Basics
Description
- Apnea of infancy is 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 in infants with gestational age (GA) of 37 weeks or more at the onset of apnea.
- Apnea of prematurity (AOP) is a pause of breathing for >15 " 20 seconds or accompanied by oxygen desaturation (Spo2 ≤80% for ≥4 seconds) and bradycardia (heart rate <2/3 of baseline for ≥4 seconds) in infants born <37 weeks GA.
- Mechanisms of apnea
- Central apnea
- Caused by decreased central nervous system (CNS) stimuli to respiratory muscles
- No evidence of obstruction to airflow but absent chest wall motion
- Obstructive apnea
- Can be due to factors such as pharyngeal instability, neck flexion, nasopharyngeal occlusion
- Characterized by absent airflow but persistent chest wall motion
- Mixed apnea
- Mixed etiology, with obstructive apnea preceding (usually) or following central apnea
- Periodic breathing is a normal neonatal breathing pattern, defined by ≥3 pauses, each ≥3 seconds, with <20 seconds of regular respiration between pauses.
Epidemiology
- Apnea and bradycardia occur in ~2% of all healthy term infants.
- AOP is inversely correlated to GA. It occurs in <10% of neonates 34 " 35 weeks GA and in almost all neonates <28 weeks GA at birth.
Risk Factors
- Prematurity is the most common cause of apnea.
- Risk factors common to both AOP and apnea of infancy are as follows:
- Age (infant <30 days old at higher risk)
- Upper respiratory tract infections
- Gastroesophageal reflux (GER)
- Anemia
- Cardiac arrhythmias
- CNS insult (hemorrhage, seizure, tumors)
- Immunizations (after DTaP injection)
- Maternal medications, such as magnesium sulfate, prostaglandins, or narcotics
Pathophysiology
- Immature respiratory control in neonates
- Immature chemoreceptors in brainstem and in the periphery (carotid body) may lead to decrease in respiratory drive and apnea.
- Hypoxic ventilatory depression
- Newborn infants have enhanced sensitivity of respiratory control system to inhibitory neurotransmitters (such as gamma aminobutyric acid [GABA], adenosine, serotonin, and prostaglandin) that can lead to apnea.
- Impaired hypercapnic ventilatory response
- Prolonging expiratory time (but not increasing frequency or overall tidal volume) may lead to less minute volume as well as uncoordinated movements of respiratory muscles in response to hypercapnia, resulting in apnea.
- Laryngeal chemoreflex
- Activation of laryngeal chemoreceptors (via superior laryngeal nerve afferents) as seen in GER can result in apnea, bradycardia, and hypotension.
- Sleep state
- Neonates spend majority of their time in active sleep. Apneas are more common during active sleep when respirations are irregular.
- Changes in neuromodulatory inputs and generalized inhibition of skeletal muscle activity during sleep are also contributory.
- Congenital central hypoventilation syndrome (CCHS)
- Alveolar hypoventilation due to abnormality in the central integration of chemoreceptor information as a result of PHOX2B mutation
Diagnosis
History
- Most important part of the evaluation is a thorough and appropriately tailored history.
- Detailed review of the event including time, duration, surrounding circumstances, relation to feeds, appearance of the infant, need for stimulation or resuscitation efforts, and extent
- Thorough details of past medical history including prenatal, birth, and neonatal course; history of prematurity, lung disease, previous apparent life-threatening events (ALTEs)
- Evaluate for recent illness, exposure to infection, feeding difficulties, medications, or vaccines
- Significant family history includes smoke exposure, previous infant deaths, genetic disorders, and cardiac/respiratory disorders.
- Probe for evidence or suspicion of child maltreatment.
Physical Exam
- Detailed physical examination, including vital signs, with particular attention to cardiorespiratory and neurologic system is very crucial in determining any underlying condition.
- Examine for signs of child abuse.
Diagnostic Tests & Interpretation
- Routine screening tests for various etiologies without historical risk factors or suggestive physical exam findings is a very low-yield process.
- Further testing should be based on clinician judgment depending on history and physical exam findings.
Alert
Initial diagnostic panel for ALTE patients should include CBC with differential, CRP, serum glucose and electrolytes, ABG, urine culture, urine toxicology screen, EKG, respiratory viral panel (RSV, flu, rhinovirus), and pertussis culture.
Lab
Ammonia, lactate, pyruvate if there are concerns of a metabolic syndrome
Imaging
- Chest x-ray to evaluate for infection or cardiac disease
- Skeletal survey if child abuse is suspected
- Head CT or head ultrasound (if <6 months old) in suspected trauma or elevated intracranial pressure
- Head MRI, if indicated, to evaluate for congenital malformations
Diagnostic Procedures/Other
- EKG/Holter monitoring to evaluate for arrhythmias or conduction problems
- Lumbar puncture if sepsis/meningitis is in the differential diagnosis
- EEG to rule out seizures, especially in case of recurrent ALTE
- A pH probe or modified barium swallow if concerning ALTE is associated with feeding
- Sleep study for evaluation of different types of apnea
- Ophthalmologic exam to identify retinal hemorrhages if child abuse is suspected
Differential Diagnosis
Immaturity of respiratory control is the primary cause for AOP, but many coexisting factors can potentiate or worsen apnea. Apnea of infancy is uncommon and should warrant a thorough evaluation.
- Infections
- Respiratory illness: respiratory syncytial virus, pertussis, or pneumonia
- Sepsis, urinary tract infection, necrotizing enterocolitis, or CNS infection
- Environmental
- Suffocation, head injury
- Child abuse
- Hypothermia or hyperthermia
- Neurologic
- Seizure
- Intracranial hemorrhages, CNS malformations
- Hydrocephalus
- Neuromuscular disorders
- CNS tumors
- Post general anesthesia
- Respiratory
- Obstructive sleep apnea
- Nasal obstruction
- Airway obstruction
- Foreign body aspiration
- Breath-holding spells
- Vocal cord abnormality: laryngotracheomalacia
- Chest masses/malformations
- Pneumonia
- Upper respiratory tract infection
- Metabolic
- Inborn errors of metabolism
- Hypoglycemia or electrolyte disturbances
- Cardiovascular
- Congenital heart disease, patent ductus arteriosus (PDA)
- Arrhythmias: long QT syndrome, Wolff-Parkinson-White syndrome
- Cardiomyopathy
- Myocarditis
- Gastrointestinal
- GER, feeding hypoxemia
- Dysphagia or swallowing disorder, intussusception
- Toxin/drugs
- Overdose
- Sedatives, seizure medications, pain medications
- Hematologic
- Genetic
- CCHS
- Craniofacial anomalies (Pierre Robin sequence)
- Down syndrome
- Prader-Willi syndrome
Alert
Preterm infants with a high frequency of apnea associated with chronic intermittent hypoxia need prolonged respiratory support, take longer to achieve oral feeds, have a greater incidence of retinopathy of prematurity, and have greater risk of adverse neurodevelopmental outcomes.
Treatment
Medication
- AOP: Methylxanthines (theophylline and caffeine citrate) are used in hospital settings. Caffeine is preferred due to better absorption, less toxicity, and a wider therapeutic window and half-life that allows once-daily dosing.
- Caffeine citrate (IV or PO) dosing: Loading dose of 20 mg/kg and maintenance dose of 5 " 8 mg/kg/day. Common side effects include tachycardia, arrhythmia, feeding intolerance, seizures, and diuresis.
- Usually, AOP resolves by 36 " 40 postmenstrual weeks; however, in more immature infants, born at less than 28 weeks ' gestation, apnea may continue until 40 " 43 weeks postmenstrual age. Once caffeine is discontinued, it is recommended to watch for 5 " 7 days.
Additional Treatment
General Measures
- Continuous positive airway pressure (CPAP) splints open the upper airway and improve oxygenation by increasing functional residual capacity. CPAP may be used to treat mixed and obstructive apnea. Positive pressure ventilation may be needed for severe or persistent apnea.
- Patients with a major ALTE should be observed with continuous cardiorespiratory monitoring for a minimum of 23 hours in a hospital setting.
- In case of ALTE where a specific cause was identified, medical or surgical treatment of underlying disorder is indicated.
- Follow-up of the infant with a health care practitioner is recommended within 48 hours after discharge.
Ongoing Care
Follow-up Recommendations
- Infants born before 37 weeks should pass a car seat test prior to discharge after birth.
- Caregivers should be instructed on back-to-sleep, crib safety measure, and avoidance of tobacco smoke exposure and trained in cardiopulmonary resuscitation.
- Home cardiorespiratory monitoring may be considered for infants with chronic lung disease (especially those requiring oxygen supplementation, CPAP, or ventilator). Home monitoring should be used in infants with a tracheostomy or with neurologic, genetic, or metabolic conditions affecting respiratory control. Parents should be appropriately counseled about the purpose, stresses, end point, and proper usage. Parents should be made aware that use of home monitoring does not reduce the risk for sudden infant death.
Prognosis
- Premature infants have 3 " 5% increased risk for sudden infant death syndrome (SIDS).
- AOP has not been found to be precursor or predictor of SIDS; however, there may be increased risk of SIDS in patients with ALTE.
Additional Reading
- Chu A, Hageman JR. Apparent life-threatening events in infancy. Pediatric Ann. 2013;42(2):78 " 83. [View Abstract]
- Di Fiore JM, Martin RJ, Gauda EB. Apnea of prematurity " perfect storm. Respir Physiol Neurobiol. 2013;189(2):213 " 222. [View Abstract]
- Fu LY, Moon RY. Apparent life-threatening events: an update. Pediatr Rev. 2012;33(8):361 " 368. [View Abstract]
- Tieder JS, Altman RL, Bonkowsky JL, et al. Management of apparent life-threatening events in infants: a systematic review. J Pediatr. 2013;163(1):94 " 99. [View Abstract]
- Zhao J, Gonzalez F, Mu D. Apnea of prematurity: from cause to treatment. Eur J Pediatr. 2011;170(9):1097 " 1105. [View Abstract]
Codes
ICD09
- 770.81 Primary apnea of newborn
- 770.82 Other apnea of newborn
- 327.21 Primary central sleep apnea
- 327.23 Obstructive sleep apnea (adult)(pediatric)
- 786.03 Apnea
ICD10
- P28.4 Other apnea of newborn
- P28.3 Primary sleep apnea of newborn
- G47.31 Primary central sleep apnea
- G47.33 Obstructive sleep apnea (adult) (pediatric)
SNOMED
- 13094009 Apnea in the newborn (finding)
- 276544005 Apnea of prematurity (disorder)
- 276545006 Obstructive apnea of newborn (disorder)
- 361208003 Primary sleep apnea of newborn (disorder)
- 1091000119108 obstructive sleep apnea of child (disorder)
FAQ
- Q: Should infants on caffeine for AOP be discharged home?
- A: It is not universal practice that infants with AOP are discharged home on caffeine and home monitoring. It is more common to discharge the infant home 5 " 7 days after caffeine has been discontinued.
- Q: What should be the end point of home monitoring?
- A: For AOP, if no true events are detected for several weeks and the infant is older than 43 weeks post menstrual age (PMA) and off of all respiratory stimulants for 7 days. For infants who are born at 23 " 25 weeks, apnea could persist beyond 43 weeks PMA. For monitoring in other cases, it would depend on the frequency and severity of the events.
- Q: What is the role of antireflux medication in the treatment of apnea?
- A: Controversy exists regarding the role of GER in causing apnea in premature infants. Reflux is most likely to trigger apneic events in term infants. Nevertheless, if there is a clear relationship between the apneic event and reflux, then a trial of antireflux medication is recommended. However, if there is no clinical improvement, it should be discontinued.