obstruction and identifying comorbid airway abnormalities. Infants with Stickler syndrome typically have isolated micrognathia, whereas infants with Treacher Collins syndrome or Nager syndrome commonly have secondary sites of obstruction. MDO is reserved for infants in whom the tongue has been documented to abut the posterior pharyngeal wall, either directly or with the soft palate interposed. Infants with evidence of obstruction other than the posterior tongue may not benefit from MDO, and tracheostomy should be considered (rx). After MDO, infants with PRS may generally have successful closure of their cleft palate (rx). Complications of MDO, rarely reported, include facial nerve injuries, facial scarring, disruption of tooth buds, and temporomandibular joint dysfunction.

Infants with craniosynostosis (midfacial hypoplasia) often experience relief of OSA after placement of a nasopharyngeal tube (rx, rx). However, one large series reported that 48% of patients with syndromic craniosynostosis required tracheotomy for airway obstruction (rx). Infants with craniosynostosis usually have OSA due to naso- and oropharyngeal crowding that is multifactorial. Several surgical options are available depending on the age of the child and the site of obstruction. T&A is helpful in older infants and children with craniosynostosis, although residual OSA is frequently present (rx). Single-stage midfacial advancement is associated with considerable morbidity and has variable success in relieving OSA in children with craniosynostosis (rx, rx). Gradual craniofacial distraction may provide greater advancement and more resolution of OSA (rx). Often multiple surgeries are required and a tracheostomy and CPAP should be discussed and considered.

Tracheostomy placement in infants with craniofacial abnormalities is generally reserved for those with multiple sites of obstruction. The mean duration of tracheostomy placement in infants with OSA is 17 months in nonsyndromic children with PRS, and 32 months in syndromic children with PRS (rx). Most infants undergoing tracheostomy will have a resolution of their OSA after mandibular growth during this interval (rx). Tracheostomy may also be considered in an infant with OSA who is difficult to intubate and is likely to require multiple future surgeries. Tracheostomy in infants is associated with considerable morbidity including infections, tracheal stenosis, granulomas, bleeding, fistulas, tracheomalacia, and accidental decannulation (rx, rx).

Investigational Therapies

Studies are ongoing to determine the causes of and new therapies for infantile apnea. Some drugs (e.g., primidone, etc.) are being studied for use in the treatment of this disease in infants who are resistant to theophylline. More studies are needed to determine the long-term safety and effectiveness of these drugs for the treatment of infantile apnea.