Respiratory Embryology and Common

Pathophysiology

Sharon Fichera RN, MSN, CNS, NNP-BC Newborn & Infant Critical Care Unit

Children’s Hospital Los Angeles

Embryonic development week 1 – 5 The foregut provides a single lung bud which begins to divide. At the same time the pulmonary vein develops and joins the lung bud. The Trachea is developed by the end of the embryonic period Trachea, L & R mainstem with beginning development of the lobes of the lung

End of the Embryonic Period

Embryonic lung development

1 – left main stem bronchus

11 – Right inferior bud

12 – Right middle bud

13 – Right superior bud

Pseudoglandular period 6 – 16 weeks Lung under goes 14 generations of branching and the formation of the terminal bronchioles

Canalicular period 16 – 24 weeks gas exchanging units beginning to form. Type II alveolar cells are present. Vascular system develops and is closer to the conducting airways

Terminal sac period 26 weeks – birth more budding and there is an exponential increase in surface area. Type II pneumocytes are producing surfactant

Alveolar period 32 weeks to 8 years. Further development and alveolar proliferation.

Bronchiole tree of a 30 week gestation fetus

Biochemical Events Reduction of surface tension by the production of surfactant – prevents collapse of the alveoli at the end of expiration

Surfactant is produced by the type II pneumocytes at approximately 25 weeks.

It is the phospholipids that have the surface-active properties,

DPPC – Dipalmitoylphosphatidylcholine is the major phospholipid that reduces the surface tension

Surfactant Proteins Hydrophilic

Surfactant Protein A – most abundant, with B makes the tubular myelin lattice network Activates the alveolar macrophages – host defence

Surfactant Protein D – is upregulated during inflammation and may have a role in host defence

Hydrophobic

Surfactant B – important in making the tubular myelin lattice. Also enhances the update and recycling of surfactant

Surfactant C – Assists with the absorption and spreading of the surfactant. Also assists with surfactant recycling

Gestational Age Assessment &

Surfactant Fetal kidney makes most of the amniotic fluid, the fetal lung makes fluid independently of the kidney

Sphingomyelin - a phospholipid (fat) is produced in the Endoplasmic Reticulum (ER) within the cell. Level remains constant after 30 weeks.

Lecithin - a phospholipid that is in low concentrations until 30 weeks and increases with a peak at 36 weeks

Phosphatidylglycerol - a phospholipid that also peaks at 36 weeks

Phospholipids and usefulness in gestational age assessment

L/S ratio: The lecithin to sphingomyelin ratio to assess for lung maturation

>2:1 is considered mature

Presence of Phosphatidylglycerol - PG most reliable measurement for IDM

ACOG 2011 - Position on Corticosteroids

risk of delivery at 24-34 weeks

May not be beneficial if delivery is imminent

No contraindication if chorioamnionitis is present

Meerstadt, PWD., Gyll, C. Maanual of Neonatal Emergency X-Ray interpretation. 1994; London, W.B. Saunders.

Meerstadt, PWD., Gyll, C. Maanual of Neonatal Emergency X-Ray interpretation. 1994; London, W.B. Saunders

Meerstadt, PWD., Gyll, C. Maanual of Neonatal Emergency X-Ray interpretation. 1994; London, W.B. Saunders

RDS Respiratory Distress

Syndrome Surfactant deficiency Lung immaturity RDS/Pneumonia 48-72 hours - type II pneumocytes will make surfactant Treatment - Surfactant (1990's) Natural surfactants: Survanta -bovine Curosurf - porcine Infrasurf - calf lung Routine NICCU care

Treatment Approach Prophylaxis - In the DR, preferably prior to breathing (15 min)

Early rescue - Within 1-2 hours

Late rescue - within 4-12hours and progressive FiO2 requirement

Insure - Intubate - surfactant - extubate

Non-invasive administration

Outcomes for infants randomly assigned to continuous positive airway pressure (CPAP) initiated in the delivery room or intubation and surfactant treatment in the delivery room. The combined outcome of death or bronchopulmonary dysplasia significantly favored the CPAP group. Data from Schmölzer et al. (24)

Alan Jobe Neoreviews 2014; 15:e236-e245; doi:10.1542/neo.15-6-e236

Decrease in death from respiratory distress syndrome (RDS) from 1970 to 2010. Infant mortality has decreased by 95%, although the infants coded as having RDS have gotten smaller and more immature. The years for introduction of the interventions into clinical practice are indicated on the graph. Figure redrawn from data in Lee et al (49) with additional data for 2010 to 2011 from Hamilton et al. (50) CPAP=continuous positive airway pressure; PEEP=positive end-expiratory pressure. • Alan Jobe Neoreviews 2014; 15:e236-e245; doi:10.1542/neo.15-6-e236

Can We Prevent RDS? Maternal glucocorticoids/antenatal steroids

Elective C/Section a Neonatal Danger

Determine lung maturity

L/S ratio of at least 2:1

Presence of PG

Transient Tachypnea of the Newborn (TTN)

Retained Lung Fluid Syndrome Delayed clearance of lung fluid – who is at risk? A. Term, near term and post term – new terminology B. Elective C/Section without labor C. Prematurity, precipitous delivery

How does the lung fluid get removed?

TTN Maybe difficult to distinguish from other diseases:

Differential:

RDS

Pneumonia

Maybe a diagnosis of exclusion. Pt is usually term, and symptoms may be mild

Meerstadt, PWD., Gyll, C. Maanual of Neonatal Emergency X-Ray interpretation. 1994; London, W.B. Saunders

Pneumonia Congenital vs acquired

Risk is inversely related to gestational age

Maybe associated with chorioamnionitis, or maternal UTI

Prolonged rupture of membranes

Transplacental

RDS vs Pneumonia

RDS vs Pneumonia Suspicious

Suspicious

&

More Suspicious

Any baby with respiratory distress needs an evaluation for sepsis/pneumonia and treatment with antibiotics until infection is ruled out!

Meconium Aspiration MAS – 8-29% of all deliveries

Occurs in the near term, term and post dates babies

Aspiration occurs about 5%

Ball valve effect vs chemical pneumonitis

Hyperinflation, with areas of collapse

Chemical pneumonitis initiates an inflammatory response

Causing cytotoxic edema, washing out inactivating the surfactant

Meconium Aspiration Asphyxia, effects of chronic hypoxia may result in PPHN

Delivery room management

May have signs of prolonged placental insufficiency – cachectic

Barrel shaped chest

May benefit from surfactant (lessen airleaks)

Persistent Pulmonary Hypertension (PPHN) Fetal Circulation

Blood enters the umbilical vein from the placenta - goes through the Ductus Venosus into the IVC

Enters the right atrium crosses through the Foramen Ovale into the left Atrium

Blood (used by the body) coming back to the right Atrium, right Ventricle goes right to left through the Ductus Arteriosus into the Aorta

Lungs - high pressure

Body - low pressure

Newborn Circulation Normal Transition

Cord is clamped - placental separation SVR rises

Lungs fill with air and expand

Mechanical compression of pulmonary vessels is released and pulmonary blood flow increases PVR falls

Ductus Venosus - closes 3d-2 weeks

Ductus Arteriosus - closes 1 day - month

Foramen Ovale

When is PPHN diagnosed? Due to elevated

pulmonary vascular resistance

77% <24 hours

93% <48 hours

97% <72 hours

1.9 per 1000 births

Why do babies get PPHN? Heart/Lung/Pulmonary Vasculature

Lung *Meconium

Aspiration Syndrome

*Pneumonia

*Lung Hypoplasia

*RDS

Why do babies get PPHN? Heart/Lung/Pulmonary Vasculature

Pulmonary Vasculature Reactivity/underdevelopme

nt

Renal/pulmonary development

Congenital diaphragmatic hernia

CCAM’s

Sepsis - cytokine mediated response

Why do babies get PPHN? Heart/Lung/Pulmonary Vasculature

Heart Congenital Heart

Disease

Hypoxic ischemic injury

Microscopy of PPHN Normal Constricted

PPHN Vasodilators Vasoconstrictors

Hypoxia

Acidosis

Hypercarbia

Deficient prostacyclin

Deficient NO

Excessive thromboxane, leukotrienes, endothelin & platelet-activating factor

Oxygen

Alkalosis

Hypocarbia

Nitric Oxide

Phosphodiesterase inhibitors

Prostacyclin

Diagnosis of PPHN Cardiac ECHO

Pre & post ductal oxygen saturation

Complications Air leaks DIC

Systemic hypotension HIE

AKI (ARF, ATN)

Treatment Normalize blood gases

Oxygen/ventilation

iNO

Surfactant replacement?

Sedate

Maintain systemic blood pressure – inotropes

Antibiotics

Phosphodiesterase 3 inhibitor

Phosphodiesterase 5 inhibitor

(sildenafil)

ECMO

Mortality and need for ECMO vary by center and is somewhere between 20-40%

Long term morbidity is often hidden and may be seen in sensorineural hearing loss and abnormal neurologica outcomes

Bronchopulmonary Dysplasia Chronic Lung Disease

First described in 1967 by Northway

(2001) Jobe/Bancalari - <32 week who has been on O2>28 days by 36 weeks PCA is still requiring O2 or Ventilation

Introduction of surfactants has changed the presentation of classic BPD

Inflammatory mediators may play a role in BPD (chioamnionitis)

Acute lung injury, arrested development and abnormal repair processes

BPD Inflammatory mediators

Oxygen toxicity - ROS, Pulmonary edema

Assisted Ventilation/PPV – Barotrauma, volutrauma

L R shunting via a PDA

Inverse relationship to gestational age

Nutrition

Prevention & Management Prevention

Prevent preterm birth

Antenatal corticosteriods ?

Gentle ventilation/permissive hypercapnia and early extubation

HFOV?

Steriods - AAP does not recommend (2010)

Management

Minimize length of intubation/IMV

nCPAP/NIPPV

SIMV/NAVA

Oxygen targeting

OWL

Oxygen swings

Management Diuretics ?

Caffeine – lung protective, reduces length of time on the ventilator

Nutrition – 150-180 kcal/kg

Steroids ? Inhaled steroids?

Morbidities -

neurodevelopmental, hearing loss, vision, cerebral palsy

Pulmonary Air Leaks Pneumothorax Anterior pneumothorax

Airleaks Sail sign Pneumopericardium

Pneumomediastium

Pulmonary Interstitial Emphysema

Apnea Periodic Breathing

An irregular pattern with 5-10 second pauses, followed by rapid breahing

30-90% of preterm infants, disappears near term

No changes in HR or color

Apnea

20 second pauses

Shorter if HR or color change occurs

Most apnea occurs in healthy premies

<1000gms – 80% will have apnea

Apnea Types Primary apnea – will respond to stimulation and resume breathing

Secondary apnea – requires PPV to establish breathing for each minute of PPV the baby has been in secondary apnea for 2 minutes

Central apnea – no air flow (15% of all apneas)

Obstructive apnea – may appear to be breathing, but with no air flow (30% of apneas)

Mixed apnea – combination of central and obstructive (50-60%)

Idiopathic apnea – diagnosis of exclusion, found in otherwise healthy preterm infants

Evaluation & Treatment R/O airway anomalies

If new onset >than 48 hrs – sepsis evaluation and ECHO

R/O seizures

Methylxanthines – aminophylline, caffeine

Doxapram

References Verklan, T., Walden, M. Core curriculum for neonatal intensive care nursing (5th Ed.) 2010, St. Louis, Elvsevier Saunders, pp.447-511.

Meerstadt, PWD., Gyll, C. Maanual of Neonatal Emergency X-Ray interpretation. 1994; London, W.B. Saunders

England, M. A color atlas of life before birth: normal fetal development 1990. Chicago, Ill. Year Book Medical Publishers.

Moore, k., Persaud, T., The developing human: Clinically oriented embryology 1993. St. Louis, W.B.Saunders.

Jobe, A. Surfactant: The basis for clinical treatment strategies. In Polin, R., Banacalari, E.’s The newborn lung: Neonatology questions and controversies. 2008. St. Louis, Elvsevier Saunders, pp.73-101.