Embryologic
Development of the
Cardiopulmonary System
with Clinical Implications
Robert L.
Joyner, Jr., PhD, RRT
Associate
Professor and Chair
Department
of Health Sciences
Director
Respiratory Therapy Program
Case
Scenario
You are a respiratory therapist working at a
525 bed suburban medical center assigned to labor and delivery. Your responsibilities
include airway management at all high risk deliveries and cardiopulmonary
resuscitation as necessary. You are called to a stat cesarean section of a mom
who has had no prenatal care. The mom admits cocaine abuse and consumes alcohol
every day. Ultrasound estimates her to be in her 32nd week of
pregnancy and suggests fetal distress. How would you prepare for the delivery of
this premature newborn, keeping in mind the problems that can be associated
with fetal exposure to material drugs and alcohol?
Content Outline
The following text describes in utero
cardiopulmonary development of the human fetus. Respiratory Care Practitioners require
basic knowledge of cardiopulmonary embryology as a foundation for understanding
the clinical signs and symptoms of fetal distress and risks associated with
premature delivery.
Overview of
Embryologic Development
Fertilization to
Implantation
Ovum
Sperm
Cellular stages
from implantation to birth
Germ layers
Development of
the Pulmonary System
Embryonic Stages
of Lung Development
Surfactant/Surface
Tension
Development of
the Cardiovascular System
Fetal Circulation
Placental
nutrient and gas exchange with a discussion of the importance of amniotic fluid
Polyhydramnios
Oligohydramnios
Overview
of Embryologic Development
Fertilization to Implantation1-4
Fertilization occurs when the male sperm cell
unites with a mature female ovum in the outer one-third of the fallopian tube.
This process initiates a 40 week gestational period of fetal growth and
development. It can sometimes be useful to divide this 40 week gestational
period into 10 lunar months (4 weeks each), nine calendar months, or three
trimesters (3 months each).
The male and female gametes (sperm and ovum,
respectively) each carry half of the genetic information of a fertilized egg
and are termed haploid. The
fertilized egg contains the genetic contribution of the male as well as the
female and is termed diploid.
When the nuclei of the male and female gamete fuse,
fertilization is accomplished, and a zygote
is formed. As the process continues the nomenclature of the growing
baby changes to reflect the state of the babys development:
Zygote: Conception to
completion of implantation (12 14 days).
Embryo: From
end of ovum stage to time it measures 3cm head to rump. This is the time of
major organ development. Most susceptible time of pregnancy (2nd 8th
week)
Fetus: End
of embryonic period to the end of pregnancy. Growth and maturation occur at
this time.
Cellular Divisions
Once
fertilized, the zygote divides rapidly and begins to the process of developing
into a viable fetus. The
first divisions (cleavages) produce ball of cells called blastomeres
surrounded by a transparent tissue called the zona pellucida. When the
ball is constructed of 16-50 cells it is called a morula, and the morula is the cell
structure that enters the uterus. As the morula develops, it is surrounded by
fluid and the cells migrate toward the edges creating a cavity in the center. When
this process is complete the ball of cells is called a blastocyst and
the zona pellucida is replaced by an outer layer of cells called trophoblasts.
As the blastocyst continues to divide, the cells begin to differentiate into
their respective germinal layers with a group of cells gathering at one end to
form the blastoderm (i.e., embryonic
disk). The embryonic disk will become
the fetus and the trophoblasts will become the placenta and other structures. The
loss of the zona pellucida allows the trophoblasts to implant into the
endometrium (uterine lining) of the upper part of the uterus. The endometrial
lining of the uterus will then begin to provide nourishment to the developing
embryo.
Germinal
Layers
The cells of the embryonic disk orient
themselves in a manner that allows the development of various organ systems and
the fetus itself. During this process the cells organize into layers called germ layers. The positioning of the germ
layers within the blastocyst is crucial to type of cells and organ systems they
will eventually differentiate into.
The three germ
layers are named with reference to there position from the center of the
blastocyst. That is the endoderm is
closest to the center of the blastocyst, the mesoderm is in the center of the embryonic disk, and the ectoderm is the most distant from the
center of the blastocyst (toward the outside edge). Each of the three germinal
layers give rise to specific cells and organ systems as outlined below:
|
Endoderm |
Mesoderm |
Ectoderm |
|
Respiratory Tract Lining of the digestive tract, bladder,
thyroid Parenchymal tissue of the liver and
pancreas |
Cardiovascular system Mesenchymal cells [continue to
differentiate into fibroblasts, myoblasts (muscle), osteoblasts (bone),
chrondoblasts (cartilage), and angioblasts (blood vessels] Genitourinary and lymphoid organs Dermis |
Central and peripheral nervous systems Sensory epithelium of the nose, ears, and
eyes Hair and nails Epidermis (skin) Skin glands |
Development of the Pulmonary System
The pulmonary system develops in five stages. The
process begins with the development of lung buds and bronchi with the diaphragm
being completed in about seven weeks, followed by the development of the hard
and soft palates. The lobes of the lungs are identifiable by the twelfth week.
From that time there is a maturation process that brings the capillaries closer
to the developing alveoli allowing gas exchange at about the twenty-fourth
week. True alveoli appear at about the thirty second week and more alveoli
appear until the age of eight.
Some of the important aspects of the five stages are
outlined below:
Five stages.
Embryonic
stage (Day 26 to 52 days)
|
Lung development begins approximately 24 days after conception.
|
Right and left lung buds approximately 28 days after
conception.
|
Lobar bronchi approximately 31
days after conception.
|
Diaphragm completely developed by end of 7 weeks
gestation.
|
|
|
Pseudoglandular
stage (weeks 5 week 16)
|
Anterior (hard) and posterior (soft) palates
develop.
|
Airway branching occurs during 4 25 weeks
gestation.
|
Around week 11 cartilage
begins to develop.
|
Major lobes of the lung become identifiable by week
12.
|
Goblet cells, bronchial glands and ciliated cells
become functional.
|
|
|
Cannulicular stage (weeks 17 24).
|
Terminal and respiratory bronchioles multiply.
|
Vascularization occurs.
|
Beginning differentiation of type
I and type II alveolar cells.
|
Capillaries in proximity to
alveolar cavity (20 21 weeks).
|
Not close enough for gas exchange until 24 25
weeks.
|
|
|
Saccular
and Alveolar stages (25 weeks term and post-term).
|
True alveoli appear ~ 32 34 weeks.
|
Number of alveoli increase until 8 years of age.
|
Fetal Lungs
The lungs of the fetus are filled with fetal lung
fluid. This fluid is produced in the periphery of the lungs and migrates out of
the airways into the amnion where it becomes a constituent of the amniotic
fluid. Fetal lung fluid functions to maintain the patency of the airways
allowing formation of the developing airspaces. At birth, fetal lung fluid is eliminated
from the airways by two mechanisms. Fetal lung fluid is expelled from the
airways as the chest is squeezed during the trip through birth canal and reabsorbed
by the lymphatic system after delivery. Cesarean section reduces the efficiency
of fetal lung fluid clearance increasing the risk of Transient Tachypnea of the Newborn (TTN).
Development of the Heart
Driven by the nutritional needs of the quickly
growing fetus, the heart is the first major organ to develop. The structures of
the heart develop out of the mesoderm of the embryonic disk.
Toward the end of the third week of gestation
the cells from the mesoderm have formed two endocardial tubes. These tubes fuse
at their center creating a single chamber structure that twists and folds to
eventually form a four chamber heart. The heart begins to beat in the fourth
week of gestation creating bidirectional blood flow. The blood flow is
bidirectional at this point because the one-way valves (e.g., tricuspid,
mitral, etc.) separating the four chambers of the heart have yet to develop.
Within the inferior portion of the emerging
heart develops the sinus venosus,
which will eventually become a portion of the right atrium and vena cavae (inferior
and superior). The superior portion of the lower heart forms a primitive
ventricle and atrium with the truncus
arteriosus appearing from the ventricle and eventually developing into the
aorta and pulmonary artery.
As the heart continues to develop, it assumes
the shape of an S, pushing the
inferior structures (sinus venosus and atrium) upward and behind the developing
ventricle. The single ventricle is divided by the bended S shape and forms the right and left ventricular chambers.
By the 5th week of gestation, blood
flow becomes unidirectional with blood entering the sinus venosus, traveling through the primitive atrium to the right
and left ventricles and out through the truncus
arteriosus.
In the most superior portion of the developing
heart, the veins and arteries of the developing circulatory system are
incorporated into the pathways of the heart. The single atrium is divided into
two chambers by the septum primum,
and it is at this time when openings between the atria and ventricles become apparent.
During the sixth week the truncus arteriosus becomes divided into
the pulmonary artery and the aorta. The newly formed pulmonary artery becomes
the pathway of blood leaving the right ventricle and the aorta becomes the
pathway for blood leaving the left ventricle. Valves are formed assuring
unidirectional blood flow, and by the end of two months the heart is
responsible for circulating blood through the embryo.
Fetal Circulation
Gas and nutrient exchange (replenishment) in
the fetus is accomplished by the placenta. The newly replenished blood from the
placenta returns to the fetus via the umbilical vein. Fetal circulation is
necessarily different from adult circulation to facilitate movement of blood
from the placenta to the organ systems of the fetus and back again.
As outlined below there are a number of blood
flow and vascular pressure differences in the fetus as compared with adult
circulation. These differences allow replenished blood in the fetus to pass
from the placenta directly to the major organs of the fetal body (e.g., liver,
brain, kidneys, etc.).
In adult circulation all of the blood entering
the right heart passes through the pulmonary vasculature to allow for external
respiration (exchange of gases between the environment and the blood) and in
addition provide the necessary nutrients and gas exchange to the metabolically
active tissues that make up the lungs. In the fetus, external respiration of
the fetus occurs in the placenta. Therefore, only the portion of cardiac output
required to sustain the metabolic demands of the developing lung is required to
perfuse the pulmonary circulation. This constitutes about 10% of the total
cardiac output.
Blood flow through the pulmonary vasculature
is reduced by hypoxic pulmonary vasoconstriction (HPV) and two vascular shunts;
the foramen ovale and ductus arteriosus. HPV increases
pulmonary vascular resistance and the vascular shunts provide less resistant
pathways for blood to flow. The foramen
ovale allows blood to flow from the right atrium (higher pressure) to the
left atrium (lower pressure). The ductus
arteriosus allows blood to flow from the pulmonary artery (higher pressure)
to the aorta (lower pressure).
In order to understand fetal circulation, it
must always be remembered that the placenta is the organ responsible for
nutrient and gas exchange (external respiration) of the fetus. Differences in
fetal circulation compared to adult circulation are necessary to distribute
replenished blood to the organ systems that most need it, and bring gas and
nutrient depleted blood back to the placenta as quickly as possible.
Fetal circulation is accomplished as outline
below:
Blood replete
with nutrients and gas flows from the placenta to the umbilical vein toward the
fetus with:
50%
going directly into the portal circulation (liver) and 50% directly through the
ductus venosus to the inferior vena cava and on to the right atrium.
At the right
atrium blood flow has two directional opportunities
Either blood flows from the
right atrium through the foramen ovale to the left atrium, to the left
ventricle, out to the aorta and body, to the umbilical arteries and back
to the placenta (most blood flow will follow this route).
Or blood flows from the right ventricle to the
pulmonary artery where blood flow divides again:
»
Either blood flows through the ductus arteriosus
to the aorta out to the body to the umbilical arteries and back to the
placenta.
»
Or (about 10%) of the blood flow will go through
the lungs via pulmonary circulation, to the left atrium to the left ventricle
out to the body to the umbilical arteries and back to the placenta.
With reference to
the umbilical arteries:
- At approximately the level of the kidneys,
the two common iliac arteries diverge from the aorta.
- The iliac arteries divide into external
and internal iliac arteries.
- The two umbilical arteries branch off of
the external and internal iliac arteries, returning approximately 60% of the
circulating blood to the placenta.
Fetal
Development and Clinical Correlations
The information presented above provides a
synopsis of pulmonary and cardiovascular development. This following text will
conclude with the importance of amniotic fluid physiology and assessment of
lung maturity.
Amniotic Fluid5
The amnion is
the sac containing the growing fetus and is filled amniotic fluid. The function of amniotic fluid is to cushion the
fetus from traumatic injury, provide thermoregulation, provide some protection
from infection, serve as a reservoir of fluid and nutrients, and allow fetal
movement, which facilitates growth and development. Amniotic fluid consists of fetal
lung fluid exiting the mouth of the fetus and fetal urine from the expelled
from the kidneys of the fetus. Under normal physiological conditions the amount
of amniotic fluid present is dependent upon the amount of fluid entering the
amnion versus the amount of fluid exiting the amnion. The majority of the fluid
entering the amnion comes from fetal urination and lung fluid secretion.
Amniotic fluid leaves the amnion through the action of fetal swallowing, and
absorption by tissues of the uterus and endometrium. At birth there is
approximately one liter amniotic fluid present in the amnion.
During pregnancy, ultrasound can be used to assess the
amount of amniotic fluid present. There
are a number of pathological states that can alter the amount of amniotic fluid
within the amnion. An abnormally large volume of amniotic fluid is termed polyhydramnios (>2000 cc).
Polyhydramnios may indicate structural defects that interfere with fetal
swallowing, such as gastrointestinal obstruction (e.g., duodenal, esophageal, or
intestinal atresia). Decreased swallowing can also be due to neuromuscular
disorders (e.g., anencephaly or myotonic dystrophy). In isolation,
polyhydramnios increases the risk of premature rupture of membranes and
premature delivery.
Oligohydramnios
is defined as an abnormally small
amount of amniotic fluid present within the amnion (less than 2 cm on single
deepest pocket measurement). The causes of oligohydramnios can include premature
rupture or leaking of membranes (amnion), and congenital anomalies in the fetus
that impede fetal urination (e.g., renal agenesis and urethral stenosis). The
presence of oligohydramnios is associated with lung hypoplasia and significant
skeletal deformities due to intrauterine growth restriction.
Surface Forces / Surface Tension
Surfactant and Work of Breathing
In utero, the lungs of the fetus are not responsible
for gas exchange and are filled with fetal lung fluid. Therefore, work of
breathing, as defined in the adult, is absent in fetus. At birth, the lungs
assume the role of sole gas exchanger. From the first breath, the newborn must
eliminate the fluid present in the lungs and maintain a level of lung expansion
that allows for survivable gas exchange. As with blowing up a balloon, the
initial inflation of the lung is difficult, but becomes easier as the lung
expands. This phenomenon is at least partially explained by the Law of LaPlace. The Law of LaPlace can
be used to describe how the distending pressure of an alveolus (pressure
required to keep the lung open) is dependent on 1) the surface tension of the fluid within the alveolus, and 2) the radius
of the alveoli itself.
Initially, inflation of the lungs from a collapsed
state is difficult because of the high degree of surface tension existing
within the lungs. This surface tension is present because the molecules of
fluid present within the alveoli are attracted to one-another with a force
known as cohesion. The Law of LaPlace suggests the degree of surface tension
exerted by this fluid is inversely related to the radius of the alveoli. Or
simple put, as the radius of the alveolus decreases, the molecules within the
alveoli move closer together allowing the cohesive force (surface tension) to
increase. This increase in surface tension can dramatically increase a newborns
work of breathing, leading to respiratory distress and sometimes overt
respiratory failure.
The maturing fetus prepares to contend with
surface tension after birth, by producing a complex compound within the alveoli
called surfactant. The chemical
structure of surfactant disrupts the cohesive forces within the lungs limiting
the increase in surface tension, and thereby reducing the newborns work of
breathing at low lung volumes. If surfactant were not present in the lung, the
smaller the volume of the lung (i.e., during exhalation), the greater the force
required to reopen the lung on the next inspiration.
In addition to reducing surface tension, surfactant
serves a number of vital functions including enhancing capillary circulation,
allowing for normal ventilation / perfusion ratios, protecting alveolar tissues
from barotrauma, stabilizing alveoli, and aiding evacuation of fetal fluid.
Surfactant is produced by alveolar type II pneumocytes, which first appear in the 17 26
weeks of gestation. The major components of surfactant include phosphatidylcholine (PC) and phosphatidylglycerol (PG). As with all
other organ systems in the developing fetus, the process of surfactant
production by the fetus must mature to become efficient at reducing the surface
tension created by the cohesive forces of the liquid within the lung. Mature,
functional surfactant is produced at approximately 35 weeks gestation.
Because of the importance of surfactant/lung
maturity on the mortality and morbidity of the newborn, there may be times when
it is important to assess the maturity of the lungs/surfactant prior to
delivery. This assessment allows the caregivers to prepare whatever may be
needed to care for the fetus once it is born.
Conditions that Delay or Interfere with
Maturation and Production of Surfactant
|
Conditions Accelerating
Surfactant Production
|
§
Acidosis
|
·
Infants of diabetic mothers |
|
§
Hypoxia |
·
Maternal heroin addiction |
|
§
Shock |
·
Premature rupture of membranes |
|
§
Hyperinflation |
·
Maternal hypertension |
|
§
Underinflation |
·
Maternal infection |
|
§
Pulmonary edema |
·
Placental insufficiency |
|
§
Mechanical ventilation |
·
Maternal administration of betamethasone |
|
§
Infants of diabetic mothers |
·
Abruptio placentae |
|
§
Erythroblastosis fetalis |
|
|
§
The smaller of the twins |
|
Laboratory Assessment of
Surfactant and Lung Maturity6, 7
Because the premature pulmonary system has an impaired
ability to exchange gases with the outside environment, premature delivery
results in a significant morbidity and mortality. It is therefore important to
establish the level of pulmonary maturity in the fetus at risk of delivering
early. There are a number of laboratory tests that can be done to evaluate
lung. Generally, these tests require a sample of amniotic fluid to test, and each
test has advantages and disadvantages regarding prediction of respiratory
distress and risk of injury to the fetus.
L/S
Ratio (Lecithin/Sphingomyelin Ratio)
In requires an amniotic fluid sample (acquired by
amniocentesis) to quantify the ratio of lecithin and sphingomyelin present. A
ratio greater than 2:1 in amniotic fluid indicates mature lungs and reduced risk
for developing RDS. A ratio of less than 1:1 indicates immaturity and a high
risk for developing of Respiratory Distress Syndrome (RDS). A ratio between 1
and 2 RDS is less helpful in predicting when RDS may develop.
Phosphatidylglycerol
(PG) level
PG is a minor, but important, component of surfactant
that begins to increase in the amniotic fluid several weeks after the rise in
lecithin. PG enhances the spread of phospholipids on the alveoli and its
presence indicates an advanced state of fetal lung development and function. An
advantage for assessing fetal lung maturity by PG level is that PG is not
affected by blood, meconium, or other contaminants, since these substances are
commonly found in amniotic fluid. The test is reported as PG present or PG
absent.
Foam
Stability Index (FSI)
The FSI is a predictor of fetal lung maturity based
upon the ability of surfactant to generate a stable
foam in the presence of ethanol. Ethanol is added to a sample of amniotic fluid
and the mixture is shaken. A stable ring of foam will be present if surfactant
is present. The FSI is calculated by utilizing serial dilutions of ethanol to
quantitate the amount of surfactant present. The value indicative of lung
maturity is usually set at 47 or greater. A positive result excludes the risk
of RDS; however a negative test often occurs in the presence of mature lungs.
The presence of blood or meconium interferes with results of the FSI.
Fluorescence
Polarization
This test uses polarized light to determine the
ratio of surfactant to albumin in an amniotic fluid sample. A ratio of 55 mg of
surfactant per gram of albumin or greater suggests fetal lung maturity. The
accuracy of predicting fetal lung maturity by fluorescence polarization is
comparably with L/S and PG tests. However vaginal specimens of amniotic fluid
are not acceptable and blood and meconium contaminants interfere with the accuracy
of the test result.
Lamellar
body count
Lamellar bodies are particles in the amniotic
fluid that contain surfactant. Conveniently, the lamellar bodies are
approximately the same size as blood platelets, and therefore counting the
lamellar bodies can be accomplished with the same Coulter counter used to count
platelets. Values of 30,000 50,000 per microliter indicate pulmonary
maturity.
|
Test |
Value Predicting Lung Maturity |
Accuracy |
Predictive Value for
Lung Immaturity |
Advantages/Disadvantages |
|
L/S Ratio |
>2.0 |
95 100% |
33 55% |
Large laboratory
variation |
|
PG |
present |
95 100% |
23 53% |
Not affected by
blood, meconium. Can use vaginal
pooled sample. |
|
FSI |
>47 |
95% |
51% |
Affected by blood,
meconium, and silicon tubes. |
|
Fluroecence Polarization |
>55 mg/g |
98% |
47 61% |
Simple test. |
|
Lamellar Bodies |
30,000 50,000 / μL |
97 98% |
29 35% |
Investigational |
Therapy for Premature Lungs
The most effective treatment for premature lung
disease is prevention of early delivery. This may or may not be feasible depending
on each patients individual circumstances. Tocolysis (stopping labor) can be
accomplished a number of ways including bed rest, pharmacologic intervention
with smooth muscle relaxants (e.g., terbutaline, magnesium sulfate, etc.)
and manual closure of the cervix with a cervical stitch.
If terminating
premature labor is not realistic, enhancing lung maturity becomes an important
goal. If the mom is in the 27 34 weeks of gestation, providing her with
antenatal steroids (e.g., betamethasone) 48 hours before delivery can be
helpful in reducing the incidence of respiratory distress syndrome in the
premature newborn.
END