Neonatal Adaption and Breathing Flashcards
When is a baby premature?
There are sub-categories of preterm birth, based on gestational age: extremely preterm (less than 28 weeks) very preterm (28 to 32 weeks) moderate to late preterm (32 to 37 weeks)
When does surfactant production start?
24 weeks gestation
What are the different stages of embryonic lung development?
What growth factors are required for lung development?
• Forkhead transcription factors FOXA1/2 (HNF 3β) -proliferation, branching, cell differentiation, regulation SH
• Fibroblast growth factor-10, Sonic Hedgehog, bone
morphogenetic protein 4 – outgrowth of new end buds
• Gli proteins – transcription factors, controlled by SH,
branching
• Vascular endothelial growth factor (VEGF) – angiogenesis
When does alveolar development occur?
24 weeks of gestation
What occurs in alveolar development?
Saccules develop, capillaries develop around each (VEGF)
Most development post term
• Mainly by growth in number
• Adult numbers of alveoli by 4-5 years
Pneumocytes
• Type I and II present at 22 weeks
• From 24 weeks, lamellar bodies present (storage for surfactant)
What are lamellar bodies?
lamellar bodies are secretory organelles found in type II pneumocytes. They are oblong structures and fuse with the cell membrane and release pulmonary surfactant into the extracellular space
What impact does malnutrition (vit A) have on structural pathology of foetal lung?
Malnutrition and Vit A: reduced lung function (PEFR), reduced lung growth
Vit A: reduced septation
What impact does smoking have on foetal lungs?
Smoking – reduces fetal lung volumes. Reduced PEFR Alveoli reduced in number, and increased in size – in animal models due to reduced formation of saccule partitions, hence a reduce surface area for gas exchange.
Extrinsic vs intrinsic restriction
Extrinsic restriction:
- Congenital diaphragmatic hernia (CDH)
- Effusions
- Thoracic or vertebral abnormalities
Intrinsic restriction
-Lung cysts (Cystic adenomatoid malformation)
How is structural pathology affected before and after 16 weeks gestation?
Time of onset
< 16 weeks, branching irreversibly affected, potentially permanent reduction in number of alveoli
> 16 weeks, predominantly alveolar numbers
How does the fluid filing foetal lungs change over time?
Increases closer to term
4-6mls/kg mid-gestation -> 20mls/kg at term
Helps with lung growth
Secondary active transport of chloride from interstitium to lumen (passive absorption of sodium and water into lung fluid)
Liquid production allows for positive pressure of 1cmH20
What is lung fluid required for?
Lung fluid required for lung growth, but NOT branching
How does absorption occur in lung fluid?
- active sodium transport in apical membranes
- labour & delivery: adrenaline release -> reduced secretion and resorption begins.
- thyroid hormone and cortisol required for maturation of the fetal lung response to adrenaline
- exposure to postnatal oxygen increases sodium transport across the pulmonary epithelium
What lung liquid pathologies could occur in foetus?
- OLIGOJUDRAMNIOS- too little amniotic fluid, usually due to membrane rupture or kidney abnormalities
- FOETAL BREATHING ABNORMALITIES- due to neuromuscular disorders, CDH (congenital diaphragmatic hernia)
Why are foetal breathing abnormalities bad for lung fluid?
Normally foetal breathing SLOWS liquid loss and maintains expansion, without this more lung liquid would be lost and foetus wouldn’t be able to maintain expansion.
What can result in TTN (transient tachypnoea newborn)?
Delivery without labour- elective caesarean section
What produces surfactant, where is it stored and how does it work?
Produced by type II pneumocytes
• Surfactant phosphatidylcholine (PC) produced in
endoplasmic reticulum
• Stored in lamellar bodies
Degraded in alveoli
• Absorbed and recycled by alveolar cells
• > 90% PC is reprocessed
• Turnover time 10 hours
Negative feedback system to regulate release
• Also stretch receptors
• ß-adrenergic receptors on type 2 cells – increases with
gestation
What does surfactant prevent? How does it do this?
Prevents atelectasis – reduces work to breathe
Achieved by reduced surface tension
• Solid at body temperature – becomes a solid monolayer,
stabilises alveoli
• Laplace equation
• Internal pressure =
2 x Surface tension / radius
What happens to surface tension with an increased radius?
Surface tension reduced
Surfactant cycle
The surfactant cycle involves surfactant being produced by type II pneumocytes and stored in lamellar bodies.
Surfactant is then released into the aqueous hypophase from where it is converted into tubular myelin (intermediate form of surfactant). From this surfactant multilayers and monolayers are formed. Finally an active layer is formed at the air–liquid interface. Once the surfactant has been used a proportion is reabsorbed as liquid vesicles by type II pneumocytes, the rest is taken up by alveolar macrophages and other processes. This pathway is underdeveloped within premature infants
Respiratory distress and surfactant- how are they related?
RDS is the direct consequence of surfactant deficiency. Surfactant has three predominant roles; to increase pulmonary compliance to prevent atelectasis at the end of expiration and to facilitate recruitment of collapsed airways. In addition surfactant has a role in protecting the lungs from injury and infection caused by foreign bodies and pathogens. Surfactant is synthesized and stored in type II pneumocytes from about 22 weeks gestation. Surfactant is present within an intra-alveolar and intracellular pool. Maintaining adequate surfactant pools within the air spaces is crucial for lung function and dependant on the surfactant metabolism cycle. The surfactant pool is less than 10 mg/kg in preterm infants with RDS compared with term infants who have on average 100 mg/kg.
Tubular myelin
As phospholipid bilayer is compressed:
less water exposed, reducing surface tension
prevents further collapse
at 37C surfactant forms tubular myelin
TM is: Highly organized structure
When compressed transforms from gel to liquid crystal phase
–> Surface tension approaches zero
Surfactant composition
Mix of phospholipids, neutral lipids and protein
Lipids most important: phosphatidylcholine 80%
phosphatidylglycerol 10%
Neutral lipids: cholesterol, alter fluidity of membranes
Proteins: 4 types of SP- A, B, C, D
(5-10% of surfactant)
Why are glucocorticoid steroids given to premature babies?
• Increased production at end of gestation
• Increases dipalmitophophatidylcholine
• Dexamethasone enhances β2-adrenoreceptor gene
expression – leads to increased surfactant secretion
Promotes lung development
What two steroids are typically given to preterm babies?
Betamethasone
Dexamethasone
Why are thyroid hormones important for premature baby lung development?
T4 increases surfactant production
T3 crosses placenta
TRH increases phospholipid independent of T3,4
Why are thyroid hormones important for premature baby lung development?
T4 increases surfactant production
T3 crosses placenta
TRH increases phospholipid independent of T3,4
Why does gestational diabetes mean a baby would have delayed lung growth?
Increased sugar levels delay lung maturation
insulin delays maturation of type 2 cells, decreases % saturated PC and delayed PG
Surfactant composition in prematurity
• PC relatively unsaturated – unstable monolayer
which buckles on expiration
• Phosphatidylglycerol replaces Phosphatidylinositol
with increased gestation
• Leaky capillary membranes – fibrin deposition –
inhibits reduction of surface tension – hyaline
membranes
What is the key factor in the development of RDS?
Surfactant deficiency is the key factor in the development of RDS. Surfactant deficiency results in a ventilation–perfusion mismatch.
The combination of deficient synthesis or release of surfactant within small respiratory units and a compliant chest wall results in the alveoli being perfused but not ventilated which results in hypoxia and atelectasis. The decreased lung compliance, small tidal volumes, increased physiologic dead space, increased work of breathing and poorly ventilated alveoli leads to hypercapnia. The end result is hypoxia, hypercapnia and acidosis.
This state results in right to left intrapulmonary shunting of blood through collapsed lung and extrapulmonary shunting across the patent ductus arteriosus and the foramen ovale
What deficiencies occur in surfactant proteins?
SP – B: Absence leads to markedly reduced PG
No secretion of normal surfactant
Lethal.
SP – C: Interstitial lung disease
What happens to lung liquid at birth?
Lung liquid production ceases during labour
Fetal breathing ceases
Cooling stimulates breath along with other senses
Central chemoreceptor detection of hypoxia
First breath median time 10 sec
High inspiratory pressure
Active expiration with high pressure
How long does it take for air to replace fluid in lungs at birth and where does the fluid go?
Air replaces fluid within minutes
Some squeezed out
Most absorbed into lymphatics (1 hour) and capillaries (6-24 hours)
Rapid fall in airway resistance, increase FRC
Slower increase in compliance over 24 hours
What is a normal rhythm of breathing?
Inspiration – inspiratory muscle contraction
Passive expiration
Active expiration
Where is breathing generated?
Generated in respiratory centre -> Ventrolateral brainstem
How is breathing control in prematurity?
Respiratory centre less well developed
Very immature neonate responds like a fetus – Apnoea
Cold babies don’t have initial hyperventilation
Sometimes, preterm babies just stop breathing
How are neonatal brains built to withstand labour?
Newborn brains utilise non-oxidative (anaerobic) glycolysis
Utilise ketone bodies as energy source
? Fewer synapses and reduced oxygen requirement
Hypoxia leads to redirection of blood flow in the fetus
What is the purpose of the placenta?
Foetus totally dependant on it for nutrients, vitamins, water and oxygen.
The uterine arteries deliver oxygen and nutrients to the placenta and the veins remove the waste products (CO2 and urea). There is a large surface area between the maternal and foetal circulation.
How is oxygen carried in placenta?
Oxygen carried in two forms
2% Dissolved in Plasma and RBC water
98% Haemoglobin
What prenatal globin chains are similar to alpha and beta?
Zeta -> alpha
Epsilon -> beta
Foetal Hb affinity for oxygen
HbF binds Oxygen with greater affinity than HbA
Allows Oxygen to be transferred from mother to baby across placenta
At a lower level of oxygen the HbF is better saturated than adult Hb.
What does 2,3 bisphosphoglycerate do?
2,3 Bisphosphoglycerate binds to deoxygenated Hb with greater affinity than oxygenated Hb
Promotes release of Oxygen
In adults and older children.
By selectively binding to deoxyhemoglobin, 2,3-BPG stabilizes the T state conformation, making it harder for oxygen to bind hemoglobin and more likely to be released to adjacent tissues. 2,3-BPG is part of afeedback loopthat can help prevent tissuehypoxiain conditions where it is most likely to occur.
What happens to 2,3 bisphosphoglycerate in pregnant women?
In pregnant women, there is a 30% increase in intracellular 2,3-BPG. This lowers the maternal hemoglobin affinity for oxygen, and therefore allows more oxygen to be offloaded to the fetus in the maternal uterine arteries. The foetus has a low sensitivity to 2,3-BPG, so its hemoglobin has a higher affinity for oxygen. Therefore although the pO2 in the uterine arteries is low, the foetal umbilical arteries (which are deoxygenated) can still get oxygenated from them.
Why does oxygen bind to HbF with a greater affinity than HbA?
2,3 BPG does not bind to HbF as effectively as it binds to HbA
So oxygen binds to HbF with greater affinity than to HbA
O2 and 2,3 BPG levels in mother vs foetus
Mother: O2 13kPa -> 7kPa when crosses placenta
Foetus: O2 2kPa -> 4kPa when received from placenta
A baby’s foetal haemoglobin levels will be less than 10% at…
1 year of age
Where does blood travel through before reaching the right side of the heart in foetal circulation?
Oxygenated haemoglobin travels from placenta through umbilical vein- some goes to liver via portal sinus, while 60% bypasses hepatic circulation via ductus venosus to inferior vena cava (IVC)
Saturations of blood from:
Legs
Left atrium
Superior vena cava
in foetal circulation?
Legs- 25-40%
LA- 65%
SVC 25-40%
What is the junction of IVC and right atrium?
Junction of IVC and R Atrium is a tissue flap Eustachian valve
Directs oxygenated blood across dorsal aspect of IVC across Foramen Ovale into LA
Why are left atrium sats 65% in foetal circulation?
Sats in LA 65% so myocardium and brain get blood with higher oxygen
What keeps the ductus arteriosus open?
The “E” series ofprostaglandinsare responsible for maintaining the openness of the ductus arteriosus (by dilation of vascular smooth muscle) throughout the fetal period.Prostaglandin E2 (PGE2), produced by both the placenta and the DA itself, is the most potent of the E prostaglandins, but prostaglandin E1 (PGE1) also has a role in keeping the DA open
What is the journey of blood after it reaches the inferior vena cava in foetal circulation?
Blood enters right atrium passes Eustachian valve which streams blood through foramen ovale between RA and LA. Therefore most oxygenated blood travels to LA then LV and then up to aorta -> carotid arteries and brain, some goes down to abdomen and lower limbs, some goes back to placenta via umbilical arteries
Some blood goes to RV, joined by blood coming back from brain to SVC -> pulmonary artery -> ductus arteriosus which allows blood to go from pulmonary artery to aorta
Why is there very little blood flow to lungs in foetus?
Pulmonary vessels very narrow so vascular resistance very high
Where does blood in pulmonary artery go in foetal circulation?
Through ductus arteriosus to aorta
Umbilical artery course vs umbilical vein course
The umbilical arteries course downward to the internal iliac arteries before entering the aorta. They supply the buttocks and the lower extremities via the latter part of the internal iliac arteries
The umbilical vein courses upward along the falciform ligament to the underside of the liver. Here it divides into two vessels, the portal vein and the ductus venosus. The ductus venosus joins with the inferior vena cava.
Where does gas exchange occur in foetal circulation?
Gas exchange occurs in Placenta
Receives deoxygenated blood
Delivers oxygenated blood
Umbilical Vein (80-90% saturated, 4.7kPa)
Foetal circulation: where is preferential streaming of oxygenated blood?
Myocardium and brain
In the foetus blood flows through the ductus arteriosus between
The pulmonary artery and the aorta
What happens to placental circulation and shunts at birth?
Placental circulation ceases
-Umbilical vessels constrict: stretch and rise in oxygen tension
Shunts close
- Flow through ductus venosus falls
- Fall in venous return through IVC
- Closes over 3 – 10 days
Right ventricular input comes only from the IVC, SVC and coronary sinus – normal child/adult venous return
What happens to the vessels when pulmonary vascular resistance falls?
Lung expansion
Pulmonary stretch receptors
Increased Oxygen tension
8-10x rise in blood flow
How are the foramen ovale and ductus arteriosus closed?
Fall in Pulmonary Vascular Resistance (PVR) leads to massive rise in venous return to left atrium
RA and LA pressures equalise
Flap of foramen ovale pushed against atrial septum
Foramen Ovale closes within minutes to hours of birth
Fall in PVR leads to bidirectional flow in DA
Mechanism of DA closure: Oxygen rise
What closes the ductus arteriosus?
Oxygen increase
Why would the circulation transition after birth not be permanent?
Pulmonary arterioles very reactive and constrict to certain stimuli Hypoxia Hypercarbia Acidosis Cold
Rise in PVR and Right to Left shunting: foetal circulation
Why would the circulation transition after birth not be permanent?
Pulmonary arterioles very reactive and constrict to certain stimuli Hypoxia Hypercarbia Acidosis Cold
Rise in PVR and Right to Left shunting: foetal circulation
Atrial septal defect
Most common congenital cardiac malformation in adults.
Atrial septal defect causes left to right shunt due to the high compliance of the right atrium and the difference in pressure between the two atria. Secondary to this mechanism, the pressure in the pulmonary circulation is increased.
A person with no other heart defect, or a small defect (less than 5 millimeters) may not have symptoms, or the symptoms may not occur until middle age or later.
Symptoms that do occur may begin at any time after birth through childhood.
They can include:
Difficulty breathing (dyspnea)
Frequent respiratory infections in children
Feeling the heart beat (palpitations) in adults
Shortness of breathwith activity
In infants, small ASDs (less than 5 mm) will often not cause problems, or will close without treatment. Larger ASDs (8 to 10 mm), often do not close and may need a procedure.
Important factors include the size of the defect, the amount of extra blood flowing through the opening, and whether the person has any symptoms.
Some people with ASD may have other congenital heart conditions. These may include a leaky valve or a hole in another area of the heart.
What do we do to reduce risk of baby developing hypothermia?
Energy needed to maintain a normal temperature
Environment which minimises energy required to maintain core temperature (36.5-37.5oC)
Thermoneutral zone- minimum energy required to maintain body temp
Glucose is converted into what before becoming pyruvate and acetyl CoA? What are the missing products and processes?
Glucoose-8-phosphate
Fructose 1,6 bisphosphate
3 key rate limiting steps of gluconeogenesis?
G-6-phosphatase converts G-6-phosphate into glucose
Fructose- 1,6-bisphosphatase converts F-6-phosphate into F1,6-diphosphate
PEPCK converts axaloacetic acid into phosphoenolpyruvate
Glycogen storing disease Type 1
Deficiency of glucose-6-phosphatase (affects rate limiting step in gluconeogenesis so cant convert G6p into glucose)
- > hypoglycaemia and lactic acidosis in newborn
- > hepatomegaly in older infant (due to build up of glycogen that cant be broken down in liver)
Why do we need to modulate the rate of ventilation?
Ventilation rate constantly adjusted to meet body’s demand for O2 and production of CO2.
(greater breathing rate -> increased ventilation -> increased O2 in alveoli -> less Co2)
Adequate O2 absorption and CO2 expulsion from body achieved via maintaining pressure gradients between alveoli and blood
Which muscles are used in:
quiet expiration/inspiration?
forced expiration/inspiration?
QUIET:
Insp: diaphragm
Exp: elastic recoil
FORCED:
Insp: respiratory - external intercostals
accessory - pectorals, sternomastoid, scalene
Exp: respiratory - elastic recoil, internal intercostals
accessory - abdominals
What generates the basic breathing pattern?
Neuronal systems in brain:
Medulla (brainstem) has complex network of neurones (central pattern generator) determines overall rate frequency and depth of breathing
takes inputs from parts of body and decides the breathing rate
sends signals first to inspiratory muscles
then to expiratory muscles
How does central pattern generator determine rate and depth of breathing?
Takes various inputs (physiological readings) from different parts of body eg chemoreceptors responding to levels of oxygen, acidity etc
feeds back to CPG -> triggers increased rate of ventilation etc
receives inputs from higher brain centres
What chemoreceptors are key in responding to changes in arterial PCO2?
CENTRAL CHEMORECEPTORS
Central respiratory chemo-receptors (CRC) present in the medulla indirectly monitor changes in arterial CO2.
Co2 increases -> CO2 levels in blood increase -> increased CO2 diffuses from blood through BBB into cerebrospinal fluid -> indirectly activates CRC via converting into carbonic acid which dissociates into H+ ions
Although CRC respond to changes in [H+] within cerebrospinal fluid, as H+ does not cross the blood brain barrier, CRC do not directly respond to changes in blood pH (except via CO2).
So increased activation of CRCs signals to respiratory control centres to increase ventilation
so negative feedback
Which type of sleep apnoea does each patient have?
Patient A: CENTRAL
Patient B: OBSTRUCTIVE
Why?
Airflow stops but airways still open, but CPG not sending signals to diaphragm so diaphragm excursions stopping then starting due to lack of signals
Whereas for patient B, CPG is fine so diaphragm contracting, but due to blocked airway the airflow stops
Cheyne-Stokes respiration
Oscillating apnoea and hyperpnoea
Overcompensation in not enough breathing and then too much ventilation
Goes through period of apnoea due to environmental circumstances, eg lower rate of breathing and peripheral chemoreceptors respond to increase level of breathing because we need oxygen, but it overshoots due to dysfunction in CPG
Central chemoreceptors then sense this overcompensation, pH change due to not enough CO2 now so stops breathing and so overcompensates
Apgar score
What does this CXR indicate in a neonate?
Sepsis
Sagittal USS in asphyxia- what are the two features being pointed out?
Periventricular flare - oedema in this watershed area
Cystic leukomalacia - loss of some brain area
What do you expect to see in CXR of baby with RDS?
