16 Apnea

About 30-45% of preterm neonates exhibit periodic breathing

pattern characterized by three or more respiratory pauses of
greater than 3 seconds duration. Periodic breathing is a normal
event in preterm infants, reflective of immaturity of respiratory
control system and does not merit any treatment. In contrast,
apnea is a pathological cessation of breathing that results in
hemodynamic disturbances and merits treatment.

Definition
Apnea is defined as cessation of breathing for longer than 20 sec,
or for shorter duration in presence of bradycardia or change in
skin color (pallor or cyanosis).1 Significant bradycardia has been
defined as heart rate <80 bpm and significant desaturation
defined as oxygen saturation <80-85%.2

Incidence
Apnea is usually related to immaturity of the respiratory control
system in preterm infants and called as apnea of prematurity
(AoP). Apnea can also be a manifestation of many other diseases
in neonates.

The incidence of AoP is inversely proportional to gestational

age. It varies from 10% in infants born at gestation of 34 weeks or
more to more than 60% in infants born at less than 28 weeks of
gestation.

Etiology of apnea3,4
Apnea of prematurity(AoP)
It is related to immaturity of the brainstem and peripheral
chemoreceptors resulting in abnormal ventilator response to
hypercarbia and hypoxia, along with immature reflex
responses. . This condition usually presents after 1-2 days of life
(detection may be delayed by the presence of ventilatory
support in the initial few days of life) and within the first 7 days.

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Apnea occurring in first 24 hours and beyond 7 days of life is

more likely to have a secondary cause than being AoP.

Secondary causes
Secondary causes of apnea include:
a) Temperature instability: hypothermia and hyperthermia,
especially frequent fluctuations in body temperature
b) Metabolic: acidosis, hypoglycemia, hypocalcemia,
hyponatremia, hypernatremia
c) Hematological: anemia, polycythemia
d) Neurological: intracranial infections, intracranial
hemorrhage, seizures, perinatal asphyxia, and placental
transfer of drugs such as narcotics, magnesium sulphate, or
general anesthetics
e) Pulmonary: respiratory distress syndrome (RDS),
pneumonia, pulmonary hemorrhage, obstructive airway
lesion, pneumothorax, hypoxemia, hypercarbia, airway
obstruction due to neck flexion
f) Cardiac: congenital heart disease, hypo/hypertension,
congestive heart failure, patent ductus arteriosus
g) Gastro-intestinal: gastro esophageal reflux, abdominal
distension, NEC
h) Infections: sepsis, pneumonia, meningitis, necrotizing
enterocolitis

AoP is a diagnosis of exclusion. It should be considered after the

secondary causes have been excluded. Common causes of secondary
apnea include temperature instability, airway obstruction,
metabolic causes such as hypoglycemia and hypocalcemia,
respiratory distress syndrome, sepsis, polycythemia and anemia.

Types of apnea5
a) Central apnea (40%): Central apnea is characterized by
cessation of inspiratory efforts due to reduced central drive.
b) Obstructive apnea (10%): In obstructive apnea, the infant is
not able to breathe due to obstructed airway. In this type of
apnea, there is chest wall motion without any airflow.

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c) Mixed apnea (50%): has both components- reduced central

drive followed by obstructed airway.

The source of obstruction in preterm neonates is generally

abnormal neck position (undue flexion or extension) and/ or
secretions. Other sources of obstruction are uncommon.

Monitoring
All neonates less than 35 weeks gestation should be monitored
for apnea in the first week of life.

Management
Emergency treatment
The neonate should be checked for bradycardia, cyanosis and
airway obstruction. The neck should be kept slightly extended.
The airway should be suctioned if secretions are present. Most
apneic spells respond to tactile stimulation. Oxygen by head
box or nasal cannula is provided if the infant is hypoxic. If the
neonate does not respond to tactile stimulation, positive
pressure ventilation (PPV) should be initiated.

Clinical examination
After stabilization, the neonate should be evaluated for possible
underlying cause. History should be reviewed for secondary
causes such as perinatal asphyxia, maternal drugs, neonatal
sepsis and feed intolerance. He should be examined for
temperature instability, hypotension, pallor, cardiac murmur
for PDA and poor perfusion.

Investigations
Affected neonates should be subjected to following
investigations, on an individualized basis, to exclude common
secondary causes of apnea: blood glucose, hematocrit,
electrolytes, sepsis work up, chest x-ray, ultrasound head and
other investigations depending on the history and physical
examination (Table 16.1).

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Table 16.1: Investigations to rule out secondary causes of apnea

Suspected cause Clinical features Investigations
for apnea
Sepsis, pneumonia, Lethargy, decreased Sepsis work-up
meningitis feeding, fast breathing, chest X-ray
retraction, brady/
tachycardia, shock
Patent ductus arteriosus Tachycardia, bounding Chest X-ray,
pulses, hyperkinetic echocardiography
precordium, cardiac
murmur, increased
requirement for
respiratory support
Periventricular- Sudden onset of pallor, Cranial
intraventricular shock, deranged ultrasonography
hemorrhage sensorium
Metabolic: hypoglycemia, Jitteriness, poor Measurement of
hypocalcemia, feeding, seizures blood sugar,
hyponatremia calcium or
electrolytes
Anemia Pallor, poor weight gain, Hb
history of increased
blood letting
Polycythemia Plethora, dullness, Hb
jitteriness, feed
intolerance

Management
Prevention
• Nurse the infant in servo-controlled radiant warmer or
incubator to avoid fluctuations in body temperature
• Maintain head and neck in neutral/slightly extended
position (use appropriate shoulder roll, if required).
• Maintain the patency of upper airway by gently removing
the secretions, if present. Avoid vigorous suction. For
feeding, orogastric tube is preferred over nasogastric tube
as the latter increases airway resistance.
• Maintain oxygen saturation in range of 90% to 95% by
rational use of supplemental oxygen. Hyperoxia should be
avoided. Saturation should be monitored by continuous
pulse oximetry.

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Management
General measures
• Maintain airway, breathing and circulation.
• Clear airway by suctioning if required.
• Maintain environmental temperature in the lower end of
thermo-neutral zone and avoid large swings.
• Oral feeding can be continued if the apnea is occasional and
not severe. Avoid oral feeds in case of repeated episodes
requiring positive pressure ventilation. Decreasing the
volume of bolus feeding may be considered by giving feeds
in small volumes more frequently (e.g. every one hour
instead of every two hours).
• Treatment of the underlying cause: sepsis, anemia,
polycythemia, hypoglycemia, hypocalcemia, respiratory
distress syndrome (RDS)
• Transfuse packed cells, if required (follow transfusion
guidelines)

Specific measures

Methylxanthines
Methyxanthines (Mx) are the mainstay of pharmacotherapy of
AoP. Mx therapy is not indicated for prevention of AoP or for
secondary causes of apnea.

Mx increases minute ventilation, improves CO2 sensitivity,

decreases hypoxic depression of breathing and periodic
breathing and, enhances diaphragmatic contractility. The major
mechanism of action is through competitive antagonism of
adenosine receptors. Adverse effects include tachycardia,
jitteriness, irritability, feed intolerance, vomiting and
hyperglycemia.

There are two drugs in Mx group for treating AoP-caffeine and

aminophylline (theophylline). The efficacy of both the drugs is
similar but caffeine has lesser side effects and better dosage
convenience, as it requires once daily administration compared
to thrice daily dosing of aminophylline.

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Table 16.2: Comparison of caffeine citrate and theophylline

Caffeine citrate6 Theophylline7
Half life (h) 25-371 hrs (Mean 101 hrs) 13-29 hrs
Dose Loading dose: 20 mg/kg of caffeine Loading dose: 5-6
citrate (10 mg/kg of caffeine alkaloid) mg/kg
Maintenance dose: 5-10 mg/kg/d of Maintenance dose:
caffeine citrate (2.5 to 5 mg/kg of 1.5-3 mg/kg
caffeine alkaloid) Q8-12h
Therapeutic 8-20 µg/mL 5-10 µg/mL
drug level
Toxicity Broad therapeutic window Narrow therapeutic
window

What is evidence?
A recent Cochrane review regarding the use of Mx concluded that
they are effective in reducing the number of apneic attacks and the
need for mechanical ventilation 2 to 7 days after starting treatment.8
The ‘caffeine therapy for apnea of prematurity (CAP)’ trial9 has
shown that infants <30 weeks treated with caffeine have:
• Decreased Need for supplemental oxygen at a postmenstrual age
of 36 weeks
• Shourter duration of respiratory support.
There is insufficient evidence to recommend the use of prophylactic
caffeine in extremely preterm neonates. Cochrane evidence does not
support the use of prophylactic Mx therapy for AoP.10

Management (Mx) therapy for AoP is indicated in following

circumstances:
a) When apneic episodes are frequent, or
b) If the baby requires PPV for apnea that is unresponsive to
tactile stimulation
Mx therapy is initiated as IV therapy. Oral formulation of both
the drugs can be used in place of intravenous formulation once
the infant is stable and tolerating oral feeds.11
Mx therapy should be continued until 34 weeks post-menstrual
age and stopped thereafter if no episode of apnea has occurred
in the last 7 days. Caffeine or aminophylline initiated in order to
facilitate extubation may be stopped after 5 to 7 days of
therapy.12

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Mx therapy should be discontinued at least 5 to 7 days prior to

discharge. This is especially relevant for caffeine because of its
longer half-life.

Doxapram13
The evidence for efficacy and safety of doxapram therapy for
treating AoP is limited. Moreover, doxapram is associated with
serious side effects and hence it should not be employed in treating
neonates with AoP.

Continuous positive airway pressure

Continuous positive airway pressure (CPAP) is usually
administered using nasal prongs when clinically significant
episodes persist despite optimal Mx therapy.14At CPAP level of
5 cm of H2O, infants with AoP will have fewer episodes. This
reduction is primarily related to significant reduction in
episodes of obstructive and mixed apneas and the effect has
been attributed to splinting open of the upper airways by the
positive airway pressure.

Nasal intermittent positive pressure ventilation

Infants with AoP and not responsive to Mx and CPAP therapy
can be given a trial of nasal intermittent positive pressure
ventilation (NIPPV). NIPPV may improve patency of the upper
airway by creating intermittently elevated pharyngeal
pressure. This intermittent inflation of the pharynx may activate
respiratory drive by Head’s paradoxical reflex, where in lung
inflation provokes an augmented inspiratory reflex.15 This
results in resumption of breathing in neonates with apnea.

What is evidence?
A Cochrane review has shown the beneficial effect of nIPPV for
treating preterm infants with apnea that are frequent or severe. It
showed a greater reduction in frequency of apneas (events/hr)
compared to nCPAP [WMD -1.19 (-2.31,-0.07)].15

Mechanical ventilation
The neonate should be ventilated if significant apnea persists
despite both pharmacotherapy and CPAP. As there is no
underlying lung disease in AoP, only minimal settings (PIP of

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Neonate with apnea

Emergency treatment: Maintain

temperature, ABC

Yes
Exclude secondary causes of
apnea: BS, PCV, ABG, Septic Start specific
screen, CXR, S. Na, K, Ca, USG treatment
head

Apnea of prematurity

Start
caffeine/aminophylline

No apnea No response

Continue till 34 week CPAP

Stop drugs if No response

apnea free for 7
days
NIPPV/SIMV

(ABC: airway, breathing, circulation; BS: blood sugar; PCV: packed cell volume; ABG: arterial
blood gas; Na: sodium; K: potassium; Ca: calcium; USG: ultrasound; CPAP: continuous positive
airway pressure; SIMV: Synchronized intermittent mandatory ventilation; NIPPV: Nasal
intermittent positive pressure ventilation )

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10-12 cm of H2O and PEEP of 3-5 cm of H2O, low rate of 20-25 per
minute, short Ti of 0.35-0.40 seconds, and low FiO2 of 0.21 to 0.3)
are required.

Persistent apnea
Apneic episodes may persist beyond 37 to 40 weeks in some
infants, especially those born before 28 weeks of gestation. Mx
therapy should be continued in such infants if apneic episodes
continue to occur beyond 34 weeks of post-menstrual age. The
neonate should be re-evaluated for secondary causes of apnea,
especially neurological problems and gastro-esophageal reflux.

Sudden infant death syndrome (SIDS) and apnea

AoP is not found to be an independent risk factor for SIDS.

Neurodevelopment outcome16-18
The precise effect of fluctuations in breathing, heart rate and
saturations during the episodes of apnea is not clearly defined.
Retrospective studies have suggested that recurrent episodes of
apnea are associated with worse neurodevelopment outcomes
at 1-2 years of age. Prospective studies are required to define the
association of apnea with neurodevelopment.

References
1. American Academy of Pediatrics. Task Force on Prolonged
Infantile Apnea. Prolonged infantile apnea: 1985. Pediatrics. 1985
Jul;76:129–31
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proceedings from the apnea-of-prematurity group. Pediatrics.
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3. Bhatia J. Current options in the management of apnea of
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4. Thompson MW, Hunt CE. In Avery’s Neonatology
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Mechanisms Underlying Apnea of Prematurity. Neo Reviews
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