Respiratory changes at Birth Flashcards
1
Q
What happens at birth?
A
Shunts are removed with major changes in heart due to altered resistance and demands in vascular system and a shift from a right to a left sided dominated system.
2
Q
Neonate oxygen expenditure
A
Twice the rate of the adult/kg body mass.
3
Q
Neonate ardiac output
A
4x of the adult.
4
Q
Pressure change in heart
A
Right ventricular pressure halves while left ventricular pressure rises.
5
Q
Heart muscle development before birth
A
Growth is hyperplasia, so number of cardiac cells increase.
6
Q
Heart muscle development after birth
A
Growth shifts to entirely hypertrophic.
7
Q
When does energy requirement increase stop in man?
A
At 18 years of age.
8
Q
Myocardium in a 2 month old foetus
A
Lots of glycogen, no striation and many cells undergoing mitosis with immature RBCs in a nucleus.
9
Q
Birth vs adult heart
A
Very similar other than cells are smaller in the baby, adult has more mitochondria but less mitochondrial DNA.
10
Q
Foetal cardiomyocytes
A
Stop cell division at or shortly after birth.
11
Q
What is phosphorylated in mitosis?
A
Histone H3.
12
Q
Postnatal cardiomyocytes
A
Bi-nucleated and mature.
13
Q
Ventricle differences in binucleation
A
Left ventricle peaks at around day 125 at 65% and then tails off while right ventricle peaks at day 140 at 70%.
14
Q
What regulates cardiomyocyte proliferation in foetal life?
A
Both haemodynamic forces and circulating factors.
15
Q
Factors that stimulate progression of cardiomyocyte proliferation
A
Increased arterial load, angiotensin II, cortisol and insulin-like growth factor-1, these all increase blood pressure.
16
Q
Factors that suppress progression of cardiomyocyte proliferation
A
T3, reduced systolic load and ANP.
17
Q
What do reduced systolic load and ANP lead to?
A
Decrease in blood pressure.
18
Q
Effect of cyclin D1
A
Drives cell division.
19
Q
Effect of p21
A
It blocks cyclin dependent kinases so inhibits cell division.
20
Q
When does TSH peak?
A
After birth.
21
Q
What does TSH do?
A
Up to birth it induces T3 and T4 production that are important for tissue maturation and driving change in cell divisions in the heart.
22
Q
Critical window pre-birth
A
Where proliferative, hypertrophic and apoptotic responses determine cell population for ongoing hypertrophy.
23
Q
What happens in critical window that reduces number of cells?
A
Poor nutrition, hypoxia and environmental stress, these limit number of cells and therefore limit population that can support myocardial growth trajectory.
24
Q
What happens if maturity happens early?
A
A premature T3 surge so heart may be hypocellular with increased hypertrophy required to produce sufficient cardiac muscle strength, can lead to cardiac failure later in life.
25
Changes required for lung function at birth
Low surface tension, fluid removal, surface for gaseous exchange needed, need blood supply and protection from infective agents and oxygen radicals.
26
5 lung stages
Embryonic, pseudoglandular, canalicular, saccular and alveolar.
27
When does surfactant appear?
Week 25.
28
2 major development steps in the lungs
Organogenesis and differentiation.
29
Lung organogenesis
Up to week 16, includes development of bronchi, bronchioles and terminal bronchioles, with formation of major airways, bronchial trees and portions of respiratory parenchyma and birth of acinus.
30
Lung differentiation
Week 16 onwards, includes development of respiratory bronchioles, alveolar ducts and sacs, formation of the air-blood barrier, surfactant, lung periphery, air space expansion and secondary septation.
31
Earliest week that can survive birth
Week 24 as surfactant is present.
32
What does secondary septation form?
Alveolar sacs.
33
Saccular lung
24 weeks to 38 weeks, terminal air sacs form along with a thick septate and blood vessels develop.
34
Alveolar lung
Week 38 onwards, primitive then definitive alveoli form, loss of inter-septal connective tissue with 15% alveoli present at birth.
35
When do lungs mature?
7 years old.
36
What lung cells form first?
Type II.
37
Type II cells
Surfactant producing, as numerous as Type I but only cover 5% of surface.
38
Type I cells
Squamous epithelium cell that make up alveolar walls.
39
Type II cell function
Produce lamellar bodies that are secreted out, expand and sit on surface of a fine layer of fluid lining cells.
40
Pulmonary surfactant general structure
90% lipid, 10% protein.
41
Main lipid in surfactant
DPPC, makes up 40-70% of surfactant lipid at birth and is amphoteric.
42
Proteins in surfactant
SP-A (5%), SP-B (0.7%), SP-C (0.8%), SP-D (0.5%)and plasma proteins (3%).
43
Innate immunity proteins in surfactant
SP-A and SP-D.
44
Stabiliser proteins in surfactant
SP-B and SP-C.
45
Surface tension of air and water at 37C
70.4mN/m.
46
Surface tension of air, water and DPPC at 37C
5mN/m.
47
How much can surfactant lower tension?
5-10 fold.
48
What does high unsaturated DPPC proportion allow?
Semi-rigid packed surface to occur which becomes more dense on compression.
49
What does DPPC do?
It breaks up semi-crystalline structure of water molecules by sitting choline into it.
50
Laplace's Law
Closing pressure is inversely proportional to alveolar size, no surfactant present will collapse bubble, if it is present as it closers further and further it inhibits collapse.
51
Biophysical properties of surfactant
Support lung expansion, prevent pulmonary oedema (balancing hydrostatic force) stabilise small airway structure and improves mucociliary function.
52
Immunological properties of surfactant
Phospholipids inhibit proliferation, Ig production, lymphocyte cytotoxicity and cytokine (TNF, IL-1 and IL-6 release) from macrophages.
53
SP-B and SP-C
Hydrophobic proteins that interact with lipids to enhance biophysical stability of surfactant and regulate response to compression and expansion.
54
What does loss of SP-B and SP-C cause?
Unstable surfactant layers and lethal pulmonary distress.
55
SP-B function
Provides mechanical stability to compressed films at aqueous interior, retained in rapid breathing.
56
SP-C function
Facilitates compression-driven folding of surfactant interfacial films upon breathing.
57
SP-A and SP-D
Hydrophilic surfactant collectins involved in innate immunity, they opsonise bacteria binding to sugar surfaces and enhance phagocytosis.
58
SP-A and SP-D structure
An N-terminal non-collagenous domain, collagenous central, alpha helical coiled coil and a CRD.
59
Bacteria opsonised by SP-A and SP-D
Haemophilus influenzae, P. aeruginosa and S. aureus.
60
Where is SP-D expressed?
In lungs and other mucus membranes.
61
When does surfactant spike?
Final fifth of gestation.
62
What increases expression before birth?
SP-A, SP-B and SP-D.
63
Pre-natal drivers of surfactant synthesis
Glucocorticoids increasing CCT and FAS in foetal lung, thyroid hormone and stress.
64
Effect of CCT
Activates choline in formation of phosphatidylcholine.
65
Effect of FAS
Needed for addition of Acetyl CoA in fatty acid chain elongation and steroids thought to stimulate mesenchymal cells to produce FGF7 altering activity of Type II epithelial cells.
66
Post-natal drivers of surfactant synthesis
Labour and breathing.
67
Lung fluid
Self-produced, expelled into amnion.
68
How much lung fluid is produced towards end of gestation?
5ml/kg body mass/hour.
69
How is lung fluid cleared?
Pre-birth chest movement, labour squeezes it out and post birth absorption (majority).
70
Fluid filled alveolus
Active Cl- secretion at alveolus transfers H2O and Na+ out of interstitial fluid, into the alveoli.
71
Drying alveolus
Active Na+ absorption at alveolus drives H2O and Cl- transfer into interstitial fluid from alveolar lumen.
72
How quick does absorption occur?
Within 2 hours.
73
Hormone changes at birth that aid absorption
Adrenaline triggers cAMP and expression of amiloride sensitive Na channel, thyroid hormones and glucocorticoids act synergistically to increase Na pumps and reduce Cl pumps.
74
Postnatal changes that aid absorption
High O2 tensions in lung inducing Redox sensitive nuclear factor NF-kB that maintains high expression of amiloride sensitive Na channel.
75
Lumen channel
Chloride ion channel pre-natally is replaced by a Na+ channel and a basal surface 2Cl-/Na+/K+ co-transporter is lost, replaced by with a Na+/K+ ATPase that puts 3Na+ for 2 K+ into interstitial fluid.
76
Amiloride channel
Opens so Na+ channels brought through from alveolar space to the interstitial space, dragging Cl- and water.
77
Change in pulmonary resistance at birth
Change from low blood volume high resistance vascular bed to high blood volume low resistance vascular bed in 60-120 seconds.
78
What reduces pulmonary resistance rapidly?
Fluid loss, ventilation & lung expansion, increase in eNOS activity driven partly by increased blood flow and oxygen levels, and local expression of PGI2 in lung endothelium.
79
Pulmonary blood flow increase at birth
21% to 50%.
80
Slower causes of reduced pulmonary resistance
Gradual post-natal loss of smooth muscle in wall of pulmonary vessels.
81
What does NO do?
Increases vascular smooth muscle relaxation surrounding arterioles.
82
What do PGI2 and PGE2 do?
Cause arterial small muscle relaxation.
83
What does NO do to cause vasodilation?
NO is produced by L-Arg which diffuses into smooth muscle cell activating guanylate cyclase producing cGMP which is vasodilatory.
84
What does PGI2 do to cause vasodilation?
It diffuses into smooth muscle cell and activates adenylate cyclase producing cAMP which is vasodilatory.
85
Effect of NO and Prostacyclin signalling pathways in vascular tone regulation
It activates PKG and PKA which phosphates and inactivates MLCK which is required for actin-myosin interactions which doesn't occur, so smooth muscle relaxes.
86
What happens to smooth muscle walls post-natally?
They reduce with cells undergoing apoptosis.
87
PPHN
Failure to achieve decrease in pulmonary vascular resistance with an altered pulmonary vascular tone, reactivity and/or structure causing severe hypoxaemia due to right to left blood shunting by DA and FO.
88
Effects of PPHN
Common in infants requiring neonatal intensive care, 1-2 per 1000 births with a 10-20% mortality rate, long term sees pulmonary arteries appear thick walled and fail to relax normally upon vasodilator exposure with capillaries remodel to form protective muscles.
89
Causes of Hyaline Disease
Caused by prematurity with development insufficiency of surfactant production and structural immaturity of the lungs OR a genetic problem in production of surfactant associated proteins/lipid metabolism.
90
Incidence of Hyaline Disease
1% of newborns at 40 weeks, 25% at 30 weeks and 50% at 28 weeks, it is the leading cause of death in preterm infants.
91
What happens in Hyaline Disease?
Smaller alveoli don't expand, so they remain collapsed and causes thick-looking walls with a loss of a large surface area.
92
Alveoli number and size at birth
15-30% of adult alveoli or 1 million.
93
Alveoli formation rate
Maximal at birth, which gradually decreases and then stops at 18 months.
94
When does septation begin?
30 weeks.
95
Surfactant composition before birth
Very low phosphatidylinositol and SA proteins only seen in late gestation such as SP-B forming at 34 weeks.
96
What causes hyaline membrane formation?
Altered surfactant composition.
97
Hyaline membrane
Raises alveolar surface tension, pulling out proteins, sit in fluid with staining as pink.
98
Effect of birth on haemoglobin
Shift of subunits used.
99
Haemoglobin structure
It is a heterotetramer of 2 chromosome 11 beta-like subunits and 2 chromosome 16 alpha-like subunits.
100
What haemoglobin genes in chromosome 11?
1 epsilon, 2 gamma, 1 delta and 1beta.
101
What haemoglobin genes in chromosome 16?
2 zeta and 2 alpha.
102
Haemoglobins present in embryo
Gower 1 (zeta 2, epsilon 2), Gower 2 (alpha 2, epsilon 2), Hb Portland 1 (zeta 2, gamma 2) and Hb Portland 2 (zeta 2, beta 2).
103
Haemoglobins present in foetus
Hb F (alpha 2, delta 2, 85% of foetal Hb) and Hb A (alpha 2, beta 2, 15%).
104
Haemoglobins present after birth
Hb A (alpha 2, beta 2, >95% of Hb) and Hb 2 (alpha 2, delta 2, 1.5-3.5%).
105
When does beta subunit overtake gamma subunit?
6 weeks after birth.
106
Deoxy Hb
Inter-subunit salt bridges that resist movement, stabilising it in the tense state with low O2 affinity.
107
Oxy Hb
Salt bridges broken with rotation of dimers and changed quaternary structure giving it a relaxed form with high O2 affinity.
108
Subunits held in a salt bridge
Alpha 1 and beta 2, alpha 2 and beta 1 and alpha 1 and alpha 2.
109
What do allosteric regulators do?
They bind Hb altering its affinity for oxygen.
110
Examples of allosteric regulators
2,3-Bisphosphoglycerate (formed in glucose breakdown) and protons (captured when CO2 and lactic acid made).
111
Effect of pH (and pCO2) on curve
It shifts it to the right as it increases, lowering Hb affinity.
112
What can bind oxygen in the tense state?
Alpha.
113
When can beta bind oxygen?
Only in relaxed state.
114
2,3-BPG
Can bind to positive charged pocket between beta 1 and 2 subunits, forcing Hb toward the tense stage so will release more O2 in the presence of it.
115
Effect of high CO2
Lowers pH so protons bind to beta 2 subunit, forming a charge bridge with Asp94 of the alpha 1 subunit causing increased tense stability .
116
What effect do regulators have overall?
They have little effect on intake in lungs but a large change in oxygen release into tissues.
117
Why is foetal haemoglobin needed?
Mother sends relatively deoxygenated blood into the placenta, so if adult Hb was used then it would not pick up oxygen, so uses high affinity foetal Hb.
118
How does foetal Hb have higher affinity?
Beta subunit replaced with gamma for foetus.
119
How do beta and gamma subunits differ?
Gamma has Ser143 instead of His143, this means that 2,3-BPG has no effect keeping curve to the left.
120
Blood cell count in foetus
20% more RBCs in foetus.
121
What vascular signals does embryo respond to?
CO2 and H+.
122
Placental and foetal partial pressures
Placenta has 23ppO2 and foetal tissue is at 18ppO2, so delivers 2x as much oxygen as adult.
123
Why do we change from foetal to adult Hb/
High affinity binding is fine at low oxygen tensions, but poor at high tensions so will not deliver to post natal tissues.
124
Chronic hypoxia
Implicated in infant sudden death syndrome due to some evidence of increased/prolonged expression of Hb F.
125
Hydroxyurea
Can induce Hb F expression in older children, can replace some HbA aswith treatment for HbA mutations like sickle cell.
