Transcription:
Apnea of Prematurity- Pathogenesis

Dr. Julie Weiner:  Hello everyone and welcome back. This is Neonatal Review: Isolette to Crib. Again, the purpose of this podcast is to review high-yield common topics in neonatology. While our focus is geared towards the perinatal-neonatal boards, anyone learning or studying neonatology will find this helpful.

I will be one of your host for this podcast. I'm Dr. Julie Weiner, one of the neonatologists and current Medical Director for the NICU at Children's Mercy Hospital in Kansas City, Missouri. We're located right here in the Heartland.

Welcome and thank you for joining us. To help prepare for boards, we have a collection of neonatologists to help us along the way. Today, I'm again joined by Dr. Joti Sharma, the other host for this podcast. She is the current Fellowship Program Director here at Children's Mercy Hospital. Again, Dr. Sharma, tell everybody hi.

Dr. Jotishna Sharma: Hello!

Dr. Julie Weiner: As you remember, in our last podcast, Dr. Sharma introduced us to apnea of prematurity, discussing the definition, incidence and classification of apnea of prematurity. Now, in this episode, we are going to move on to discussing the pathogenesis of the apnea of prematurity. So Dr. Sharma, why do preterm infants get apnea?

Dr. Jotishna Sharma: Thank you, Dr. Weiner. In our previous podcast, remember we had talked about apnea of prematurity, the definition, and as we know, it is a developmental disorder that reflects physiologic immaturity rather than a pathologic process. To discuss how the physiologic immaturity leads to apnea of prematurity, we need first to understand the respiratory transition from fetal life to postnatal life.

Dr. Julie Weiner: Dr. Sharma, can you discuss a little further that transition that takes place at birth? I always say that babies got to get used to having life on the inside to life on the outside.

Dr. Jotishna Sharma: You are correct. And, as you know, life in the inside during fetal life, the respiratory muscles only have intermittent activity because everything is supplied through the placenta. After delivery in the postnatal life, you require continuous respiratory muscle activity to sustain gas exchange. The mechanism for transition from the intermittent in utero to continuous breathing postnatally is not yet fully understood. The thought is that apnea of prematurity is due to disruption of developmental ventilation control process due to immaturity resulting in impaired respiratory drive and with or without the failure to maintain airway patency.

Dr. Julie Weiner: So what I'm hearing is that respiratory drive is a very important component of the pathogenesis of apnea of prematurity. Do you mind talking us through that for a little bit?

Dr. Jotishna Sharma: Yes, Dr. Weiner, you are correct. So we will discuss more on the respiratory drive. So the central respiratory drive initiates the inspiratory effort in response to changes in the arterial carbon dioxide, oxygen, and pH levels through input from both the neural and chemical receptors.

The other interesting thing is that premature infants have an enhanced sensitivity of the respiratory control system to inhibitory neurotransmitters, such as adenosine which can lead to apnea. And this is important because when we discuss the management, caffeine is used as a treatment through this mechanism. The immaturity of breathing responses in preterm infant affects all levels of respiratory control, including the central and peripheral chemosensitivity, which leads to impaired ventilatory response to both hypercapnia and hypoxia.

Dr. Julie Weiner: So Dr. Sharma, you mentioned impaired ventilatory response to hypercapnia or increased CO2. Can you just walk us through a little bit of how hypercapnia leads to apnea of prematurity and kind of what that relation is?

Dr. Jotishna Sharma: The major chemical driver of central respiratory output is elevated carbon dioxide. This is sensed mainly through brainstem receptors with some contribution from peripheral chemoreceptors in the carotids and aortic bodies. The other important aspect with regards to carbon dioxide is that preterm infants actually have a blunted ventilatory response to inhale carbon dioxide. And more interestingly, the response to carbon dioxide is even lower in preterm infants with apnea when you compare them with preterm controls who are matched for gestational age, birth weight and postnatal age without apnea.

This decreased ventilatory response at a given carbon dioxide level is primarily due to changes in the central respiratory drive rather than the pulmonary mechanics. So as you can see, hypercapnia plays an important role in the respiratory drive of preterm infants.

Dr. Julie Weiner: So now that we know how hypercapnia plays a role, how does hypoxia affect apnea of prematurity or play a role?

Dr. Jotishna Sharma: I guess both go together, right? Hypercapnia and hypoxia. So with regards to hypoxia, increase in ventilation in response to hypoxia is actually dependent exclusively on feedback from carotid body peripheral chemoreceptors, which are situated in the thorax. Preterm infants have a biphasic response to hypoxia with an initial increase where they have hyperventilation and a subsequent decrease in inspiratory effort, resulting in hypoventilation and apnea. So this biphasic response that I just described to hypoxia, it actually can persist up to 38 weeks postmenstrual age. And this may contribute to the persistence of apnea in some infants as we had described earlier.

Dr. Julie Weiner: So now that we know how a hypoxia and hypercapnia play a role in the apnea of prematurity, another factor that I always consider is kind of an upper airway patency, can you just kind of tell us how this would lead to apnea?

Dr. Jotishna Sharma: Dr. Weiner, you are right, on the spot in terms of upper airway patency. This actually plays an essential role in adequate ventilation, allowing for gas exchange to occur. So with regards to upper airway patency, four general factors associated with upper airway obstruction in preterm infants can lead to apnea. And this four general factors include, number one, the collapse of airway due to poor hypopharyngeal muscle tone, inhibitory upper airway reflexes, viral infections and nasal obstruction.

Dr. Julie Weiner: Can we talk more about the collapse at the upper airway arising from poor hypopharyngeal muscle tone? This may be a cause of obstructive apnea for some infants.

Dr. Jotishna Sharma: Again, that is correct. So there are two important things to note. One, the patency of the upper airway is dependent on the resting muscle tone and active contraction of the hypopharyngeal muscles. And number two, the hypopharynx is a frequent site of upper airway obstruction in preterm infants because of pharyngeal muscle tone being poor and this leads to airway collapse, especially during the REM sleep. And interestingly, preterm infants actually spent 80% of their sleep time in REM sleep and we know that babies sleep a lot.

Dr. Julie Weiner: You talked about other factors affecting upper airway patency and specifically mentioning kind of the inhibitory upper airway reflexes. This is interesting. Can you elaborate a little bit on this?

Dr. Jotishna Sharma: So the inhibitory upper airway reflexes, they are also referred to as laryngeal chemoreflex, do contribute to in preterm infants. So activation of these reflexes may contribute to the pathogenesis of actually central apnea. This reflex appears to be mediated through irritant receptors in the larynx. But again, the mechanism is not fully known.

Common events, such as prolonged hypopharyngeal suctioning or aspiration of small volumes of milk may induce an apneice response through this inhibitory reflexes. However, it is important to note, no temporal relationship has been demonstrated between apnea of prematurity and gastroesophageal reflux. And as you know, Dr. Weiner, this is not an uncommon discussion that we usually have at the bedside.

Dr. Julie Weiner: Yes, Dr. Sharma. I was actually going to say let's highlight that one more time, that there has not been any temporal relationship demonstrated between apnea of prematurity and gastroesophageal reflux. I think that is a common thing that comes up in the bedside practice.

Dr. Jotishna Sharma: And I will second that, and there is no usefulness of antireflux medications when it comes to apnea of prematurity.

Dr. Julie Weiner: True. So while we're still discussing things that may affect the upper airway patency, can we talk a little bit how viral infections also play a role?

Dr. Jotishna Sharma: So viral infections, they cause edema and obstruction of the airway, right? Because they lead to a lot of inflammation of the upper airway. And with this edema and obstruction, they may lead to apnea. I just want to also mention about RSV. It may enhance apneic response and it is a common manifestation of RSV infection, but interestingly, the mechanism by which it leads to apnea is not fully known. And there is some thought that it may not be just due to the inflammation of the upper airway, that there may be a central component to the apnea in RSV infection.

Dr. Julie Weiner: Thank you, Dr. Sharma. I'm glad you mentioned apnea as a presentation for viral illnesses and RSV. I do think sometimes we lose sight that may represent a viral infection. So now that we're moving on and talking about upper airway patency, how does nasal obstruction play a role in apnea?

Dr. Jotishna Sharma: So for babies, nasal obstruction can cause lots of problems. As we know, newborns are nasal obligate breeders. Therefore, they need to have a patent nasal airway. Any process such as infections, we talked about viral infections or even vigorous suctioning or prolonged use of nasogastric tubes or the nasal prongs for CPAP can lead to nasal obstruction, giving rise to apnea.

Dr. Julie Weiner: Is there any other aspects of airway patency that you want to mention or talk about now?

Dr. Jotishna Sharma: Yes, Dr. Weiner. Before we complete the pathogenesis part of this talk, I do want to mention a little bit on laryngeal and tracheal abnormalities. While the larynx and trachea are less common sites of mechanical airway obstruction, mild obstruction caused by laryngeal edema, vocal cord dysfunction, tracheal stenosis or laryngotracheomalacia can precipitate apnea in some cases.

Dr. Julie Weiner: So as we wrap up this podcast, we have discussed in detail the factors that can lead to apnea of prematurity. This ranges from central to local airway factors. Can you, Dr. Sharma, summarize this for us for a better understanding?

Dr. Jotishna Sharma: Thank you, Dr. Weiner. So summary of the pathogenesis of apnea of prematurity. In preterm infants, the immaturity of breathing responses affects all levels of respiratory control, which includes central and peripheral chemosensitivity, leading to impaired ventilatory response to. hypercapnia and hypoxia. Upper airway patency is essential for flow of respiratory gas exchange. Factors associated with upper airway obstruction leading to apnea include, one, the collapse of airway due to poor hypopharyngeal muscle tone; two, inhibitory upper airway reflexes also known as laryngeal reflexes, viral infections, nasal obstruction, and laryngeal and tracheal anomalies.

Dr. Julie Weiner: Thank you for that summary, Dr. Sharma. Okay. I think our listeners are ready for a question to test our knowledge.

Dr. Jotishna Sharma: Thank you, Dr. Weiner. We do have one question about pathogenesis of apnea of prematurity. So the question is the proposed mechanism for apnea prematurity include all of the following except: choices are A, enhanced inhibitory upper airway reflexes; B, blunted ventilatory response to carbon dioxide; C, hypoxic ventilatory depression; D, decreased sensitivity to inhibitory neurotransmitters such as adenosine.

Dr. Julie Weiner: Okay, Dr. Sharma. I think I can answer it. So when you said the question again was the proposed mechanism for apnea of prematurity include all except... and I think the answer is D. All except, it's not correct, decreased sensitivity to neurotransmitters.

Dr. Jotishna Sharma: You are correct. It's increased sensitivity. A, B, C and D are true. And D should be increased sensitivity to inhibitory neurotransmitters.

Dr. Julie Weiner: Thank you everyone for listening to us today. Hopefully, this information will give you a better understanding of the pathogenesis of apnea of prematurity. This is Neonatology Review: Isolette to Crib. I'm Dr. Julie Weiner. And again, thank you for listening. Please join us on our next podcast where we will discuss the management of apnea of prematurity.