Overview: What every practitioner needs to know

Are you sure your patient has apnea of prematurity? What are the typical findings for this disease?

Apnea is a common feature of fetal breathing. As the fetus matures, breathing becomes more regular and sustained.

Apnea (cessation of air exchange) lasting more than 20 seconds:

Central—no diaphragmatic activity (see Figure 1)

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Figure 1.

Central apnea detected with impedence monitoring. SUM represents air flow. THOR is chest wall movement, ABD is abdominal wall movement and SAO2 represents oxygen saturation.

Obstructive—airway closure at the level of the nose, larynx, or pharynx

Mixed—components of central and obstructive (occurs in >50% of the apneic events in infants with apnea of prematurity) (see Figure 2)

Figure 2.

Impedence monitoring showing mixed apnea with associated desaturation.

Bradycardia: Heart rate less than 100 beats per minute for infants less than 37 weeks’ PCA. Short obstructive apnea may reflexively cause bradycardia.

Desaturation: A change of greater than 20% from pre existing value; desaturation can occur with shorter episodes of apnea (central, mixed, or obstructive), especially in infants with low functional residual capacity (FRC) and increased airway resistance.

What other disease/condition shares some of these symptoms?

Periodic breathing (see Figure 3): A breathing pattern characterized by cycles of hyperventilation with short respiratory pauses of 3-5 seconds. Periodic breathing is common in term and premature infants, is accentuated during hypoxemia, and results from increased activity from peripheral arterial chemoreceptors. Premature infants often experience desaturation events during periodic breathing, which is uncommon in term infants.

Figure 3.

Impedence monitoring showing periodic breathing with associated desaturation.

A number of conditions are associated with apnea. Below is a list of pathologic or transient conditions associated with apnea (in contrast to apnea of prematurity) as a developmental disorder.

Sepsis: Apneas associated with desaturation and bradycardia often increase when the infant has a concurrent bacterial, fungal, or viral infection.

Re-emerging apnea or increased frequency of apnea is a common presentation of viral infections (particularly infections with respiratory syncytial virus) in premature infants. Apnea may be seen before other signs and symptoms.

Bacteremia, meningitis, urinary tract infection, pneumonia, cellulitis, joint infections, and necrotizing enterocolitis should be ruled out in an infant with increased frequency or increased severity of apnea, bradycardia, and desaturation events.

Electrolyte imbalances: hyponatremia, hypokalemia, hypermagnesemia

Eye examinations for evaluation of retinopathy of prematurity: Cyclomidril eyedrops used to dilate eyes contain cyclopentolate hydrochloride (anticholinergic) and phenylephrine hydrochloride (α1-adrenergic receptor agonist). Systemic absorption of these agents can induce hypertension, with resulting reflex bradycardia in premature infants.

After immunizations: Immunizations with whole cell or acellular pertussis vaccine may be associated with a resurgence or worsening of apnea, bradycardia, and desaturation in former premature infants born at or before 32 weeks’ gestation.

After anesthesia: Inhalation anesthetics can lead to postoperative apnea in former premature infants with or without a history of apnea; infants who are less than 62 weeks PCA at the time of surgery should be monitored in the hospital for 12 hours after completion of the procedure.

Hyperthermia and hypothermia: Both ends of the neutral thermal environment may increase the frequency of apnea in premature infants.

Exposure to opioids and sedatives: Premature infants are particularly sensitive to the respiratory depressant effects of opioids.

Prostaglandin (PGE1): Prostaglandin infusion may cause respiratory depression in both term and premature infants.

Chronic lung disease associated with low FRC: This may increase the frequency of desaturation events in premature infants with apnea.

Gastroesophageal reflux (GER): Both apnea of prematurity and GER occur commonly in premature infants; controversy exists as to whether GER in premature infants exacerbates apnea either in frequency or severity. Some infants with intractable apnea and persistent bradycardia may benefit from a trial of transpyloric feedings or antireflux measures.

What caused this disease to develop at this time?

Birth before complete maturation of the central respiratory network and the peripheral reflexes that modulate this network, for example:

  • Immature properties of neurons that initiate inspiration and neuronal connections that drive ventilation.

  • Immaturity of cells and neurons in the brainstem that sense changes in PCO2/H+ central chemoreceptors).

  • Muscle fatigue of striatal muscles (upper airway and chest wall muscles and diaphragm).

  • Immaturity of peripheral reflexes (stretch receptors) that control the timing of inspiration and expiration.

  • Low apneic threshold (the level of arterial PCO2 that drives ventilation is within several millimeters of mercury of the level of PCO2 that causes apnea).

  • Hypersensitivity of peripheral arterial chemoreceptors to changes in oxygen and PCO2, contributing to unstable ventilation.

  • Low FRC, thereby leading to more hypoxemia during a short apneic event such as occurs during a Valsalva maneuver.

  • Narrow upper airway with decrease in pharyngeal tone.

  • Increase in nasal resistance.

  • Immature physiology contributing to ventilatory instability.

Central and peripheral mechanisms and local mechanisms contributing to ventilatory instability in premature infants:

Central chemoreceptors are primarily responsible for ventilatory responses to PCO2/H+ (although there are several groups of neurons in the brainstem that are chemosensitive, the greatest density of chemosensitive neurons are serotonergic neurons in the raphe of the caudal medulla and glutamatergic neurons in the retrotrapezoid nucleus located just below the ventral medullary surface).

Ventilatory responses to PCO2 are robust in premature infants, but less than in older infants and children and less still in premature infants with apnea.

The apneic threshold for PCO2, that is threshold at which decreasing arterial PCO2 results in apnea, is close to the resting arterial PCO2 in premature infants.

Peripheral chemoreceptors in the carotid body:

Primarily responsible for changes in ventilation in response to PO2.

Ventilatory response to hypoxia in premature infants is biphasic: an initial increase within the first 30-60 seconds followed by a decrease that can lead to apnea.

Peripheral arterial chemoreceptors have a greater influence on baseline ventilation in premature infants with apnea than they do in infants without apnea of prematurity (Figure 4).

Figure 4.

In response to hypoxia, premature infants reduce their ventilation below baseline levels in contrast to adult and older children.

Peripheral chemoreceptors are also responsive to changes in PCO2/H+, temperature, glucose, and osmolality.

Site of rhythymogenesis: Respiratory-related neurons within the brainstem orchestrate phasic network activity; some are activated during inspiratory, postinspiratory, and expiratory phases of respiration. These neurons are located in the pons and medulla.

Pre-Bötzinger neurons: These neurons are located in the ventral respiratory column, have pacemaker properties, and are essential to rhythmogenesis.

Laryngeal chemoreceptors: These are located in mucosa covering the interarytenoid space at the entrance of the larynx. Stimulation of these receptors p-precipitates the laryngeal chemoreflex (LCR) similar to the “dive reflex” reflex in animals which is characterized by apnea followed by hypoventilation, laryngeal constriction, swallowing, bradycardia, and peripheral vasoconstriction.

Laryngeal chemoreflex ( LCR): This is an airway protective reflex that is quite strong. In adults, activation of this reflex causes cough. In premature infants, activation of this reflex in premature infants causes significant and profound apnea associated with bradycardia and oxygen desaturation. This reflex may be operative in infants with discoordination of the suck and swallow who have apnea, bradycardia, and oxygen desaturation with oral feeding. These receptors may also be activated during gastroesophageal reflux when gastric contents reach the level of the oral pharynx.

Mechanoreceptors: Responds to mechanical changes and are mediated by myelinated fibers in the vagus nerve.

Upper airway mechanoreceptors: Negative pressure in the upper airway slows breathing and increases the activity of the upper airway dilating muscles: the ala nasi and geniglossus muscles in premature infants.

Lower airway mechanoreceptors:

Pulmonary stretch receptors: Slowly adapting stretch receptors (SARs) are activated by changes in lung volume: lung inflation inhibits inspiration and promotes expiration (Breuer-Hering reflex). Conversely, lung deflation promotes inspiration and inhibits expiration. The Breuer-Hering reflex is active at birth and decreases with maturation.

Rapid adapting receptors: These receptors are activated by lung deflation, mechanical stimulants, and chemical irritants and when activated induce augmented breaths (sighs) and mucus production. Rapid adapting receptors are active in premature infants, and augmented breaths (sighs) occur frequently. Augmented breaths restore lung volume, increase PaO2 and decrease PaCO2, which destabilize breathing, causing hypoventilation or apnea.

Pulmonary C fibers: These unmyelinated vagal fibers (pulmonary and bronchial) are activated by capsaicin, acidosis, reactive oxygen species, adenosine, hyperosmotic solutions and lung edema. Activation of bronchopulmonary C fibers leads to reflex bronchoconstriction and apnea in newborns. Activation of bronchopulmonary C fibers as a result of viral infections may cause apnea in premature infants. J-receptors are a subgroup of Pulmonary C fibers that are located in the alveoli, activated by pulmonary edema and causes rapid shallow breathing

Key neurotransmitters and neuromodulators regulating breathing:

NEUROTRANSMITTERS: Glutamate is the major neurotransmitter mediating excitatory synaptic input to brainstem respiratory neurons and respiratory premotor and motor neurons through binding to the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid kainite and metabotropic glutamate. GABA (gamma-aminobutyric acid) and glycine are the two major inhibitory neurotransmitters mediating inhibitory synaptic input in the respiratory network; they have a key role in pattern generation and termination of inspiratory activity. GABA (via GABAA receptors) and glycine (via glycine receptors) mediate fast synaptic inhibition via activation of chloride channels. GABAB receptors, which are metabotropic G-protein coupled receptors, have a greater role in inhibiting respiratory rhythm in adult mammals. However there is a development switch in GABA and glycine neurotransmission during embryonic and early postnatal development. Specifically during early development GABA and glycine receptors mediate excitatory neurotransmission putting the very premature infant at risk for an excitatory versus an inhibitory response to drugs that bind to these receptors, such as benzodiazepines.

NEUROMODULATORS: The major neuromodulators affecting respiratory control in infants and contribute to apnea include: adenosine, opiates, and prostaglandin E2 and E1, dopamine. All these neuromodulators can cause respiratory depression.

Upper airway hypotonia: A small pharynx with little airway tone contributes to passive closure of the pharynx specifically during active sleep and with an increase in nasal resistance.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Hemoglobin/hematocrit: There are studies that support that anemia in hospitalized infants may exacerbated apnea of prematurity and packed red blood cells transfusion (PRBCs) may improve the frequency or severity of events; however, there are many studies that do not support this hypothesis. The most recent data using highly sensitive continuous computer processing and computer algorithm to detect apnea, bradycardia and oxygen desaturations show a strong correlation between apnea and hemoglobin level in age-matched premature infants <32 weeks PMA, and an increase number of events 3 days prior to PRBC transfusion that were less for 3 days after the transfusion. PRBC transfusion is also associated with decrease in frequency of intermittent desaturations in premature infants who are > 1 week of age, although it is unlikely that hematocrits greater than 35% (12 g/dL of Hgb) would result in decreased oxygen carrying capacity with subsequent hypoxemia, hematocrits less than 26% (~9 g/dL Hgb) may. Postoperative apnea is more frequent in infants with hematocrits less than 24%. (~8 g/dL Hgb).

Platelet count.

Electrolyte, calcium, and magnesium levels; total and direct bilirubin.

Complete white blood cell count and differential.

C-reactive protein (CRP), which may be normal within the first 12-24 hours of infection and may remain low in urinary tract infections.

Blood culture, urine culture (catheterization or suprapubic tap), lumbar puncture (especially if the infant has a subgaleal or ventricular peritoneal shunt for treatment of posthemorrhagic hydrocephalus).

Would imaging studies be helpful? If so, which ones?

Chest radiograph, abdominal radiograph

In complex cases with intractable apnea that requires prolonged intubation and positive pressure ventilation, the following additional studies should be considered:

Ultrasonogram of the head to rule out an intracranial pathology such as extension of a previous intracranial bleed, or progressive hypodrocephalus.

Electroencephalogram to look for seizures that may present as apnea in infants with an intracranial pathologic condition.

Electrocardiogram with Holter monitoring to identify non-sinus bradyarrythmias that can be associated with atrial, junctional, and ventricular escape beats as a result of excessive vagal tone.

Transthoracic Echocardiogram to rule out cor pulmonale because premature infants at the limit of viability as they mature may develop cor pulmonale presenting with more severe hemoglobin desaturation episodes associated with short apneas.

Multichannel intraluminal impedance combined with polysomnography to determine whether the infant is having episodes of GER associated with apnea, bradycardia, and desaturation events.

Direct laryngoscopy to assess the vocal cords and subglottic area and to look for the presence of laryngomalacia and whether there is edema around the vocal cords suggesting GER, or subglottic narrowing in an infant who was previously intubated.

Direct Bronchoscopy to determine if bronchomalacia is present.

If you are able to confirm that the patient has apnea of prematurity, what treatment should be initiated?

Methylxanthines: Methylxanthines are the first line of therapy for apnea of prematurity. Mechanism of action: block adenosine receptors (A1, A2A) and inhibit phosphodiesterase activity, thereby increasing cyclic adenosine monophosphate levels.

Caffeine citrate is preferred over theophylline and aminophylline because caffeine has a wide therapeutic index with a long half-life (24 hours) and can be given intravenously or orally and can be dosed every 24 hours. It is not necessary to routinely obtain serum caffeine levels however, for the atypical infant who’s apnea persists and appears to be unresponsive to caffeine then a caffeine level can be helpful. Drug levels during theophylline therapy must be obtained.

Caffeine citrate has been approved by the Food and Drug Administration for treatment of apnea of prematurity, whereas theophylline has not. Caffeine citrate may also reduce the incidence of bronchopulmonary dysplasia, improve survival without an increase in neurodevelopmental disability, and reduce the incidence of cerebral palsy and cognitive delay at age 18-21 months, the protective effect of caffeine on survival without neurodevelopment impairment was no longer present at 5 years (PUBMED:17989382).

Animal data suggest that caffeine may be neuroprotective.

Doxapram hydrochloride: This is a respiratory stimulant; it activates central respiratory neurons and peripheral arterial chemoreceptors. The mechanism of action is unknown, but it increases excitability of chemoreceptor cells in the peripheral arterial chemoreceptors by inhibiting K+ channels. It increases tidal volume and respiratory frequency. It is used for persistent, significant apnea unresponsive to noninvasive ventilation (continuous positive airway pressure [CPAP]), and xanthines. It must be administered intravenously. It increases tidal volume and frequency in newborns.

CPAP administered through nasal prongs or mask: This is often used concurrently with caffeine. It splints the upper airway (nasal passages and pharynx) open and thus reduces the frequency of obstructive and mixed apnea. It also increases FRC and stabilizes oxygen levels during central apnea, improves lung compliance, decreases total pulmonary resistance, slows breathing rate by activating the mechanoreceptors in the lung (Breuer-Hering inflation index), and decreases periodic breathing because improved FRC increases oxygen stores.

Low-flow (<2 L/min; humidified at room temperature) and heated high-flow (2-8L/min; 100% humidified at 37ºC):

Nasal cannulas are often used concurrently with caffeine. They supply flow to upper airway mechanoreceptors and potentially generate distending pressure as well (CPAP). Both low-flow and heated high-flow nasal cannulas can potentially generate CPAP, resulting in increasing FRC. The level of generated CPAP is contingent on the diameter of the nasal cannula, the tightness of the fit in the nose, the size of the infant, and whether the mouth is open or closed.

Flow rate is more directly related to the level of generated CPAP in infants weighing 1500 g or less, with a nasal cannula outer diameter of 0.2 cm and the mouth closed. Tighter fitting nasal cannulas with lower flow rates can potentially generate high levels of CPAP (PUBMED:8416477).

Non-invasive ventilation: nasal intermittent positive pressure ventilation, synchronized and non-synchronized is often used concurrently with caffeine therapy. The positive pressure splints the upper airway (nasal passages and pharynx) open and therefore reduces the frequency of mixed and obstructive apnea. It also increases FRC thereby stabilizing oxygen levels during central apnea, improving lung compliance. Theoretically it may improve ventilation in the mechanical breaths or synchronized with the infants breaths. Nasal CPAP can increase FRC and thus stabilize oxygen levels during central apnea, improving lung compliance, and decreasing pulmonary resistance. It may provide effective ventilation when synchronized. Synchronized positive pressure non-invasive ventilation also decreases thoracoabdominal asynchrony, when synchronized, although it does not routinely improve carbon dioxide elimination. It appears to be more effective in reducing the frequency of apnea than CPAP alone (PUBMED:11869635).

Novel therapies for treatment of apnea of prematurity:

Inhaled carbon dioxide (0.8%) may be as effective in decreasing the frequency of apnea as theophylline without significant adverse effects (PUBMED:18534618).

Olfactory stimulation: Introducing a pleasant odor into the incubators of premature infants decreases the frequency of events over the next 24-hour period (PUBMED:15629985). Whether the infant acclimates to the stimulus over time has not been determined.

What are the adverse effects associated with each treatment option?

Methylxanthines: Caffeine, theophylline, and aminophylline may be associated with tachycardia, jitteriness, feeding intolerance (increases risk for GER), irritability, and seizures.

Doxapram hydrochloride must be administered by continuous infusion. Administration may result in elevated blood pressure, abdominal distention and increased gastric residuals, excessive irritability, jitteriness, and hypokalemia.

CPAP (nasal CPAP) may be associated with pressure necrosis of the nasal septum. Rotating nasal prongs with nasal mask decreases the frequency of this complication. Other effects may include deformation of the nares, abdominal distention and feeding intolerance, nasal obstruction (mechanical), and edema of the nasal mucosa.

Nasal intermittent positive-pressure ventilation may also be associated with pressure necrosis of the nasal septum, deformation of the nares, abdominal distention and feeding intolerance, and nasal obstruction and edema of the nasal mucosa.

Heated high-flow humidified nasal cannulas can cause 1) inadvertent high positive end-expiratory pressure, 2) rainout from increased water vapor stimulating laryngeal chemoreflexes, which may increase the frequency of apnea, and 3) increased work of breathing and carbon dioxide retention if the infant is unable to expire against a high flow rate.

What are the possible outcomes of apnea of prematurity?

Apnea of prematurity usually resolves between 34 and 37 weeks in infants born after 28 weeks’ gestation. Both frequency and duration of apnea decrease with increasing PCA. Apnea of prematurity may persist past term gestation in infants born before 25 weeks’ gestation.

Former premature infants have an increased incidence of sleep-disordered breathing during early infancy and childhood and as young adults. Former premature infants have a three- to fivefold increased risk of dying of sudden infant death syndrome (SIDS), although a previous history of apnea of prematurity does not increase this risk.

Former premature infants are at increased risk for having apnea and bradycardia after surgical procedures, eye examinations, and immunizations. Pre treatment with caffeine in former premature infants for surgical procedures occurring before 52 wks PMA, shows promise in reducing the frequency in postanesthesia apnea.

It is important that “back to sleep” guidelines be followed after discharge from the hospital for all infants including all infants born prematurely and even those infants with GER.

During the season when infections with respiratory syncytial virus is high, former premature infants should receive immunoprophylaxis (palivizumab) as outlined by the American Academy of Pediatrics.

Home apnea monitoring is not recommended for former premature infants in whom apnea of prematurity has resolved. Home apnea monitoring may be appropriate for the infant who is being discharged and still has apneic/bradycardic events not requiring intervention and who is otherwise maintaining body temperature out of an incubator and is taking adequate volume feedings by breast or bottle.

Prevalence of apnea of prematurity occurs in 7% of infants born between 34 and 45 weeks, 14% of infants born between 32 and 33 weeks, 54% of infants born between 30 and 31 weeks, and 80% of infants born before 30 weeks.

How do these pathogens/genes/exposures cause the disease?

Apnea of prematurity is a developmental, not a pathologic, disorder. As mentioned above, it may be worsened by pathologic conditions. The genetic contribution to apnea of prematurity is high. Concordance among same-gender twins is 87% (95% confidence interval, 0.64-0.97). Genetic factors account for 99% and 78% of the variance in male and female twins, respectively.

What is the evidence?

The following are classic papers describing ventilatory responses to changes in oxygen and carbon dioxide tension in premature infants: a must read for all neonatologists:

Alvaro, R, Alvarez, J, Kwiatkowski, K. “Small preterm infants (less than or equal to 1500 g) have only a sustained decrease in ventilation in response to hypoxia”. Pediatr Res. vol. 32. 1992. pp. 403-6.

Gerhardt, T, Bancalari, E.. “Apnea of prematurity: I. Lung function and regulation of breathing”. Pediatrics. vol. 74. 1984. pp. 58-62.

Henderson-Smart, DJ.. “The effect of gestational age on the incidence and duration of recurrent apnoea in newborn babies”. Aust Paediatr J. vol. 17. 1981. pp. 273-6.

Henderson-Smart, DJ, Pettigrew, AG, Campbell, DJ.. “Clinical apnea and brain-stem neural function in preterm infants”. N Engl J Med. vol. 308. 1983. pp. 353-7.

Poets, CF, Stebbens, VA, Samuels, MP. “The relationship between bradycardia, apnea, and hypoxemia in preterm infants”. Pediatr Res. vol. 34. 1993. pp. 144-7.

Ramanathan, R, Corwin, MJ, Hunt, CE. “Cardiorespiratory events recorded on home monitors: comparison of healthy infants with those at increased risk for SIDS”. JAMA. vol. 285. 2001. pp. 2199-207.

Rigatto, H, Brady, JP.. “Periodic breathing and apnea in preterm infants. I. Evidence for hypoventilation possibly due to central respiratory depression”. Pediatrics. vol. 50. 1972. pp. 202-218.

Rigatto, H, Brady, JP.. “Periodic breathing and apnea in preterm infants. II. Hypoxia as a primary event”. Pediatrics. vol. 50. 1972. pp. 219-28.

Rigatto, H, Brady, JP, de la Torre Verduzco, RV. “Chemoreceptor reflexes in preterm infants: II. The effect of gestational and postnatal age on the ventilatory response to inhaled carbon dioxide”. Pediatrics. vol. 55. 1975. pp. 614-62.

Alvaro, R, Alvarez, J, Kwiatkowski, K. “Small preterm infants (less than or equal to 1500 g) have only a sustained decrease in ventilation in response to hypoxia”. Pediatr Res. vol. 32. 1992. pp. 403-6.

Eichenwald, EC, Aina, A, Stark, AR.. “Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks”. Pediatrics. vol. 100. 1997. pp. 354-59. The following are excellent recent reviews of apnea of prematurity: one from the perspective of a neonatologist (Mathew) and the other from the perspective of an anesthesiologist (Sale).

Mathew, OP.. “Apnea of prematurity: pathogenesis and management strategies”. J Perinatol. vol. 31. 2011. pp. 302-10.

Sale, SM.. “Neonatal apnoea”. Best Pract Res Clin Anaesthesiol. vol. 24. 2010. pp. 323-36. The following are reviews describing the central neurocircuits involved in regulating breathing and associated neurotransmitter systems.

Alheid, GF, McCrimmon, DR.. “The chemical neuroanatomy of breathing”. Respir Physiol Neurobiol. vol. 164. 2008. pp. 3-11.

Doi, A, Ramirez, JM.. “Neuromodulation and the orchestration of the respiratory rhythm”. Respir Physiol Neurobiol. vol. 164. 2008. pp. 96-104.

Carroll, JL, Agarwal, A.. “Development of ventilatory control in infants”. Paediatr Respir Rev. vol. 11. 2010. pp. 199-207. The following are reviews describing the contribution of peripheral arterial chemoreceptors to respiratory instability in infants.

Al-Matary, A, Kutbi, I, Qurashi, M. “Increased peripheral chemoreceptor activity may be critical in destabilizing breathing in neonates”. Semin Perinatol. vol. 28. 2004. pp. 264-72.

Gauda, EB, McLemore, GL, Tolosa, J. “Maturation of peripheral arterial chemoreceptors in relation to neonatal apnoea”. Semin Neonatol. vol. 9. 2004. pp. 181-94.

Gauda, EB, Carroll, JL, Donnelly, DF.. “Developmental maturation of chemosensitivity to hypoxia of peripheral arterial chemoreceptors—invited article”. Adv Exp Med Biol. vol. 648. 2009. pp. 243-55. The following are reviews addressing the contribution of GER on the frequency of apnea of prematurity and the potential contribution of laryngeal chemoreflex.

Slocum, C, Hibbs, AM, Martin, RJ. “Infant apnea and gastroesophageal reflux: a critical review and framework for further investigation”. Curr Gastroenterol Rep. vol. 9. 2007. pp. 219-224.

Thach, BT.. “Reflux associated apnea in infants: evidence for a laryngeal chemoreflex”. Am J Med. vol. 103. 1997. pp. 120S-4S. The following articles provide evidence supporting therapies for apnea of prematurity—tried , true, and new.

Al-Saif, S, Alvaro, R, Manfreda, J. “A randomized controlled trial of theophylline versus CO inhalation for treating apnea of prematurity”. J Pediatr. vol. 153. 2008. pp. 513-8.

Henderson-Smart, D, Steer, P.. “Doxapram treatment for apnea in preterm infants”. Cochrane Database Syst Rev. 2004. pp. 4

Henderson-Smart, DJ, de Paoli, AG.. “Prophylactic methylxanthine for prevention of apnoea in preterm infants”. Cochrane Database Syst Rev. 2010. pp. CD000432

Henderson-Smart, DJ, Steer, PA.. “Caffeine versus theophylline for apnea in preterm infants”. Cochrane Database Syst Rev. 2010. pp. CD000273

Kubicka, ZJ, Limauro, J, Darnall, RA.. “Heated, humidified high-flow nasal cannula therapy: yet another way to deliver continuous positive airway pressure?”. Pediatrics. vol. 121. 2008. pp. 82-8.

Lemyre, B, Davis, PG, de Paoli, AG.. “Nasal intermittent positive pressure ventilation (NIPPV) versus nasal continuous positive airway pressure (NCPAP) for apnea of prematurity”. Cochrane Database Syst Rev. 2002. pp. CD002272

Locke, RG, Wolfson, MR, Shaffer, TH. “Inadvertent administration of positive end-distending pressure during nasal cannula flow”. Pediatrics. vol. 91. 1993. pp. 135-8.

Marlier, L, Gaugler, C, Messer, J.. “Olfactory stimulation prevents apnea in premature newborns”. Pediatrics. vol. 115. 2005. pp. 83-8.

Schmidt, B, Roberts, RS, Davis, P. “Caffeine therapy for apnea of prematurity”. N Engl J Med. vol. 354. 2006. pp. 2112-21.

Weintraub, Z, Alvaro, R, Kwiatkowski, K. “Effects of inhaled oxygen (up to 40%) on periodic breathing and apnea in preterm infants”. J Appl Physiol. vol. 72. 1992. pp. 116-20. The following are references describing the heritability of apnea of prematurity, epidemiology of SIDS, and later occurrence of sleep-disordered breathing in former premature infants.

Bloch-Salisbury, E, Hall, MH, Sharma, P. “Heritability of apnea of prematurity: a retrospective twin study”. Pediatrics. vol. 126. 2010. pp. e779-87.

Calhoun, SL, Vgontzas, AN, Mayes, SD. “Prenatal and perinatal complications: is it the link between race and SES and childhood sleep disordered breathing?”. J Clin Sleep Med. vol. 6. 2010. pp. 264-9.

Halloran, DR, Alexander, GR.. “Preterm delivery and age of SIDS death”. Ann Epidemiol. vol. 16. 2006. pp. 600-6.

Malloy, MH.. “Sudden infant death syndrome among extremely preterm infants: United States 1997-1999”. J Perinatol. vol. 24. 2004. pp. 181-7.

Montgomery-Downs, HE, Young, ME, Ross, MA. “Sleep-disordered breathing symptoms frequency and growth among prematurely born infants”. Sleep Med. vol. 11. 2010. pp. 263-7.

Paavonen, EJ, Strang-Karlsson, S, Raikkonen, K. “Very low birth weight increases risk for sleep-disordered breathing in young adulthood: the Helsinki Study of Very Low Birth Weight Adults”. Pediatrics. vol. 120. 2007. pp. 778-84.

Rubens, D1, Sarnat, HB. “Sudden infant death syndrome: an update and new perspectives of etiology”. Handb Clin Neurol.. vol. 112. 2013. pp. 867-74.

Ongoing controversies regarding etiology, diagnosis, treatment

Are there adverse consequences related to frequent apnea/bradycardia and associated desaturation that occurs in premature infants?

Intermittent hypoxemia is associated with cardiovascular and cognitive morbidities in adults with sleep-disordered breathing. Infants with a more prolonged course of apnea of prematurity during 31-37 weeks postmenstrual age have worse neurodevelopmental outcomes measured by Bayley scores (Mental Developmental Index and Psychomotor Developmental Index ) at 13 months.

This effect remains significant after adjusting for birth weight, duration of mechanical ventilation, and gestational age at birth. However, an intracranial pathology was also associated with higher frequency of apnea in infants between 31-37 weeks PMA. Thus it is unclear if the intracranial pathology contributed to the increased frequency of apnea, as suggested by the study from Ment et al. (PUBMED:4015773 ).

Is there a causal relationship between GER and increased frequency of apnea, bradycardia, and desaturation events in premature infants?

GER and apnea, bradycardia, and desaturation events occur frequently in premature infants. Evidence does exist that GER (nonacid reflux) in premature infants is associated with increased frequency of apnea and bradycardic events, and that treatment with antireflux strategies (pharmacologic, transpyloric feeding, and positioning) improves the frequency of these events (PUBMED:17267306). Similarly, an equal body of literature exists showing no-evidence that GER exacerbates apnea of prematurity. (PUBMED:17511920). There is a risk in medically treating premature infants with histamine receptor blockers (H2R) blockers. Specifically, rantidine appears to increase the risk of necrotizing enterocolitis, infections and death.

When is home apnea monitoring indicated?

Home apnea monitoring does not prevent SIDS. It may be appropriate for the premature infant who is being discharged and still has occasional apneic/bradycardic events not requiring intervention, is otherwise maintaining body temperature out of an incubator, and is taking adequate volume feedings by breast or bottle.

Home monitoring with pulse oximetry ± apnea monitor with data download capabilities should be considered for any infant being discharged on supplemental oxygen. Although not formally studied, home apnea monitoring should be considered for the infant who is being treated for chronic lung disease and who also has symptomatic GER. Since cardiorespiratory events can be associated with GER (detected with multichannel impedence monitor and pH probe) in a subgroup of former premature infants who are still having apnea, bradycardia and oxygen desaturations at term PMA. For infants discharged with home apnea monitoring, when to stop monitoring can be a challenge. A conservative approach is to continue home monitoring until the infant has either had an illness (such as upper respiratory tract infection) or receives an immunization, since these events can be associated with re-emergence of apnea and bradycardia in former premature infants. Infants should be monitored for 5-7 days off caffeine, either at home or in the hospital before discontinuing monitoring.

How soon after resolution of apnea of prematurity should the infant be observed before discharge to home without home monitoring?

After discontinuation of caffeine citrate, the infant should be observed for 5-7 days with no significant events occurring before discharge. For infants who were never treated with caffeine, it is customary to observe the infant for 5 days without apnea, bradycardia or desaturation events prior to discharge to home without monitoring