Apnoea & Bradycardia

Introduction

Brief pauses in breathing (five to ten seconds) are common particularly in preterm infants and when they
alternate regularly with breathing efforts, this is called periodic breathing. In some infants the pauses are
prolonged and rapid depletion of oxygen stores leads to hypoxaemia and reflex vagal bradycardia. 1
Prolonged apnoea in the newborn infant is defined as a pause in breathing of more than 20 seconds or a
shorter pause associated with bradycardia or hypoxaemia 2 . Where the event is associated with an
absence of breathing movements, this is defined as central apnoea where breathing movements continue
without air flow it is defined as obstructive. Most commonly they are mixed apnoeas, with both an initial
central apnoea followed by obstructive efforts 1 .

Incidence and risk factors

Recurrent prolonged apnoea and bradycardia occurs in most infants born before 30 weeks gestation; in
about half of those at 30-32 weeks; in only about 10% of those at 34-36 weeks; it rarely occurs at term1,3 .
The specific reason for this is not clear although immaturity of the brainstem has been documented to be
associated with apnoea 4 and in preterm infants who have apnoea, it almost always ceases by term age.

Incidence
Gestational of
age recurrent
apnoea 3

< 30
80%
weeks

30-31
50%
weeks

32-33
14%
weeks

34-35
7%
weeks

Although immaturity is a major underlying factor, various insults may contribute. Recognition of any
underlying cause is important since specific treatment (such as antibiotics for infection) might be indicated.

Conditions causing or accentuating apnoea

Hypoxaemia.
Central nervous system disturbances.
Asphyxia
Intracranial haemorrhage
Seizures
Drug depression
Malformations
Systemic illness.
infection
shock (e.g. NEC)
 heart failure (e.g. PDA)
Metabolic disturbance.
hypoglycaemia
hyponataemia
hypocalcaemia
inborn error
Thermal disturbance.
hyper- or hypothermia
Anatomical narrowing of airways.
Choanal atresia
Micrognathia
Macroglossia
Tracheomalacia

Consequences of disease
If prolonged, apnoea can lead to hypoxaemia and reflex bradycardia which may require active resuscitative
efforts to reverse. There are clinical concerns that these episodes might be harmful to the developing brain
or cause dysfunction of the gut or other organs. Follow up studies show that recurrent apnoea is not an
independent predictor of later abnormal neurodevelopment1, 5 . Frequent episodes may be accompanied by
respiratory failure of sufficient severity as to warrant intubation and the use of intermittent positive pressure
ventilation (IPPV). A major concern for parents is whether their baby will have apnoea at home and die
from sudden infant death syndrome (SIDS). Epidemiological studies indicate that while preterm infants are
at increased risk of SIDS this is not related to apnoea of prematurity. However, an insult such as RSV
infection or pertussis can cause a recurrence of apnoea in the first few months after discharge. Polygraphic
studies at discharge from neonatal units do not predict future SIDS 6, 7 .

Diagnosis
The breathing and heart rate of infants born at less than 35 weeks gestation (or more mature infants who
are very ill) are usually monitored to detect apnoea/bradycardia that may warrant clinical attention. In RPAH
Newborn Care the nursing staff grade events and keep a chart.

Grade 1 = Apnoea > 15-20 seconds &/or bradycardia &/or cyanosis associated with cessation of effective
breathing efforts, which respond quickly to stimulation.

Grade 2 = As above or more prolonged, and responding slowly to stimulation or requiring bag and mask
resuscitation. If considered necessary the type of apnoea (central or obstructive) can be defined by
multichannel polygraph recording, although this can often be determined by careful clinical observation of
the events.

Interventions
Management includes correction of any aggravating factors and adequate monitoring of breathing
movements (impedance apnoea alarm) and heart rate. If oxygenation is inadequate between apnoeas
(SaO 2 < 85%) then a small increase in environmental oxygen (e.g. 23-25%) may reduce the severity of
apnoea. Care must be taken to avoid hyperoxia since the lungs are relatively normal and these immature
infants are at risk of retinopathy. If supplemental oxygen is used the target saturation level is 90 -95% 8 .

Kinesthetic Stimulation

A recent small cross over trial in 10 preterm infants showed a reduction in short pauses in breathing and
duration of desaturation 9 . This does not change the conclusions of the review published by the Cochrane
collaboration showing no benefit compared with methylxanthines and that this cannot be recommended to
prevent apnoea 10 .
Positioning

There is less apnoea when infants are nursed in the prone position compared with supine 11 . A randomised
study has shown that nursing a preterm infant prone does not reduce the rate of apnoea when compared
with side sleeping 12 .

Continuous Positive Airway Pressure

Continuous positive airways pressure (CPAP, 4-6cm H 2 O) via nasal prongs will usually reduce the severity
of the apnoea 13 . Nasal intermittent positive pressure ventilation (NIPPV) is more effective than nasal
continuous positive pressure ventilation (NCPAP) 14 . Short bi-nasal prongs are more effective than single
prong NCPAP15 . Only short term outcomes are reported.

L Carnitine

One randomised controlled trial has reported no effect on apnoea rate with L-carnitine supplementation 16 .

Creatine

One randomised controlled trial has reported no effect on apnoea rate with creatine supplementation 17 .

Blood transfusion

This has not been shown to be effective in reducing apnoea in anaemic infants 18 .

Doxapram

Doxapram is as effective as methylxanthines in prevention of apnoea. However there are concerns about
the side effects of doxapram and there are no long term data on this drug 19 . Side effects include
hypertension, QTc prolongation, seizures, respiratory distress, vomiting, diarrhoea, and urinary retention.

Methylxanthines

Caffeine is the preferred treatment for apnoea in this unit.

Of the two methylxanthines in use, caffeine, which is just as effective, has potential therapeutic advantages
over theophylline due to its higher therapeutic ratio and thus less side effects, more reliable enteral
absorption and the longer half life allows once daily administration20, 21 . The standard dosing with caffeine
citrate is 20 mg/kg load (IVI or oral) and then 5 mg/kg/day (IVI or Oral). If apnoeas persist the daily
maintenance dose can be increased to a maximum of 10 mg/kg/day of caffeine citrate. Blood levels do not
need to be monitored routinely. Caffeine has been proven safe and effective in large multicentre
randomised controlled trials 22, 23, 24 . Short term benefits, aside from the reduction in apnoea, included less
need for mechanical ventilation, oxygen supplementation, chronic lung disease, and patent ductus
arteriosus 22 . At 18 month follow up there was a 23% reduction in the primary outcome of death or
disability outcome (OR: 0.77; 95% CI: 0.64–0.93). The effect on cerebral palsy was a reduction to 4.4 vs.
7.3% (RR: 0.58; 0.39–0.87) . Apart from antenatal magnesium sulphate no other drug has shown an effect
on reducing cerebral palsy in NICU graduates25 . A subsequent subgroup analysis of the study has shown
that the improvement in the primary outcomes were confined to those infants who received caffeine and

were on respiratory support

were treated for apnoea
had caffeine to facilitate extubation.

There was also evidence that caffeine given early had a greater beneficial effect26 .

Treatment with Caffeine.

When to start treatment.

Where infants do not spontaneously recover during apnoea/bradycardia alarms, cutaneous stimulation is
usually sufficient to terminate the apnoea. If the response is slow or cyanosis severe, bag and mask
ventilation with the infant's usual environmental oxygen may be needed. Avoid over-oxygenation during and
after bag and mask ventilation. There are no data indicating what rate of apnea/bradycardia warrants
further treatment. It is probably more important to consider the effect of events on the infant rather than the
absolute number of events. If episodes are frequent (more than two to four apnoea or bradycardia alarms
per hour) or the infant is slow to respond to any event, then some other assistance is usually given.
Apnoea and the associated hypoventilation can be a clinical problem following extubation from IPPV and
both methylxanthines27 and nasal CPAP 28 are effective in reducing this, and increasing the chances of
successful extubation.

At what gestation?

The CAP and other randomised trials enrolled infants less than 30 weeks gestation22, 23 and less than 32
weeks gestation24 .

In RPAH caffeine is given to infants less than 30 weeks gestation to facili-tate extubation, infants less than
30 weeks who have any apnoea, and infants greater than 30 weeks who have 2 or more apnoeas requiring
intervention.

When to cease treatment

There are no trial data to support decisions about when to cease treatment. Based on experience in RPAH
Newborn Care, treatment with caffeine is usually ceased when there have been no significant
apnoea/bradycardia events for one week. If after a further week there are no more events, monitoring is
ceased. Discharge home occurs when parents are ready and ‘criteria for discharge’ are met. In the
absence of some unusual clinical indication predischarge pneumograms and use of apnoea monitors at
home are discouraged, as there is no evidence of need6 and their use could impair the parental
development of normal family relations by perpetuating an ICU attitude.

If a baby on caffeine is to be back transferred to a referring hospital in the next few days the usual practice
is to stay on caffeine until stabilised in the local unit.

What dose of caffeine to use.

Caffeine has a wide therapeutic index and levels need not be checked 29 .

A small randomised trial compared a standard loading dose of 25 mg/kg of caffeine citrate(12.5 mg/kg
caffeine) followed by maintenance of 6 mg/kg caffeine citrate (3 mg/kg caffeine) compared with a loading
dose of 50 mg/kg of caffeine citrate (25mg/kg caffeine) followed by 12 mg/kg caffeine citrate (6 mg/kg
caffeine). Both arms showed equal reduction in apnoea with the higher dose regime having benefits in the
first 8 hours 30 .

A larger randomised trial compared three regimes of 60 mg/kg, 30 mg/kg and 6 mg/kg loading dose of
caffeine citrate, followed by 30 mg/kg, 15 mg/kg and 3 mg/kg maintenance doses. This trial showed no
difference in extubation failure although there were fewer failures in the lowest dose group (p=0.06). There
were fewer apnoeic events in the higher dose groups and no statistically significant increase in side
effects 24 .

A further randomised trial compared a loading dose of 80 mg/kg followed by maintenance of 20 mg/kg with
a loading dose of 20 mg/kg followed by 5 mg/kg/day of caffeine citrate. There were short term benefits with
less extubation failure and fewer apnoeas in the high dose group. At follow up at 1 year of age there was
no evidence of harm in the high dose regime23 .

The CAP trial22 used a loading dose of 20 mg/kg followed by a daily maintenance dose of 5 mg/kg of
caffeine citrate (equivalent to 10 mg/kg and 2.5 mg/kg of caffeine base). The maintenance dose could be
doubled but it not clear how often this happened.

In this unit the oral and intravenous caffeine preparations are presented as caffeine base. The dose is 10
mg/kg loading dose (equivalent to 20 mg/kg caffeine citrate) followed by a maintenance dose of 2.5 mg/kg
(equivalent to 5 mg/kg caffeine citrate) given once daily. The dose can be increased if clinically indicated.
Key Points

Apnoea is usually due to cessation of breathing efforts level of evidence 5

although airway obstruction may prolong recovery in
individual episodes or be the predominant problem in
some infants

The accompanying bradycardia is a vagal reflex

level of evidence 5
response to hypoxia

Apnoea is most common at lower gestations and

level of evidence 4
usually ceases by term

Apnoea is accentuated with additional insults (hypoxia,

level of evidence 5
infection etc)

Apnoea per se is not a risk for subsequent

level of evidence 4
neurodevelopmental delay

Caffeine reduces apnoea and use of IPPV level of evidence 1a

Nasal CPAP reduces apnoea level of evidence 4

Caffeine and CPAP reduce post extubation apnoea level of evidence 1a

NCPAP is less effective than theophylline at reducing

level of evidence 2
apnoea
Caffeine reduces important short term outcomes level of evidence 1b

Caffeine reduces death and disability level of evidence 1b

Caffeine should be given to infant receiving mechanical level of evidence 1b

ventilation Grade of recommendation A

Caffeine should be given to infants with recurrent level of evidence 1b

apnoea Grade of recommendation B

Caffeine should be given early level of evidence 1b

Grade of recommendation B

References
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3. Henderson-Smart DJ The effect of gestational age on the incidence and duration of recurrent apnoea in
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4. Henderson-Smart DJ, Pettigrew AG, Campbell DJ Clinical apnea and brain-stem neural function in
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6. National Institutes of Health consensus development conference on infan-tile apnea and home
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Author: Professor David Henderson-Smart

Updated: August, 2010, Dr G Malcolm