Respiratory Flashcards
Fetal Lung Fluid
Lung spaces filled with fluid due to net chloride influx into lungs
Periodic laryngeal movements allow exit of fluid into amniotic sac
Pressure gradient 3-5 cmH2O across larynx
Channels involved in secretion of FLF (into alveoli)
Na/K/2Cl transporter Chloride channels (ClC2, ClCN2)
Channels involved in absorption of FLF
Epithelial Na channel (ENaC)
Na/K-ATPase
Composition of fetal lung fluid
High Cl (150) Low pH (6.27) Low protein (0.03)
Clearance of FLF postnatally

35% cleared
- lung distention (incr transpulmonary pressure)
- increased lymphatic oncotic pressure a/w low fetal alveolar protein

Sodium channels (FLF)
ENaC on apical surface - Bring sodium into the cell from alveoli
Na/K-ATPase - allow sodium to leave cell and enter interstitium
Water follows sodium out of alveoli and into interstitial space

Fetal breathing
Discrete episodes that resemble REM sleep and periods of low-voltage cortical activity
During later half of gestation 40-50% FBM alternating with apnea
No FBM = reduction and lung volume
Bradycardia after delivery
Due to lack of pulmonary stretch
Asphyxia -> hypoxia -> carotid chemoreceptor activation -> bradycardia
Periglottic stimulation activates laryngeal reflex
Lung inflation in the DR
Immediate increase in HR and BP
Gradually: establishes FRC, improves pulmonary and blood flow, improves gas exchange
Hering Breuer reflex
Lung overinflation leads to cessation of inspiration (apnea)
Pulm stretch receptors -> vagus
Paradoxical reflex of Head
Inhibition of Hering Breuer reflex results in extended inspiration
Periodic deep sighs = initial newborn breaths
J receptor reflex
Juxtacapillary receptors -> rapid, shallow breathing (TTN)
Laryngeal chemoreflex
Age related response to stimulators of larynx
Response: hypertension, bradycardia, swallowing, apnea
Stimulus: water, milk, suction catheter
Enhanced by sedation and hypoxemia
Carotid body reflex
Stimulus: hypoxemia (not hypoxia)
Response: initial increase in ventilation, followed by depression
Leads to peripheral vasoconstriction, stimulation of breathing, vagal (bradycardia)

Distal esophageal reflex
Afferent: vagal nerve
Stimulus: irritation of distal esophagus
Response: laryngospasm and stridor
Lung expansion and pulmonary vasodilation
Lung aeration -> increased oxygen and pH -> Vasodilation
NO, PGs further increase pulmonary blood flow
Stimulates FLF clearance and surfactant release
Diving reflex
Response to asphyxia
Redistribution of cardiac output to heart, brain, adrenals
High PVR with R to L shunting
Increase in BP followed by hypotension
Nitric oxide
Activation of guanylyl cyclase-> increased CGMP -> K channels -> pulmonary vasodilation
Sildenafil
Inhibits PDE5 to prevent degradation of cGMP
At end of which stage of lung development is the lung considered viable?
Canalicular
Late stages of lung development
Alveolar and microvascular
- secondary crests
- capillary bilayer
Timing of lung development stages
Embryonic: 0-6 weeks Pseudoglandular: 6-16 weeks Canalicular: 16-26 weeks Saccular: 26-36 weeks Alveolar and vascular: 36 weeks to 3-5 years
Embryonic phase
Ventral lung buds off of esophagus at 4 weeks
Progressive elongation & dichotomous branching to form proximal airway
Pulmonary vascular development from 6th aortic arch
Coincides with development of kidneys
Pseudoglandular phase
Branching continues
Trachea & segmental bronchi by 7 weeks
Closure of pleuroperitoneal folds at 7 weeks (CDH)
By 16 weeks all bronchial divisions are done (24 total)
Canalicular phase
Completion of conducting airways through terminal bronchioles
Rudimentary gas exchange units
Saccular phase
Gas exchange enabled by alveolar capillary membrane by 24 weeks
Expanding surface areas
Double capillary network
Alveolar phase
True alveoli appear at 36 weeks
Expansion of surface area via formation of septae or secondary crests
Postnatal alveolar growth for 3-5 years
Vascular phase of lung development
Birth to 3 years
Micro vascular maturation with single capillary bed
Late alveolarization 2-20 years
Early mediators of lung development
FGF 10, 9, 2 (fibroblast growth factor)
Sonic hedgehog (SHH)
Bone morphogenetic protein (BMP)
Fibroblast growth factor (FGF)
Polypeptide ligand
Works with tyrosine kinase receptor (FGF-R)
FGF 10 initiates primary branching

Mediators of lung development (C & S)
FGF1, FGF7, keratinocyte growth factor
TGFB super family: Regulates cell proliferation, differentiation, migration, and extracellular matrix formation
Linked to glucocorticoid signaling -> maturational effect of betamethasone on type 2 cells
Morphogens
Concentration gradients to give different developmental signals to growing tissue
Transcription factors in lung development
T-Box
FOX
HOX
TITF1
What leads to left-right asymmetry during cardiac development?
Lefty 1
Lefty 2
Nodal
Defects in these can lead to transposition, situs inversus
Vascular development of lungs
Vascular endothelial growth factor (VEGF)
FLT1, FLK1 (high affinity receptors)
Mesenchyme
Development of lungs regulated by mesenchyme
Removal arrests branching
Physical mediators of lung development
Lung fluid: promotes growth through chronic stretch
FBM: increased pressure when coupled with upper airway contractions
Peristaltic airway contractions: pressure on distal buds
Vitamin A and lung development
No vitamin A -> tracheal stenosis & pulmonary agenesis
Inhibition of alveolarization
Mechanical ventilation of preterm lungs Glucocorticoids, insulin, PKC Inflammatory cytokines (TGF-a, TNF-a, IL11, IL6 Hyperoxia or hypoxia Poor nutrition
Abnormal development in embryonic phase
Atresias (laryngeal, esophageal, tracheal) Bronchogenic cysts TEF Pulmonary agenesis/aplasia Pulmonary sequestration
Abnormal development in pseudoglandular phase
Renal agenesis -> pulmonary hypoplasia CPAM Pulmonary lymphangiectasia CDH Tracheo/bronchomalacia
Abnormal development in cannalicular phase
Renal dysplasia and pulmonary hypoplasia
Alveolar capillary dysplasia
Surfactant deficiency
Abnormal development in saccular phase
Oligohydramnios and pulmonary hypoplasia
Alveolar capillary dysplasia
Surfactant deficiency
Abnormal development in alveolar phase
Lobar emphysema
Pulmonary hypertension
Surfactant deficiency
Tracheoesophageal fistula
M»_space; F
1:2500 births
Due to incomplete fusion of TE folds in embryonic phase
Five types
Bronchopulmonary sequestration
Mass of abnormal pulmonary tissue Not connected to tracheobronchial tree Blood supply from aorta No gas exchange COMPLETELY ABNORMAL
Intralobular BPS
Within visceral pleural lining of lobe, most often LLL
Present with recurrent pulmonary infections
Extralobular BPS
Outside pleural lining, has own pleural sac
Associated with CDH
Most asymptomatic, some become infected
Bronchogenic cyst
Abnormal budding & branching of tracheobronchial tree
Most in mediastinal area
Neonates there can be a one-way valve between the cyst and the bronchial tree
Can get rapid expansion & CV compromise/death
Can fill with serous fluid and enlarge over time
On chest x-ray there is no lung parenchyma appears clear dark/black
Congenital lobar emphysema
Usually upper/middle lobe
Becomes overinflated and causes compression of other lobes/mediastinum
Most cases caused by partial bronchial obstruction
- extrinsic: pulmonary vessels, excessive pulmonary flow
- intrinsic: defects in bronchial cartilage leading to collapse and distal air trapping
Pulmonary aplasia
In embryonic phase - lung bud fails to partition
Only rudimentary bronchi are present which end in a blind pouch
Lung volume in lung hypoplasia
<2/3 of normal lung volume
Causes of pulmonary hypoplasia
Renal agenesis/dysplasia Urinary outlet obstruction Anhydramnios/PROM CDH Large pleural effusions Neuromuscular abnormalities Aneuploidy
Bronchiolar and alveolar cysts
Communicate with proximal branches of bronchiolar tree and alveolar ducts Restricted to single lobe, well defined Fluid +/- Air filled R>L lung Lower lobes>upper lobes
CPAM
Lung immaturity and malformation of airways/lung parenchyma
25% of all congenital lung lesions
5 types - type 1 most common (>1 cyst 3-10 cm)
Frequently diagnosed on prenatal ultrasound
Small CPAMs may present with recurrent infections
Alveolar capillary dysplasia (ACD)
Inadequate vascularization of alveolar parenchyma -> reduced number of capillaries in alveolar wall
Pulmonary lobules can be malformed
Pulmonary veins are frequently misaligned
Presents as PPHN early, 10-15% can present at 2-6 weeks of life
Due to failure of fusion of double capillary network
Diffuse disease in 85% of patients
Congenital pulmonary lymphangiectasis
Extremely rare, males 2:1
Dilated pulmonary lymphatics, chylothorax
CDH
1:2200-4000 births
85% on left side, 1% bilateral
Posterolateral (Bochdalek, more common) or central (Morgagni) defects in diaphragm
20-60% have multiple anomalies
Frequently have pulmonary hypoplasia and PPHN
Severity related to size of defect, early onset in gestation, presence of liver
CDH severity assessment
Observed/expected LHR (lung area/head circumference) - Extreme < 15% - Severe 15-25% - Moderate 26-35% - Mild 36-45% Lung/chest transverse diameter ratio Fetal liver in chest Fetal lung volume by MRI/US Size of pulmonary artery
Surfactant
Made up of highly organized lipids and surfactant proteins
Reduces surface tension, regulates surfactant structure/metabolism, enhances host defense
Decrease surface tension: saturated phosphatidylcholine, surfactant proteins B & C
Advantages of surfactant
Low surface tension increases compliance and reduces work of breathing
Stabilizes alveoli
Keeps alveoli dry by reducing transudation of fluid
Surfactant composition
Disaturated phosphatidylcholine (DPPC) = 40% Monounsaturated PC = 25% Protein = 10% Phosphatidylglycerol = 8% Other = 8% Neutral fat = 5% Cholesterol = 4% 
Surfactant life cycle
Starts in endoplasmic reticulum (ER) of type 2 cell
Goes to Golgi body
Forms a lamellar body and adds proteins/lipids/ABCA3 transporter
Forms tubular myelin
Stretches across surface of alveolus
Then destroyed by alveolar macrophage or recycled
Surfactant deficient lungs (RDS)
Stiff lungs = Low compliance
Increased WOB
Atelectasis/low lung volumes
Alveoli filled with transudate 2/2 lack of stretch
Gas diffusion block -> hypoxia and hypercapnia
PPHN
Variables that impact distribution of surfactant
Gravity Volume of instillation (larger better) Speed of instillation (faster better) Surfactant type Fluid volume in lung (helps early on, surfactant spreads more quickly/evenly)
Phosphatidylglycerol test for fetal lung maturity
Appears at 35 weeks
If it is in the amniotic fluid the lungs are mature
Requires thin layer chromatography
Lamellar body count for fetal lung maturity
10,000-200,000/mL
>45,000 = mature lungs
Requires infrared spectroscopy
Fetal lung maturity testing
High sensitivity for diagnosing maturity (90%)
Lower specificity (60-80%)
Mature -> high PPV
Immature results -> accurate prediction of RDS only 30-50% of time
L/S ratio
Sphingomyelin: General membrane lipid Lecithin (phosphatidylcholine) - <0.5 at 20 wks - 1 at 32 wks - 2 at 35 wks Not good with contaminated specimens Long turnaround time
Surfactant protein A
Hydrophilic
Gene on chromosome 10
Involved in tubular myelin and host defense
Surfactant protein D
Hydrophilic
Gene on chromosome 10
Involved in surfactant lipid homeostasis, host defense, antioxidant
No human diseases found
Surfactant protein B
Hydrophobic
Gene on chromosome 2
Involved in surface tension reduction, tubular myelin, type 2 cell functions
Surfactant protein C
Hydrophobic
Gene on chromosome 8
Involved in surface tension reduction, film stability
ABCA3 mutations
Autosomal recessive
30-40% of all refractory acute respiratory failure in a newborn
Most severe forms need lung transplant
Less severe forms can respond to steroids
SP-B Deficiency
Autosomal recessive
Presents as term RDS
Lethal
No lamellar bodies, no tubular myelin, no surfactant function
No sustained response to exogenous surfactant
Treatment requires lung transplant
SP-C Deficiency
Autosomal dominant 50% de novo mutations Chronic lung disease of infancy RDS, nonspecific interstitial lung disease Treatment is lung transplant
Alveolar proteinosis
GM – CSF signaling
Dead space
Physiological = anatomic + alveolar
Calculated by Bohr equation
Comparison of lung mechanics (adult vs neonate)
Neonate
- Inc RR
- Inc MV
- Inc alveolar ventilation
- Inc oxygen consumption
Adult
- Inc TV
- Inc total lung capacity
- Inc inspiratory capacity
- Inc Vital capacity
Hypoxic pulmonary vasoconstriction
Tries to keep ventilation and perfusion matched
Blood vessels constrict so that blood isn’t going to alveoli that are not ventilated
Normal physiology
Pulmonary Vascular resistance and lung volume
PVR is lowest near FRC
Increases at both high and low lung volumes
-> septal capillaries in alveolar walls are stretched -> diameters reduced
PPHN due to Maladaptation
Pulmonary structure normal but PVR elevated
- hypoxia
- hypothermia
- hyperviscosity
- pneumonia
- meconium aspiration
- sepsis
PPHN from Maldevelopment
Abnormal pulmonary structural development
Smooth muscle hypertrophy
- intrauterine hypoxia, fetal ductal closure
Decreased total pulmonary artery cross-sectional area
- pulmonary hypoplasia (CDH, congenital)
- Alveolar capillary dysplasia
PPHN
Usually in term or post-term infants
Single S2
Pre- and post-ductal saturation differential if PDA present due to R ->L shunting
Suspect if hypoxic and failing to respond as expected
- for every 1% increase in FiO2, PaO2 to should increase by 7
HFV plus iNO is better than HFV or iNO alone in severe PPHN
Factors affecting diffusion
Diffusion distance
- immature lung
- interstitial edema or emphysema
Area for diffusion
- atelectasis
- pulmonary edema
- immature lung
- new BPD
Partial pressure gradient
- alveolar MV
- PaCO2

Factors affecting anatomical dead space
ETT size ETT length Flow sensor Suction apparatus Acquired tracheomegaly End tidal CO2 detector
Factors affecting alveolar dead space
Hyperinflation
Heterogenous inflation
Decreased pulmonary blood flow
Causes of elevated PaCO2
Decreased tidal volume - decreased lung compliance, increased airway resistance, decreased patient effort
Increased physiologic dead space - added instrument, overinflation
Diffusion block - pulmonary edema
Loss of surface area - atelectasis, alveolar edema
Increased CO2 production - fever, sepsis, cold stress
Beneficial effects of acidosis
- increased respiratory drive
- increased release of oxygen
- increased ionized calcium
- dilation of small airways
- improved V/Q matching
- increased sympathetic tone (inc HR, inc contractility)
Hypoxemia
Decreased oxygen tension (PaO2)
Hypoxia
Decreased oxygen delivery to the tissues
Factors that affect mean airway pressure
PEEP (biggest)
PIP
IE ratio
Rise time/flow
Right shift on oxyhemoglobin dissociation curve
Decreased oxygen affinity
Increased temperature
Acidosis (inc H, inc pCO2)
Increased 2,3-DPG
Left shift on the oxyhemoglobin dissociation curve
Increased oxygen affinity
Decreased temperature
Alkalosis (decreased H and pCO2)
Decreased 2,3-DPG
Fetal hemoglobin
Bohr effect
Increased PCO2 leads to more unloading of oxygen from hemoglobin
Haldane affect
Deoxygenation of blood increases its ability to carry CO2
Type I pneumocytes
Shaped like a fried egg Spread thinly across the alveolar surface (covers 90%) Fewer number of cells in alveolar lining Important role in gas exchange Derived from type II cells
Type II pneumocytes
Cuboidal shape
Covers 10% of alveolar surface
Greater number of cells in alveolar lining
Important role in surfactant metabolism and secretion
Progender to type I cells
Total respiratory system resistance
Chest wall 25%
Airway 55%
Lung tissue 20%
50% of airway resistance is contributed by resistance in the nasal passages
How much FLF is actively secreted every day?
250-300 ml/day
Average fetal lung volume
20-30 mL
What medication inhibits the secretion of fetal lung fluid?
Bumetanide
What medications inhibit absorption of FLF?
Na/K-ATPase inhibited by Ouabain
ENaC inhibited by amiloride
FLF clearance prior to labor
35% cleared during days prior to birth
- decreased secretion via decreased Cl secretion
- increased Na transport from alveolar space (ENaC)
- increased lymphatic oncotic pressure
FLF clearance during labor
30% cleared
- ENaC - active Na reabsorption
- hormones increase Na uptake (epinephrine, glucocorticoids, vasopressin, aldosterone)
How much FRC is established in the first hour after birth?
80-90%
Early stages of lung development
Embryologic and pseudoglandular
Branching morphogenesis occurs
Middle stages of lung development
Canalicular and saccular
- terminal unit capable of gas exchange
- type 2 -> type 1 cell differentiation
- capillary bed formation
Mutations on FGFR2
Pfeiffer, Apert, Crouzon (laryngomalacia, tracheomalacia, lobar atresia, pulmonary aplasia)
Angiogenesis during lung development
Proximal development, new blood vessels from previous ones
Vasculogenesis during lung development
Distal vessels form from blood lakes in mesenchyme
Linked with angiogenesis during pseudoglandular phase
Stimulation of alveolarization
Vitamin A
Thyroxine (T4)
What is tracheoesophageal fistula associated with?
VACTERL
Esophageal atresia
What is the most common type of TEF?
EA with distal TEF
Pulmonary agenesis
Embryonic phase - lung bud fails to partition
Complete absence of one or both lungs including bronchi, bronchioles, and vasculature (if unilateral has hyperplasia of contralateral lung, no clinical consequences)
Primary congenital pulmonary lymphangiectasis
Fatal, a/w Noonan, Ulrich-Turner, T21
- Present with RDS and pleural effusions
- failure of normal regression of lymphatic channels in fetal lung (20 wk)
- Hemihypertrophy and lymphedema may be present
Secondary congenital pulmonary lymphangiectasis
Associated with CDH
- HLHS, Cor triatriatum
- thoracic duct agenesis
- TORCH infections
Fetal lung testing specimens
Most tests are affected by quality of the amniotic fluid specimen
Ideal is from amniocentesis
Vaginal pool specimens after ROM can be unreliable
ABCA3
ATP – binding cassette transporter A3 (ABCA3)
Type 2 cells
Critical for formation of lamellar bodies and surfactant function
Anatomical dead space
Gas in the conducting areas of the respiratory system, air does not come into contact with the alveoli
Alveolar dead space
Air contacting alveoli without blood flow in their adjacent pulmonary capillaries
Ventilation without perfusion
Echo findings in PPHN
Structurally normal heart R->L shunting Flattening or bowing of the IVS Tricuspid regurg Must see all 4 pulmonary veins to rule out TAPVR
Negative effects of acidosis
- increased PVR
- cerebral vasodilation
- increased intracranial pressure
- decreased cardiac output
- hyperkalemia
- altered cellular energy and enzyme functions
Exudative effusion
pH <7.4
WBC >1000
LDH >200
Transudative effusion
pH >7.4
WBC <1000
LDH <200
Chylothorax fluid - classically appears milky with >80% lymphocytes, elevated triglycerides, xanthochromia
Is CPAM connected to tracheobronchial tree?
Yes
Blood supply for CPAM?
Pulmonary vessels
Location preference for CPAM
Slight predilection for lower lobes
R = L
Ouobain
Inhibits Na/K-ATPase, decreased FLF absorption
Amiloride
Inhibits ENaC channels
Which surfactant protein is most abundant?
SP- A
What happens if you knock out FGF10 during lung development?
Complete agenesis of lungs with only trachea visible
Alveoli present at birth
50-150 million
Composition of fetal lung lymph and plasma
Lower Chloride 107
Higher pH 7.31
Higher protein 3.27
(Than fetal lung fluid)
Effect of antenatal corticosteroids on fetal lung fluid
Increases absorption of FLF
Increased expression and activity of ENaC channels
Lung:body weight ratio for lung hypoplasia
- <0.015 <28 weeks
- <0.012 >28 weeks
Lung DNA content for lung hypoplasia
<100 mg/kg body weight
Lung weight (for lung hypoplasia)
- <1kg = 15g/kg
- >1kg = 12g/kg
