APNEA OF

PREMATURITY

Dr. Radhika Batra

Neonatalogy Fellow
Fortis La Femme, Hospital
Introduction

• Apnea is defined as the cessation of respiratory airflow. Short breathing pauses

(5 to 10 seconds) occur frequently in preterm infants and are normal.
• Apnea of prematurity is most widely defined as cessation of breathing for more
than 20 seconds or a shorter respiratory pause associated with oxygen
desaturation and/or bradycardia in infants who are younger than 37 weeks
gestation.
• The frequency of symptoms is inversely proportional to gestational age, and
almost all infants with a GA less than 28 weeks are affected.
• Apnea of infancy refers to infants with a gestational age (GA) of 37 weeks or
greater at the onset of apnea.
 Apnea is classified as central, obstructive, or
mixed depending on the presence of continued
inspiratory efforts and upper airway obstruction.

Central apnea – Inspiratory efforts are absent

Classificatio
n Obstructive apnea – Inspiratory efforts persist,
but are ineffective in the presence of upper
airway obstruction

Mixed apnea – Upper airway obstruction with

inspiratory efforts that precedes or follows
central apnea
Most apnea spells in preterm infants are central or mixed.

This was illustrated in a study of physiologic recordings of

2082 apneic episodes in 47 infants: 40 percent of
episodes were central, 50 percent were mixed, and 11
percent were obstructive.
(Finer NN, Barrington KJ, Hayes BJ, Hugh A. Obstructive,
mixed, and central apnea in the neonate: physiologic
correlates. J Pediatr. 1992 Dec;121(6):943-50. doi:
10.1016/s0022-3476(05)80349-x. PMID: 1447664.)
Of note, longer episodes are most likely to be mixed
apnea as opposed to short respiratory pauses, which are
primarily classified as central apnea.
 • Periodic breathing episodes are characterized by a
pattern of alternating breaths and brief respiratory
pauses.
• Although descriptions vary, periodic breathing is
usually defined as repetitive cycles of breathing

Periodic and respiratory pauses that are approximately 5 to

10 seconds in duration.

Breathing • These pauses may be accompanied by modest

oxygen desaturation and bradycardia that do not
require clinical intervention.
• Periodic breathing is common in preterm infants-
needs to be differentiated from apnea of
prematurity as it typically does not require
intervention.
Incidence

• Increases with decreasing gestational age (GA).

• Term infants – The incidence of apnea is quite low.
• The cause of apnea in term infants should be assumed to be
pathologic and can include hypoglycemia, seizure disorder,
infection, severe birth asphyxia, intracranial hemorrhage or stroke,
drug depression, and micrognathia with obstruction of the airway. 
Henderson-Smart DJ. The effect of gestational age on the incidence and duration
of recurrent apnoea in newborn babies. Aust Paediatr J. 1981 Dec;17(4):273-6.
doi: 10.1111/j.1440-1754.1981.tb01957.x. PMID: 7347216.
• Moderately preterm infants – In a multicenter study, apnea
was diagnosed in 50 percent of infants born between 33 and
34 6/7 weeks gestation based on documentation in the
medical record.
Eichenwald EC, Zupancic JA, Mao WY, Richardson DK, McCormick MC,
Escobar GJ. Variation in diagnosis of apnea in moderately preterm infants
predicts length of stay. Pediatrics. 2011 Jan;127(1):e53-8. doi:
10.1542/peds.2010-0495. Epub 2010 Dec 27. PMID: 21187315.
• Very preterm infants – Apnea occurs in virtually all infants
born at less than 28 weeks gestation based on review of
cardiorespiratory recordings from pneumography and cardiac
and pulse oximetry monitoring.
• Infants born at 24 to 28 weeks gestation may continue to
exhibit apnea beyond 38 weeks postconception, which
prolongs their hospitalization, although resolution of apnea is
typically complete by around 43 to 44 weeks postmenstrual
age (PMA).
Pathogenesis

• Apnea of prematurity is a developmental disorder that reflects physiologic

immaturity rather than a pathologic process.
• Developmental and functional immaturity of the factors regulating
respiration
• Signals for involuntary control of breathing originate from the brainstem
in the area of medulla oblongata.
• Input into the respiratory center arises from : chemoreceptors (central and
peripheral ) , mechanoreceptors in lung and upper airway, and the
cerebral cortex
• Delayed maturation of any of these sites could cause apnea.
• Depressed ventilatory response to CO2 and hypercapnia ( hypercapnia
causes hyperventilation)
• In babies hypoxia elicits an excitatory response with an augmentation of
respiratory effort.
• Preterm babies exhibit a biphasic response-with an increase in ventilation
followed by respiratory depression and an inhibition in breathing.
• Cessation of respiration following laryngeal stimulation- normal reflex to
prevent aspiration is exaggerated in preterms.
• Impaired coordination of muscles of respiration and muscles of upper
airway.
• Exaggerated response to inhibitory neurotransmitters ( GABA, adenosine)
• Mechanisms leading to obstructive apneas include-
• Instability of the upper airway, decreased tone leading to
collapse and obstruction,
• Asynchrony of musculature of the upper airway and
diaphragm
• Spontaneous neck flexion
• Anatomical abnormalities – Pierre Robins sequence,
Down’s syndrome
• Mixed apnea- most apneas commence with central component followed
by obstruction- narrowing of the airway occurs about 1 second into
central apnea (loss of tone of muscles of upper airway)
• Obstruction can also lead to central apnea- increased frequency of
central apnea seen following obstruction ( as observed by Upton et al)
• All apneas persisting for more than 20 seconds fall into the category of
mixed apneas.
 • Apnea may become evident in the first two to three days
after birth in preterm infants who are breathing
spontaneously without respiratory support or being treated
with continuous positive airway pressure (CPAP).
• Breathing pauses usually are accompanied by bradycardia
and hypoxemia.

Clinical • In infants who are intubated and receiving mechanical

ventilation, episodic desaturation and bradycardia are also
Manifestations quite common and are manifestations of ineffective
ventilation and possibly cardiorespiratory reflex responses
to airway stimulation by an endotracheal tube.
Di Fiore JM, Arko MK, Miller MJ, Krauss A, Betkerur A, Zadell A,
Kenney SR, Martin RJ. Cardiorespiratory events in preterm infants
referred for apnea monitoring studies. Pediatrics. 2001
Dec;108(6):1304-8. doi: 10.1542/peds.108.6.1304. PMID:
11731652.
Late Presentation

• For infants without previous episodes of apnea after the first few
weeks of life or who present with recurrent apnea after one to
two weeks without apnea spells, the cause of apnea may be due
to a serious underlying pathologic condition such as sepsis.
• These infants require a thorough evaluation to determine if there
is a precipitating cause, which may be treatable.
Natural History

• Apnea of prematurity typically resolves before 37 weeks postmenstrual age (PMA) in infants
delivered after 28 weeks gestation.
• In contrast, in infants born before 28 weeks, apnea frequently persists until term PMA.
• Significant apnea does not typically persist beyond 43 weeks PMA.
• This was best illustrated in a study that included 443 preterm infants (gestational age [GA] ≤34
weeks) that demonstrated significant cardiorespiratory events were rare beyond 43 weeks
PMA and occurred no more frequently in the preterm group than in healthy term infants.
(Ramanathan R, Corwin MJ, Hunt CE, Lister G, Tinsley LR, Baird T, Silvestri JM, Crowell DH, Hufford D, Martin RJ,
Neuman MR, Weese-Mayer DE, Cupples LA, Peucker M, Willinger M, Keens TG; Collaborative Home Infant
Monitoring Evaluation (CHIME) Study Group. Cardiorespiratory events recorded on home monitors: Comparison
of healthy infants with those at increased risk for SIDS. JAMA. 2001 May 2;285(17):2199-207. doi:
10.1001/jama.285.17.2199. PMID: 11325321.)
Diagnosis

• The diagnosis of apnea of prematurity is considered when either a respiratory

pause greater than 20 seconds or a shorter respiratory pause accompanied by
oxygen desaturation and/or bradycardia is detected in an infant with a
gestational age (GA) less than 37 weeks.
• Typically identified by the routine use of cardiorespiratory monitors and/or pulse
oximeters for preterm infants in the neonatal intensive care unit (NICU).
• Diagnosis of exclusion!
• Other causes of apnea need to be considered and eliminated before the
diagnosis can be conclusively made- especially true for any preterm infant in
whom there is a recent onset of apnea following a time period without apneic
events.
 Differential Diagnoses

• The following etiologies that may present with apnea in preterm infants need to be considered and eliminated :
• Anemia
• Infection ( including sepsis/meningitis/bronchiolitis)
• Metabolic disorders (hypoglycemia, hyponatremia, hypocalcemia, inborn errors of metabolism)
• Unstable thermal environment ( hypothermia/ hyperthermia)
• Antepartum administration of magnesium sulfate or opiates to the mother.
• Administration of opiates or general anesthesia to the infant.
• Neurologic disorders, including intracranial hemorrhage and neonatal encephalopathy.
• NEC
• Congenital anomalies of the upper airway ( Micrognathia, Macroglossia, Choanal atresia, Down’s)
• Seizures
• Dysphagia and swallowing defects
• CVS- PDA, CHF, Anemia
• Vasovagal reflex- Siting of nasogastric tube, Upper airway suctioning
Diagnostic Evaluation

The goal of the diagnostic evaluation is to differentiate apnea of prematurity from other
causes of neonatal apnea.
• Maternal and neonatal history:
• Maternal administration of magnesium sulfate or opioids
• Neonatal administration of opioid therapy,
• Risk factors for neonatal sepsis
• Traumatic delivery and/or perinatal asphyxia
• Infant of a diabetic mother.
• Assessment of the infant for other signs of an underlying etiology:

• Signs and symptoms of hypoglycemia (eg, jitteriness, hypotonia, and

lethargy
• Signs and symptoms of sepsis (eg, temperature instability, lethargy, and
poor feeding
• Signs and symptoms of neurologic impairment due to intraventricular
hemorrhage, posthemorrhagic hydrocephalus, or neonatal encephalopathy
• Signs and symptoms of necrotizing enterocolitis (NEC) (eg, abdominal
distension, feeding intolerance, and bloody stools)
• Although less likely, consider assessment of the airway to detect congenital
anomalies of the upper airway
• Oral feeds :Apnea of prematurity must be distinguished
from the hypoxemia, cyanosis, and bradycardia
sometimes associated with the introduction of oral
feedings in preterm infants.
• These changes in color and heart rate occur commonly
before 34 to 36 weeks postmenstrual age (PMA) as a
result of ineffective coordination of sucking, swallowing,
and breathing, which may cause impaired ventilation.
Lab Evaluation

Testing is typically reserved for patients with significant or abrupt increases in

events based on clinical judgement:
• Complete blood count: anemia and sepsis
• Blood culture: sepsis
• Measurements of blood glucose: hypoglycemia
• Blood gas: hypoxemia and acidosis, which may be present in patients with inborn
errors of metabolism, sepsis, or NEC
• Other laboratory studies may be indicated if a metabolic disorder is suspected 
• Cranial imaging should be obtained in cases in which intracranial hemorrhage,
infarction, or neonatal encephalopathy is suspected.
Management

Treatment of apnea of prematurity is instituted if:

• Apneic spells are frequent, prolonged, or associated with bradycardia or frequent oxygen
desaturation values.
OR
• The infant requires intervention with bag and mask ventilation, or multiple episodes of
tactile stimulation.

• Therapy often is needed for several weeks until the apnea resolves as the respiratory
control of the infant matures.
Management is a combination of the following:
• General measures that reduce the risk of apnea or its associated hypoxemia
• Nasal continuous positive airway pressure (nCPAP)
• Methylxanthine therapy

• Patients who fail to respond to these interventions require intubation and mechanical
ventilation or may be candidates for nasal intermittent positive pressure ventilation
(NIPPV).
General Measures

• Directed towards eliminating factors that increase the risk of apnea or reduce the
prevalence of associated hypoxia.
• Preventive in nature
• Applied to all infants < 35 weeks gestation
These include :
• Environmental temperature control – A servo-controlled radiant warmer or incubator is
used to provide a stable thermal environment
• Head and neck position – avoid extreme flexion or extension of the neck, which decreases
the patency of the upper airway.
• Maintain nasal patency – avoid vigorous nasal suctioning or prolonged use of nasogastric
tubes.
• Oxygen supplementation to maintain oxygen saturation (SpO2) at 90 to 95 percent – to
avoid baseline hypoxemia, which predisposes to episodes of severe oxygen desaturation.
• Kinesthetic stimulation – tactile stimulation or oscillometric mattresses
• KMC
NASAL CONTINUOUS POSITIVE AIRWAY
PRESSURE

• For preterm infants with clinically significant apnea (ie, respiratory pauses >20
seconds or a shorter duration accompanied by oxygen desaturation and/or
bradycardia), nasal continuous positive airway pressure (nCPAP) is suggested.
Kattwinkel J, Nearman HS, Fanaroff AA, Katona PG, Klaus MH. Apnea of prematurity.
Comparative therapeutic effects of cutaneous stimulation and nasal continuous positive
airway pressure. J Pediatr. 1975 Apr;86(4):588-92. doi: 10.1016/s0022-3476(75)80158-2.
PMID: 1092821.
• nCPAP reduces the incidence of mixed and obstructive apnea, maintains
functional residual capacity (FRC).
• Thought to be effective by splinting the pharyngeal airway with positive
pressure, thereby reducing the risk of upper airway collapse and obstruction.
• nCPAP decreases respiratory frequency, primarily by prolongation of
expiratory time, without altering ventilatory response to CO2.
• CPAP also increases oxygenation by improving ventilation-perfusion matching
and provides continuous distending pressure that optimizes FRC 
Nasal intermittent positive pressure ventilation

• Nasal intermittent positive pressure ventilation (NIPPV) is an augmentation of continuous

positive airway pressure (CPAP), which superimposes inflations set to a peak pressure
delivered through nasal prongs or mask.
• NIPPV may be a useful tool to augment the beneficial effects of CPAP in preterm infants
with apnea
Methylxanthine Therapy

• Methylxanthines cause stimulation of respiratory neural output,

presumably by inhibiting adenosine receptors (inhibitory
neurotransmitter) and increasing the response to CO2, and are
the primary pharmacologic therapy used to treat apnea of
prematurity.
• The two methylxanthines used in apnea of prematurity are
caffeine and theophylline.
• Caffeine is the preferred agent because of its longer half-life,
wider margin of safety, and lower frequency of adverse effects
• In a 2010 systematic review, results from five trials that studied short-term
effects of methylxanthine therapy demonstrated that patients treated with
methylxanthine compared with those who received placebo were less likely to
have apneic episodes (relative risk [RR] 0.44, 95% CI 0.32-0.60) and require
assisted ventilation (RR 0.34, 95% CI 0.12-0.97) 
Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for apnoea in preterm infants.
Cochrane Database Syst Rev. 2010 Dec 8;(12):CD000140. doi:
10.1002/14651858.CD000140.pub2. PMID: 21154343.
Caffeine Vs Theophylline

• Caffeine has therapeutic advantages over theophylline- longer half-life, ranging from 65 to 100
hours-can be administered once daily instead of the more frequent dosing required for
theophylline.
• Wide therapeutic index of caffeine minimizes side effects.
• A systematic review of the literature that included five trials reported similar rates of reduction
of apnea and bradycardia during the first week between caffeine and theophylline [33].
However, adverse reactions (ie, tachycardia and feeding intolerance) were lower in the group
treated with caffeine compared with theophylline (RR 0.17, 95% CI 0.04-0.72).
Henderson-Smart DJ, Steer PA. Caffeine versus theophylline for apnea in preterm infants.
Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000273. doi: 10.1002/14651858.CD000273.pub2.
PMID: 20091506.
• A loading dose of 20 mg/kg of caffeine citrate
(equivalent to 10 mg/kg caffeine base) is given
intravenously, or enterally
• F/b daily maintenance dose of 5 to 10 mg/kg per dose
(equivalent to 2.5 to 5 mg/kg caffeine base) is started 24
hours after the loading dose, which can also be
administered either intravenously or orally.
Adverse Effects

• The main adverse effects of methylxanthine treatment is tachycardia, which occurs less frequently with
caffeine than with theophylline.
• Theophylline can cause gastroesophageal reflux, perhaps because of delayed gastric emptying; however,
this does not present as a clinically significant problem.
• Methylxanthines also increase metabolic rate.
• In a study of metabolic rate and oxygen consumption, caffeine significantly increased oxygen consumption
(7 to 8.8 mL/kg per min) and energy expenditure (2.1 to 3 kcal/kg per hour) compared with baseline
measurements.
• During the four-week study period, treated infants required a lower incubator temperature to maintain
normal body temperature and had less weight gain with similar caloric intake than untreated infants.
Bauer J, Maier K, Linderkamp O, Hentschel R. Effect of caffeine on oxygen consumption and metabolic rate in
very low birth weight infants with idiopathic apnea. Pediatrics. 2001 Apr;107(4):660-3. doi:
10.1542/peds.107.4.660. PMID: 11335740.
When to discontinue Caffeine therapy?

• Data are lacking on when to discontinue caffeine therapy.

• Based on the natural course of apnea of prematurity, we discontinue caffeine when the infant reaches a postmenstrual age
(PMA) between 32 and 34 weeks and there have been no apneic episodes requiring intervention for approximately five days.
[37]. I
• It takes up to seven days for caffeine to be eliminated from the neonate.
• However, there are limited data that suggest prolonged caffeine therapy beyond 35 weeks PMA decreases the frequency and
severity of intermittent hypoxemia [38,39].
• An ongoing clinical study is being conducted to further investigate the role of caffeine therapy in reducing intermittent
hypoxemia.
• Whenever caffeine is discontinued, cardiorespiratory monitoring is continued and performed until the infant is discharged home,
because the mean half-life of caffeine is approximately 87 hours in patients who are 35 weeks PMA [40].
• Caffeine rarely needs to be reinstituted, but if there are frequent episodes of apnea, bradycardia, or oxygen desaturation, or if
the infant requires intervention with a bag and mask, caffeine therapy may be restarted.
Caffeine for Apnea of Prematurity Trial

• Study undertaken to ascertain whether methylxanthines have

other short- and long-term benefits or risks in infants with very
low birth weight.
• 2006 infants with birth weights of 500 to 1250 g during the first
10 days of life were randomly assigned to receive either caffeine
or placebo, until drug therapy for apnea of prematurity was no
longer needed.
• The short-term outcomes before the first discharge home were
evaluated.
Results

• Of 963 infants who were assigned to caffeine and who remained alive at a postmenstrual age of 36 weeks,
350 (36 percent) received supplemental oxygen, as did 447 of the 954 infants (47 percent) assigned to
placebo (adjusted odds ratio, 0.63; 95 per- cent confidence interval, 0.52 to 0.76; P<0.001).
• Positive airway pressure was discontinued one week earlier in the infants assigned to caffeine (median
postmenstrual age, 31.0 weeks) than in the infants in the placebo group (median postmenstrual age, 32.0
weeks; interquartile range, 30.3 to 34.0; P<0.001).
• Caffeine reduced weight gain temporarily. The mean difference in weight gain between the group receiving
caffeine and the group receiving placebo was greatest after two weeks (mean difference, −23 g; 95 percent
confidence interval, −32 to −13; P<0.001).
• The rates of death, ultrasonographic signs of brain injury, and necrotizing enterocolitis did not differ
significantly between the two groups.
• Caffeine therapy for apnea of prematurity reduces the rate of bronchopulmonary dysplasia in infants with
very low birth weight.
5 year follow up

• The main outcome at 5 years was a composite of death or

survival with disability in one of 6 domains including
neuromotor function, cognition, behaviour, and general health.
• Standardized tests included the Gross Motor Function
Classification System (GMFCS), the Wechsler Preschool and
Primary Scale of Intelligence, and the Child Behavior Checklist
Parent Form.
 • A total of 1932 children were eligible for the
study. Vital status was ascertained for 1810
children (94%).
Results • Adequate data for the composite outcome
of death or disability were available for 1641
children (85%).
Table 1 shows the results for the composite outcome and
for 5 of its components.
Academic Performance, Motor Function, and Behavior
11 Years After Neonatal Caffeine Citrate Therapy
for Apnea of Prematurity

• To evaluate whether neonatal caffeine therapy is associated with improved

functional outcomes 11 years later.
• A total of 1202 children with birth weights of 500 to 1250 g were eligible for this
study; 920 (76.5%) had adequate data for the main outcome
• Functional impairment was a composite of poor academic performance (defined
as at least 1 standard score greater than 2 SD below the mean on the Wide Range
Achievement Test–4), motor impairment (defined as a percentile rank of 5 on the
Movement Assessment Battery for Children–Second Edition), and behavior
problems (defined as a Total Problem T score 2 SD above the mean on the Child
Behavior Checklist)
Results

• Among the 920 children (444 females and 476 males; median age, 11.4 years
[interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were
not significantly different between the 457 children assigned to receive caffeine compared
with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted
odds ratio, 0.78; 95% CI, 0.59-1.02; P = .07).
• With all available data, including those from up to 24 Swedish trial participants, the rates
of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462
[13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P = .58) and behavior problems (52
of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P = .22)
were broadly similar between the group that received caffeine and the group that
received placebo.
• However, caffeine therapy was associated with a reduced risk of motor impairment
compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio,
0.66; 95% CI, 0.48-0.90; P = .009).
Conclusion

• Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate
of academic, motor, and behavioral impairments but was associated with a reduced risk of
motor impairment in 11-year-old children with very low birth weight.
• At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle
school age.
Response Failure and Other Therapies

• Infants who remain apneic despite caffeine therapy and

continuous positive airway pressure (CPAP) require intubation
and mechanical ventilation or may be candidates for nasal
intermittent positive pressure ventilation (NIPPV)
• Possible role of transfusion —consider packed RBC transfusion in
infants with hematocrits less than 25 to 30 percent who have
frequent and/or severe apnea despite administration of caffeine
therapy.
• Doxapram – not used anymore
Thank you!