Apnea of prematurity continues to be an extremely common disorder and a major source of morbidity in the growing number of premature infants who require neonatal intensive care. Apnea of prematurity has been defined as cessation of breathing for more than 20 seconds duration<xref ref-type="bibr" rid="bib001">1</xref>,<xref ref-type="bibr" rid="bib002">2</xref>. Shorter episodes of apnea may also be accompanied by significant bradycardia or hypoxia<xref ref-type="bibr" rid="bib003">3</xref>. Brief respiratory pauses of <10 seconds in duration can occur in connection with startle movement, defecation or swallowing during feeding<xref ref-type="bibr" rid="bib004">4</xref>.</sec><sec id="sec002"><title>Classification of Apnea

Apnea is traditionally classified into three categories based on presence or absence of obstruction of the upper airway. These include central, obstructive and mixed apnea. Most apnea are central or mixed in nature

Central apnea ((40%) – Characterized by total cessation of inspiratory efforts with no evidence of obstruction

Obstructive apnea (10%) – Neonate tries to breath against an obstructed upper airway, resulting in chest wall motion throughout apnea

Mixed apnea (50%) – Central apnea is either preceeded or followed by airway obstruction. This is most common variety.

Apnea needs to be differentiated from periodic breathing which is characterized by regular cycles of breathing of 10–18 seconds duration, interrupted by pauses of atleast 3 secs in duration, this pattern recurring for atleaset 2 minutes⁵. Although periodic breathing has been considered a benign respiratory pattern for which no treatment is required⁶, it shows some characteristics with apnea of prematurity. Both disorders tend to decline in frequency with advancing post-conceptional age and with administration of theophylline^7,8. However periodic breathing is not a precursor to significant apnea.

Incidence

Apneic spells occur frequently in premature infants and incidence is inversely related to gestational age. Incidence was found to be 19% for infants weighing between 1250–1750, 70% for infants weighing 1001 to 1250 and 84% for infants weighing less than 1000gms⁹.

Apneic spells occurring at term or near term are always abnormal and are nearly associated with serious identifiable causes like birth asphyxia, intracranial hemorrhage & seizures or depression from medication¹⁰.

Pathophysiology

Apnea of prematurity is thought to be secondary to immaturity of brainstem centres that regulate breathing. Immaturity in regulation of breathing is also manifested by immaturity in the respiratory response to hypoxia, hypercapnea and an exaggerated inhibitory response to stimulation of airway receptors.

Historically, immaturity of the preterm brain is manifested by a decreased number of synaptic connectors, dendritic arborization and poor myelination¹¹.

Chemoreceptor response to hypoxia and hypercapnia is decreased in preterm infants, which indicates that abnormal respiratory control may contribute to the pathogenesis of apnea¹². Often some of the active reflexes invoked by stimulation of the posterior pharynx, lung inflations, fluid in larynx or chest wall distortion can precipitate apnea. Vigorous use of suction catheters or milk in upper airway during feeding may trigger these reflexes.

Ineffective ventilation may result from impaired coordination of the inspiratory muscles namely diaphragm and intercostal muscles and the muscles of upper airways namely larynx and pharynx¹³.

Apnea of prematurity requiring intervention generally resolves by about 37–40 weeks post-conceptional age (14). In the most premature infants, however, apnea may present beyond this age, especially episodic desaturation and bradycardia associated with short respiratory pauses¹⁵.

Clinical Associations & Monitoring

Although apnea of prematurity is idiopathic, other disorders are associated with or lead to apnea. Before embarking upon, apnea in preterm infant is due to immature respiratory control, a number of potential causes should be ruled out (Figure 1). Central nervous system problems, including intracranial bleed, congenital malformations and hydrocephalus, can precipitate apnea. Infections are common in preterm infants so also anemia. Other factors that may precipitate apnea include metabolic disorders especially hypoglycemia, hypocalcemia, temperature instability and drugs like opiates and magnesium. Figure 1Some diverse factors known to precipitate development of apneic episodes in predisposed preterm infants

All preterm infants of less than 35 weeks should be monitored for apneic spells for atleast first week. Monitoring should be continued until the infant is event free for 5–7 days is widely accepted.

Cardiovascular consequences of apnea include changes in heart rate, blood pressure and pulse pressure. Bardycardia begin within 5–8 seconds after the onset of apnea¹⁶.

Even with careful monitoring, some spells of apnea and bradycardia may not be recognized

When a monitor signals, kindly respond to baby and not to monitor – check for cyanosis, bradycardia & desaturation.

Most apneic spells respond to tactile stimulation. If baby doesn't respond, please give bag and mask using FiO₂ of 40% in order to avoid elevation in arterial oxygen tension.

After attending to first apneic spell, preterm neonate should be evaluated for possible underlying causes.

Evaluation should include history and physical examination, arterial blood gas measurement, with continuous oxygen saturation monitoring & complete blood count, measurement of glucose, calcium and electrolyte levels.

Approach to an individual attack of apena and subsequent algorithmic approach is shown (Figure 2). Figure 2Algorithm for Management of Neonatal ApneaAbbrevationsABCairway, breathing, circulation;BSblood sugar:PCVpacked cell volume:ABGarterial blood gas;Nasodium;Kpotassium;Cacalcium;USultrasound;CPAPcontinuous airway positive pressure;IMVintermittent mandatory ventilation

AIIMS protocol in Neonatology-Apnea of Newborn²⁴

Diagnosis and Treatment

Neonates exhibiting frequent apnea of 20 seconds that are associated with cyanosis and bradycardia require medical intervention. Differential diagnosis must be considered and the appropriate clinical and laboratory evaluation carried out before neonate can be presumed to have apnea of prematurity. Most often, only a few diagnostic studies are required and most of the precipitatory disorders can be discarded with a thorough review of the history and physical examination (Table 1). Table 1

Evalutation of the apneic neonate

History

• Perinatal complication and note apgar score

• Gestational age and post natal age

• Details of drugs given to mother and neonate

• Details of thermoregulation

• History of risk factors for infection

• Feeding tolerance/abdominal distention, stooling patterns, physical examination

• Detailed clinical examination with special reference to cardiorespiratory and neurologic status

Laboratory (consider following tests when clinically indicated)

• Hematocrit

• Blood sugar/serum calcium

• Total and differential WBC count

• Blood culture

• Spinal tap

• Arterial blood gas

• Cranial USG

• Chest and abdominal radiograph

Babies who develop repeated and prolonged apnea requiring bag and mask ventilation, qualify for treatment of increasing invasiveness and risk. Treatment for apnea of prematurity can be categorized as general measures, pharmacotherapy and respiratory support.

General Measures

Prone positioning

Tactile stimulation

Specific therapy should be directed at an underlying cause, if one is identified

Increase FiO₂ slightly & monitor blood gases and maintain saturation between 87–93%

Avoid over extension and flexion of neck to avoid airway obstruction

Lower thermoneutral temperature to lower limit of range to lessen the number of spells

Consider blood transfusion (Packed Red Blood Cells-PRBCs) if apneic spells are frequent and baby has low hematocrit (<30%)

Pharmacotherapy

Once precipitatory factors have been ruled out (Figure 1), the premature neonate can be considered to have apnea of prematurity and most widely used agents for this disorder are the methylaxnthines, theophylline and caffeine. Indication for starting these drugs are:-

Treatment of apnea of prematurity

Post-extubation to reduce incidence of apnea

Theophylline and Aminophylline

Theophylline has been recognized as a respiratory stimulant since 1920's. Kuzemko and Paala first described the use of rectal theophylline in reducing apneic spells in newborn infants. However theophylline was first reported for use in apnea of prematurity in 1973 and aminophylline use started then¹⁹.

Mechanism of action

Several mechanism have been proposed for the action of theophylline, the most accepted being enhancement of cyclic adenosine monophosphate and catecholamines by inhibition of phosphodiesterase. It does increase respiratory center output and enhance diaphragmatic contractility²⁰.

Absorption

Theophylline is initially absorbed in total when given by mouth in neonate and infants. Aminophylline, an ethylenediamine complex of theophylline can be given IV or IM.

Distribution

The apparent volume of distribution (aVD) is significantly larger in neonates than in older infants due in part to the lower theophylline protein binding found in neonates.

Dosing & distribution

Therapeutic plasma levels of theophylline range from 5–15 mg/ml although it has been shown that serum concentration as low as 3–4 mg/ml are associated with decrease in apneic episodes (35). Recommended loading dose is 5–6 mg/kg and maintenance dose is 1–2 mg/kg every 8 hours. Aminophylline should be given slowly intravenous over 5–10 minutes.

Clinical side effects

Adverse effects of theophylline are expressed as an enhancement in the pharmacologic effects and include (1) tachycardia, arrythmia; (2) diuresis, glycosuria, ketonuria (3) hypoglycemia (4) jitteriness, seizures: (5) vomiting, hemorrhagic gastritis. Heart rate of more than 180/minute and any sign of gastritis require decrease in dosage or cessation of therapy.

Availability

Drug is available as 10ml ampoules containing 250mg of aminophylline. Oral theophylline syrup contain 50mg in every 5ml of it.

Caffeine

Caffeine (1,3,7-Trimethyl xanthine) is naturally occurring in many plants and is added to many beverages like coffee. It is available as caffeine citrate for both oral and intravenous use. Caffeine appears to offer several advantages over theophylline including wider therapeutic index, decreased need for therapeutic monitoring, longer elimination half-life, less frequent dosing, fewer peripheral effects and potential for effectiveness in some infants not responding to theophylline therapy²¹.

Pharmacokinetics

Caffeine is absorbed rapidly and completely after oral administration. Plasma concentrations as low as 3–4 mg/ml have been found to abolish apnea and regularize breathing patterns.

Dose recommendation

A loading dose of 10mg/kg Caffeine base (20mg/kg citrate caffeine) yields plasma concentrations between 8–14 mg/ml. Because of longer half life, it is used once a day. Maintenance dose is 2.5 mg/kg OD IV or PO (5mg/kg citrate caffeine).

Treatment of apnea of prematurity is shown in Table 2 Therapeutic drug monitoring should be considered especially when concomitant administration of medication which affect liver function are used (Table 3). Despite theoretical risk of decreased cerebral blow flow, retarded neuronal growth, no long term untoward effects are reported in preterm infants treated with methylxanthines. Table 2

Treatment of idiopathic apnea of prematurity

Mode	Method	Possible Mechanisms of Action

Pharmacologic	Theophylline	• Central respiratory effect (increased Co₂ sensitivity)
Stimulation	Loading 5–6 mg/kg IV	• Increased diaphragmatic contraction
	Maintenance 1–2 mg/kg. q8h	• Decreased muscle fatigue
	IV, PO	• Increased metabolic rate
	Caffeine	• Increased catecholamine activity
	Loading 10 mg/kg IV	• Central respiratory effect (increased Co₂ Sensitivity)
	Maintenance 2.5 mg/kg per day	• Increased diaphragmatic contraction
	IV, PO	• Decreased muscle fatigue
		• Increased metabolic rate
		• Increased catecholamine activity
CPAP	Nasal, low positive pressure (2–5 cm H₂O)	• Splinting of upper airway and maintenance of Patency
		• Alteration of Hering-Breuer deflation reflex
		• Increased oxygenation
		• Irritant receptor stimulation

Table 3

Drugs used for treatment of apnea: Dosage recommendations & pharmacokinetic data

Drug	Loading Dose (mg/kg)	Maintenance Dose (mg/kg)	Recommended Serum Concentration (mg/L)	Apparent Volume of Distribution (L/kg)	Half-life (hr)	Route of Administration

Aminophylline	5.0–6.0	1.1–3.0q8h	5–15	0.6–0.7	30–33	IV
Theophylline	4.0–5.0	2.0q12hr	5–15	0.6–1.0	19–30	PO
Caffeine	1.0q8hr
Citrate	20	2.5–5.0 q24hr	8–20	0.9	102.9	PO or IV
Doxapram	5.5	1–2.5 qh	1.5–5.0	7.3	8–10	IV

Doxapram

Use of doxapram as a respiratory stimulant was first described in neonates in 1973 for treatment of depression secondary to the maternal administration of narcotic analgesic drug^19,22. Current trials use doxapram for apnea when neonate fails to respond to an adequate trial with aminophylline²³.

Mechanism of action

It is thought that doxapram acts by stimulating the peripheral (carotid bodies) chemoreceptors at low doses, by exerting a central stimulant effect at higher doses.

Pharmacokinetics

Very little information is available in neonates. It is metabolized by ring hydroxylation to ketodoxapram, an active metabolite.

Dosage recommendations

Studies have shown that minimum effective concentration of doxapram is 1.5 mg/ml and concentration greater than 5 mg/ml provide no significant increase in relief of apnea. It is usually given as infusion and started at 0.5 mg/kg/hr and increased gradually to a maximum of 2.5mg/kg/hr. It is used for a minimum of 48hours. Meanwhile continue methylxanthines.

Side effects

Adverse effects include seizures, hypertension, hyperactivity, hyperglycemia and abdominal distention.

What is current evidence and recommendation for pharmacotherapy in apnea of prematurity?

Methylxanthines are used in nearly all neonatal intensive care units although the indication and frequency of use vary from center to center. Continue using drug until baby is 34 weeks of post-conceptional age and until baby remains apnea free for seven days. Though caffeine is superior to theophylline, because of its non-availability in the country, theophylline is used as first drug of choice²⁴. There is at least fair evidence that the therapy improves important short term health outcomes and benefit may outweigh harm.

A large multicenter trial (Caffeine for Apnea of prematurity trial) is in progress to determine whether survival without neurodevelopmental disability at 18 months corrected age is improved if apnea of prematuriy is managed without methylxanthines (caffeine) in infants weighing 500–1250 gms at birth. This large trial should provide results shortly that may help guide use of methylxanthines in very preterm infants²¹.

Continuous Positive Airway Pressure (CPAP)

When preterm infants continue to have apnea despite methylxanthines, one should consider continuous positive airway pressure (CPAP) which is relatively safe and effective. CPAP should be considered under following situations²⁴.

>one episode needing either BMV or oxygen supplementation within 24 hours

>Twelve episodes in 24 hours (>6 in 12 hours) needing tactile stimulations

> one episode of spontaneous apnea every hour for 12–24 hours

Can also be considered to reduce post-extubation apnea in preterm infants.

It acts by increasing functional residual capacity (FRC), stabilizing oxygenation and/or splinting of upper airway with pressure. Typically, relatively low CPAP levels of 3–5 cm H₂O are used. CPAP may be delivered by nasal prongs or cannula as well (25). However endotracheal CPAP is not used in apneic spells. One should carefully monitor for side effects of CPAP like barotrauma, abdominal distention, feed intolerance or local nasal irritation.

If infant continues to have recurrent apnea on CPAP and pharmacotherapy, consider endotracheal intubation and mechanical ventilation. If lungs are normal, ventilate the baby with minimum settings allowing baby for spontaneous respiratory efforts and to minimize the risk of barotrauma.

Effects on long term outcome

Apnea has long been suspected as a final common pathway involved in the unexpected death of an infant. It has been suggested that sudden infant death syndrome (SIDS) may result from cardiac or respiratory arrest and that respiratory arrest is the more likely cause. Relationship between apnea and SIDS is somewhat more complicated and debated.

Long-term effects of apnea with or without bradycardia on preterm infant are not clear. It has been term suspected that apneic episodes may be associated with neurodevelopmental delay²⁶. However it would seem prudent to suspect that the recurrent hypoxia experienced by these infants may affect their neusological development.

Drug therapy of apnea in neonate