It is your first day shift on the neonatology ward. You are trying to remember the way back to the coffee machine when a nurse comes to you. “Hi, I have a question about John in bed 5. He was born at 34 weeks and five days and is now two days old. Over the past two hours, he has had multiple apnoea incidents with desaturations. Can you prescribe some caffeine?”
When I first started as a resident in paediatrics, I was a bit bewildered when a nurse first came to me with this question. I somehow managed to pass my medical school internship in paediatrics without encountering apnoea of prematurity (AOP). I might not have heard about the problem as an intern, but I gained a lot of experience in my first weeks as a resident. Apnoeas seem to be the thing in pre-term babies. But why do they happen? And why do we worry about them?
The pathophysiology of apnoea of premature infants
The exact pathophysiology of AOP is unknown. However, it may be that premature babies have an impaired sensitivity of their central and peripheral chemoreceptors, with a decreased response to hypoxia and/or hypercapnia. As a result, these chemoreceptors inhibit the brain’s respiratory centres more strongly than they should, which produces a break in the regular breathing pattern.
There is no consensus on what an apnoea is exactly; some use a definition of any pause in breathing of 20 seconds or more or any pause in breathing that produces hypoxia (oxygen saturation of less than 80%) or bradycardia (heart rate below 80 beats/minute). Apnoeas should be distinguished from periodic breathing, a normal variation of breathing that also occurs in many term babies. Apnoeas of prematurity usually happen after 24 hours of life and become more prevalent in the following weeks, reaching a peak after 3-4 weeks and generally declining after 6-8 weeks. This is thought to be related to a decline in central chemosensitivity in the second week of life and diaphragmatic fatigue.
Why do apnoeas matter?
The secondary consequences of apnoeas include desaturations and/or bradycardias. These can result in hypoxic damage to peripheral organs. They may cause a pro-inflammatory response that might further impair respiratory control. They have also been shown to be related to poor neurological outcomes and severe retinopathy of prematurity in pre-term neonates. Intermittent hypoxia can cause so-called sleep-disordered breathing which may persist into adolescence and adulthood. It is hard to look at the long-term consequences as definitions and reporting standards vary. In daily practice, nurses write down their observations, and this practice varies by person and by institute. We do not know how many apnoeas a neonate can have without endangering their development.
The differential diagnosis of apnoea
The first thing to differentiate is whether the apnoea is central or obstructive. Central apnoeas are characterised by the absence of breathing movements without obstruction. Obstructive apnoeas show inspiratory breathing effort without effective ventilation. If in doubt, ask the nurse what they saw. Some apnoeic episodes will show features of both.
- AOP: premature/immature respiratory control
- Infection: be aware that apnoeas can be a presenting symptom of viral or bacterial illness
- Mechanical obstruction, e.g. when feeding and/or in supine position. Overt reflux or vomit is actually relatively uncommon
- Impaired gas exchange
- Hypoglycaemia (uncommon)
- Neonatal respiratory distress syndrome / wet lung (due to decreased functional residual capacity)
- Medication (always think of maternal medication if the baby was born recently)
- Intracranial pathology (particularly intraventricular haemorrhage)
- After vaccinations
Treatment: when to treat and what to do
Immediate management of an apnoea:
Tactile stimulation: some suggest stimulating the thoracal region is the most effective, but data is lacking on which method to use.
Try the prone position or, if not possible, ensure a neutral position of the head if supine.
Ensure the nasal passage is clear; sometimes switching a nasogastric to an oral gastric tube may help.
Ensure the body temperature is not too high; the higher the temperature, the more frequently apnoeas occur.
Nasal Continuous Positive Airway Pressure (nCPAP) or heated humidified high flow nasal canula (HHHFNC) decrease apnoea frequency.
Treat the underlying causes, for example, by starting intravenous antibiotics if there are reasons to suspect infection. Babies with recurrent apnoeas that do not respond to treatment and require frequent stimulation with resuscitation may need to be intubated.
The most commonly used drug to counteract apnoeas is caffeine or other xanthine-derived products such as theophylline. Caffeine is an A1 and A2 adenosine receptor antagonist and its working mechanism is multiple: it has central stimulating effects on respiratory drive, it increases the respiratory minute volume, it decreases the threshold for hypercapnia, increases the response to hypercapnia, and it increases metabolism. It may also decrease diaphragmatic fatigue. It thereby reduces the frequency of apnoeas and also reduces the need for intubation and the risk of bronchopulmonary dysplasia. The half-life of caffeine is much longer in babies than in adults, which makes giving a top-up dose often quite effective over multiple days. The most commonly reported side-effects are tachycardia and hyperglycaemia. Stopping caffeine can induce withdrawal symptoms, as most medical professionals can attest. There has been some controversy about long-term neurological effects of caffeine, but the largest studies currently suggest there is no need to worry.
An alternative medication in the case of persistent apnoea is doxapram. Doxapram stimulates respiratory drive through carotid artery receptors and may work synergistically with caffeine; it is usually given intravenously. There is quite a bit of controversy about side-effects of doxapram, considering possible severe gastro-intestinal sequelae (e.g. increased chances of necrotising enterocolitis) and neurological side effects; proper informed consent by parents for its use is therefore recommended. It is probably best to stop doxapram after 24 hours if it is ineffective. Clinical trials are underway to study the effectiveness of doxapram; it may be worth considering enrolling a baby in a trial if this is available in your hospital.
What do you tell the parents?
While incidents such as apnoea are very common occurrences to us on the neonatology ward, it can be quite frightening for parents, especially if some form of resuscitation is involved. It is therefore important to explain clearly what is happening and what we can do about it. You may wonder what to tell parents about long-term effects, for several reasons: not much is known about risk assessments of long-term effects in individual cases, and it is sometimes difficult to entangle all the potential effects of prematurity. It should be explained that apnoeas and subsequent bradycardia and desaturations may lead to hypoxic injury in the brain and other end organs, and that is why we do our best to prevent them; at the same time, it is likely that a few apnoeas do not cause their child any harm.
The bottom line
Apnoeas in neonates are very common. Usually, it is linked to an immature respiratory response, but it is important to distinguish it from other causes. Apnoeas of prematurity are usually treated effectively.
Abdel-Hady H et al. Caffeine therapy in preterm infants. World J Clin Pediatr 2015;4:81-93.
Cramer SJE et al. High variability in nurses’ tactile stimulation methods in response to apnoea of prematurity-A neonatal manikin study. Acta Paediatr 2021;110:799-804.
Darnall RA. The role of CO2 and central chemoreception in the control of breathing in the fetus and the neonate. Respir Physiol Neurobiol 2010;173:201-12.
Poets CF. Apnea of prematurity: What can observational studies tell us about pathophysiology? Sleep Med 2010;11:701-7.
Schmidt B et al. Caffeine therapy for apnea of prematurity. NEJM 2006 18;354:2112-21.
Vliegenthart RJ et al. Doxapram treatment for apnea of prematurity: a systematic review. Neonatology 2017;111:162-71.
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