Apnea of prematurity is common in preterm infants, especially those born before 28 weeks gestation or weighing less than 1800g. It is caused by immature development of the respiratory control centers in the brain. Treatment includes caffeine which reduces apnea by blocking adenosine receptors. Other supportive measures like positioning and CPAP may help as well. Apnea spells usually resolve by 36-37 weeks corrected gestational age. Before discharge, infants should have a period of at least 5-7 days without any recorded apnea events while off caffeine therapy.

1. Dr Joshua Chadwick Jayaraj

2.  Apnea is when absent airflow is usually ≥ 20
seconds
 Shorter duration <20 seconds can also be
defined as apnea if accompanied by oxygen
desaturation or bradycardia
-Bradycardia (heart rate <100 beats per
minute) or hypoxemia that is detected
clinically (cyanosis) or by oxygen saturation
monitoring when SpO2 80-85%.

3.  The incidence of apnea is inversely
proportional to gestational age.
 Essentially, all infants <28 weeks' gestational
age have apnea.
 As many as 25% of all premature infants who
weigh <1,800 g (~34 weeks' gestational age)
have at least one apneic episode.

4. Onset: Apneic spells generally begin at 1 or 2
days after birth; if they do not occur
during the first 7 days, they are unlikely to
occur later.
Duration: Apneic spells persist for variable
periods postnatally and usually cease by 36
to 37 weeks‘ of gestation in infants born at
28 weeks' gestation or more.

5. Term infants: Apneic spells occurring in
infants at or near term are always abnormal
and are nearly always associated with
serious, identifiable causes, such as birth
asphyxia, intracranial hemorrhage, seizures,
or depression from medication.
 Failure to breathe at birth in the absence of
drug depression or asphyxia is generally
caused by irreversible structural
abnormalities of the central nervous system.

6. Heather et al. NICUniversity.org , 2018

7. Periodic Breathing Apnea of Prematurity
Regular, recurrent cycles of breathing of
10-15 seconds’ duration that are
interrupted by pauses of at least 3
seconds’ in duration
Infants who have prolonged apnea may
fail to reinitiate ventilation entirely or do
so ineffectively
Benign respiratory pattern for which no
treatment is required
Respiratory pauses during apnea are
associated with swallowing movements
The respiratory pauses appear to be self-
limited, and ventilation does continue,
albeit cyclically

8.  Developmental immaturity of central
respiratory drive
 Chemoreceptor response
 Reflexes
 Respiratory muscles
 Gastroesophageal reflux is common in
preterm infants
 However, no association has been demonstrated
between apnea of prematurity and
gastroesophageal reflux.

9.  CO2 chemosensitivity
 Response to hypoxia and hyperoxia
 Sensitivity to neurotransmitters
 Laryngeal reflex

11.  CO2 is the major chemical driver of
respiration
 Preterm infants have decreased ventilatory
response to changes in CO2
 ↑CO2 lead to ↑TV with prolonged expiratory
duration, no change in RR
 CO2 apneic threshold only slightly below
normal baselineCO2

12. MacFarlane et al. Respir Physiol Neyrobiol, 2013; 185:170.176

13. Martin et al. NeoReviews 2002; 3(4):e59-e65

14.  Inhibitory neurotransmitters are upregulated
in preterm infants
 Dopamine, adenosine, Gamma aminobutyric
acid (GABA), prostaglandins
 Thus, adenosine receptors inhibitors play a
role in decreasing incidence and severity of
AOP

15.  Laryngeal stimulation causes a reflex to
protect the lungs from aspiration
 Mediated by the superior laryngeal nerve
 An exaggerated response in preterm infants
has been implicated as a cause for AOP

16. Martin et al. NeoReviews 2002; 3(4):e59-e65

17. Potential
Cause
Associated History or Signs Evaluation
Infection Feeding intolerance, lethargy,
temperature instability
Complete blood count, cultures, if
appropriate
Impaired
oxygenation
Desaturation, tachypnea,
respiratory distress
Continuous oxygen saturation
monitoring, arterial
blood gas measurement, chest x-
ray examination
Metabolic
disorders
Jitteriness, poor feeding,
lethargy, CNS depression,
irritability
Glucose, calcium, electrolytes
Drugs CNS depression, hypotonia,
maternal history
Magnesium; screen for toxic
substances in urine
Temperature
instability
Lethargy Monitor temperature of patient
and environment.
Intracranial
pathology
Abnormal neurologic
examination, seizures
Cranial ultrasonographic
examination

18.  Specific therapy should be directed at an
underlying cause, if one is identified.
 The optimal range of oxygen saturation for
preterm infants is not certain. However,
supplemental oxygen should be provided if
needed to maintain values in the targeted
range

19.  Care should be taken to avoid reflexes that
may trigger apnea. Suctioning of the
pharynx should be done carefully, and
tolerance of oral feedings when appropriate
should be closely monitored.
 Positions of extreme flexion or extension of
the neck should be avoided to reduce the
likelihood of airway obstruction. Prone
positioning stabilizes the chest wall and
may reduce apnea.

20.  Treatment with caffeine, a methylxanthine, markedly
reduces the number of apneic spells and the need for
mechanical ventilation.
 Recall mechanism of action?
 The primary mechanism by which methylxanthines may
decrease apnea is antagonism of adenosine, a
neurotransmitter that can cause respiratory depression by
blocking both its inhibitory A1 receptor and its excitatory
A2A receptors.
 Loading dose of 20 mg/kg of caffeine citrate (10 mg/kg
caffeine base) orally or intravenously >30 minutes,
followed by maintenance doses of 5 to 10 mg/kg in one
daily dose beginning 24 hours after the loading dose.

21.  If apnea continues at the lower range of maintenance
doses, we give an additional dose of 10 mg/kg caffeine
citrate and increase the maintenance dose by 20%.
 Caffeine serum levels of 5 to 20 μg/mL are considered
therapeutic.
 Do we routinely measure serum drug concentration?
 We do not routinely measure serum drug
concentration because of the wide therapeutic index
and the lack of an established dose-response
relationship
 Side effects?
 Tachycardia, arrythmia, feeding intolerance, GER,
irritability, jitteriness, seizures

22.  CPAP at moderate levels (4 to 6 cm H2O) can
reduce the number of mixed and obstructive
apneic spells.
 Humidified high-flow nasal cannula can be used
to provide increased end-expiratory volume,
although its effect on reduction of apnea
frequency has not been specifically evaluated.
 Nasal intermittent positive pressure ventilation
(NIPPV) may reduce extubation failure due to
apnea following mechanical ventilation

23.  Although these events are rarely temporally related
 Pharmacologic treatment of GER with agents that
increase motility or decrease gastric acidity have not
been shown to reduce apnea frequency.
 If treated with decreasing gastric acidity:what
complication would you expect?
 Because increased late onset sepsis and necrotizing
enterocolitis have been associated with use of agents
that decrease gastric acidity, we limit the use of these
medications.
 Mechanical ventilation may be required if the other
interventions are unsuccessful.

24.  Remains controversial because results of
studies are conflicting.
 Consider a transfusion of packed red blood
cells (PRBCs) if the hematocrit is <25% to
30% and the infant has episodes of apnea and
bradycardia that are frequent or severe while
continuing treatment with caffeine

25.  We typically require that preterm infants
have no apnea spells recorded for 5 to 7 days
prior to discharge, although this may be
extended for extremely low gestation infants
or those with severe events.
 Because of the long half life of caffeine (50 to
100 hours) and even longer effects in some
infants, we typically start this “countdown”
period several days to 1 week after caffeine is
stopped.

26.  Feeding-associated events are generally not
included, although severe events during feeding
may suggest lack of discharge readiness.
 Intercurrent viral illness, anesthesia, and
ophthalmologic examinations may precipitate
recurrent apnea in preterm infants.These infants
should be monitored closely at least until 44
weeks' GA.
 Immunizations (primarily2 months and rarely 4
months) may also exacerbate apnea in very
preterm infants who remain in the neonatal
intensive care unit.

27.  Apnea spells typically resolve by 36 to 37 weeks'
of gestation in infants born at 28 weeks of
gestation or more but may persist to or beyond
40 weeks' gestation in more preterm infants.
 Caffeine is a safe and effective treatment for
apnea.
-Loading dose of 20 mg/kg of caffeine citrate
orally or intravenously >30 minutes, followed by
maintenance doses of 5 to 10 mg/kg in one
daily dose beginning 24 hours after the
loading dose.

28.  Evidence does not support treatment of
gastroesophageal reflux to reduce apnea
frequency.
 Prior to discharge, a 5- to 7-day period after
discontinuation of caffeine therapy without
recorded apnea events predicts a low
likelihood of recurrent symptomatic apnea.

29.  Cloherty and Stark’s manual of neonatal care
8th edition