SDL 8 Respiratory Distress Syndrome
PULMONARY SURFACTANT
Prematurity
 Hyaline membrane disease (HMD), also known as
respiratory distress syndrome (RDS) of the neonate,
occurs almost exclusively in premature infants
 incidence and severity of hyaline membrane disease are
related inversely to the gestational age of the newborn
infant
 Prematurity = neonates born <37 weeks gestation
 Each of the immature organs of a premature infant has
functional limitations, since the baby is born before its
organs mature enough to allow normal postnatal survival
 hyaline membrane disease remains the most common
cause of neonatal morbidity
Pulmonary Surfactant
 Surfactant is a complex lipoprotein composed of 6
phospholipids and 4 apoproteins
 Dipalmitoyl phosphatidylcholine (DPPC), or lecithin, is
functionally the primary phospholipid
 Surfactant components are synthesized, secreted and
recycled by type II pneumocytes in the alveolus
o packaged in lamellar bodies in the cytoplasm
Lung Immaturity in Premature Infants
 Immaturity of the lungs poses one of the most common
and immediate threats to the viability of the low-birthweight infant
 The lining cells of the fetal alveoli do not differentiate into
type I and type II pneumocytes until late pregnancy
 The composition of lung surfactant changes as the fetus
matures
o concentration of lecithin increases rapidly at the
beginning of the third trimester and thereafter rises
rapidly to reach a peak near term
o most of the lecithin in the mature lung is dipalmitate,
in the immature lung it is the less-surface-active αpalmitate species
o Phosphatidylglycerol is not present in the lungs before
the 36th week of pregnancy
o Before the 35th week, the immature surfactant
contains a higher proportion of sphingomyelin than
adult surfactant
 Pulmonary surfactant is released into the amniotic fluid,
which can be sampled by amniocentesis to assess the
maturity of the fetal lung
o lecithin-to-sphingomyelin ratio (L/S ratio) above 2:1
implies that the fetus will survive without developing
the respiratory distress syndrome
o After the 36th week, the appearance of
phosphatidylglycerol in the amniotic fluid is the best
proof of the maturity of the fetal lungs
HYALINE MEMBRANE DISEASE
Def: acute lung disease of the newborn caused by surfactant
deficiency
EPIDEMIOLOGY
 principally associated with prematurity
 incidence of hyaline membrane disease increases from 5%
of infants born at 35-36 weeks to 65% of infants born at
29-30 weeks of gestation (incidence is lower, the longer an
infant is in gestation)
 2x in boys than girls
PATHOGENESIS
 Pulmonary surfactant synthesis, in type II pneumocytes,
begins at 24-28 weeks of gestation and gradually increases
until full gestation
o Pulmonary surfactant decreases surface tension in the
alveolus during expiration
 Absence of surfactant results in poor pulmonary
compliance, atelectasis (failure of pulmonary alveoli to
expand)
 Atelectasis  perfused but not ventilated alveoli 
decreased gas exchange, severe hypoxia and acidosis
 Premature infants must expend a great deal of effort to
expand their lungs with each breath, and respiratory
failure ensues
o Resultant barotrauma, and oxygen toxicity, damages
endothelial and epithelial cells lining distal airways
 Results in exudation of fibrinous material derived
from blood
 On H&E staining, this lining stains like smooth,
homogeneous, eosinophilic membranes
CLINICAL PRESENTATION
 first symptom - increased respiratory effort, with forceful
intercostal retraction and the use of accessory neck
muscles
o respiratory rate increases to more than 100 breaths
per minute, expiratory grunting (due to partial closure
of glottis), nasal flaring and cyanosis become apparent
o Long periods of apnea ensue, and the infant eventually
dies of asphyxia
 overall mortality of HMD is about 15%
 one third of infants born before 30 weeks of gestational
age die of this disorder
PATHOLOGY
Gross Appearance
 lungs are heavy, dark and airless
 hepatization - texture of cut sections of the firm,
homogeneous, atelectatic tissue is reminiscent of liver
LAB STUDIES
 Arterial blood gas studies show hypoxemia, hypercapnia,
and mixed respiratory and metabolic acidosis
o Respiratory acidosis occurs because of alveolar
atelectasis
o Metabolic acidosis results from poor tissue perfusion
and anaerobic metabolism
Microscopic Appearance
 confirms the atelectasis, with air limited to the bronchioles
 interstitial edema in the perivascular connective tissue
sheaths
o result of transudation of fluid into the interstitium from
capillary leak
 Alveolar collapse and interstitial edema are the expected
consequences
 Hyaline membranes are found at the boundary of the airfilled bronchioles and the collapsed alveoli
o Not found when death occurs in the first few hours of
life and no longer thought to play a causal role in the
alveolar collapse
o Usually well established by 12–24 hours after birth
 Hyaline membranes typically organize and separate from
the underlying bronchial wall at 36–48 hours and they are
ultimately cleared by alveolar macrophages
 hyaline membranes represent compacted plasma
exudates and cellular debris
 Hyaline membrane disease is evidently a consequence of
non-specific injury to the bronchiolar and alveolar lining
IMAGING
Mild to Moderate Cases
 decreased lung expansion, symmetric generalized
consolidation of variable severity, effacement of normal
pulmonary vessels, and air bronchograms
o Air bronchograms - air-filled bronchi seen as
radiolucent, branching bands within pulmonary
densities
Severe Cases
 dense bilateral symmetric lung consolidation (so-called
white out) may completely efface the cardiac and
diaphragm contours
EVALUATION OF LUNG MATURITY BY AMNIOTIC FLUID
ANALYSIS
 Risk of HMD is low when lecithin/sphingomyelin ratio is >
2, and phosphatidylglycerol is present
 sphingomyelin content per milliliter of amniotic fluid
tends to fall from about 32 weeks of pregnancy to term,
whereas the more saturated lecithin concentration, a large
part of which is from the fetal lung, increases
 Phosphatidylglycerol starts to increase only at 35 weeks of
gestation and is found to be predictive of fetal lung
maturity
PREVENTION
 If fetus is delivered between 24 wk and 34 wk, give the
mother 2 doses of betamethasone 12 mg IM 24 h apart, or
4 doses of dexamethasone 6 mg IV or IM q 12 h at least
48 h before delivery
o induces fetal surfactant production
o reduces the risk of respiratory distress syndrome or
decreases its severity
COMPLICATIONS
 major complications of HMD relate to anoxia and acidosis
Intraventricular cerebral hemorrhage
 periventricular germinal matrix - particularly
vulnerable to hemorrhage because the dilated, thin-walled
veins in this area rupture easily
 Most surviving infants eventually recover normal
pulmonary function, but right-sided heart failure and viral
necrotizing bronchiolitis pose threats to a favorable
outcome
RISK FACTORS FOR HYALINE MEMBRANE DISEASE
Cesarean Section
 associated with an increased risk for neonatal respiratory
problems leading to the term iatrogenic respiratory
distress syndrome (RDS)
 C-section as mode of delivery
o During vaginal delivery, most of fetal lung fluid is
removed by squeezing the baby’s chest
o This removal is missing during delivery by cesarean
section and may be one explanation as to why babies
born by cesarean section have a larger residual volume
of lung fluid
 Absence of labor
o Labor is beneficial for maturation of the surfactant
system
o Babies born by cesarean section before onset of labor
had significantly lower L/S-ratios than babies born
after the beginning of labor, either vaginally or by
cesarean section
 vaginal route of delivery is still acknowledged as a better
option for promoting pulmonary and cardiovascular
adaptation in neonates
 vaginal birth offers better prospects of neonatal adaptation
than delivery by cesarean section
Maternal Diabetes Mellitus
 Diabetic women are characterized by increased rate of
premature birth
 poor glycemic control leads to preterm delivery
Persistence of patent ductus arteriosus
 one third of newborns who survive RDS, the ductus
arteriosus remains patent
 Congestive heart failure often ensues and requires
correction of the patent ductus
Necrotizing enterocolitis
 most common acquired gastrointestinal emergency in
newborns related to ischemia of the intestinal mucosa
 injury is followed by bacterial colonization, usually with
Clostridium difficile
Bronchopulmonary dysplasia
 occurs in infants who weigh less than 1500 g and were
maintained on a positive-pressure respirator with high
oxygen tensions
 disorder results from oxygen toxicity superimposed on
RDS
 Radiographs of the lungs show a change from almost
complete opacification to a spongelike appearance
 Microscopic examination of the lungs reveals hyperplasia
of the bronchiolar epithelium and squamous metaplasia in
the bronchi and bronchioles
ACUTE RESPIRATORY DISTRESS SYNDROME
Introduction
 infantile syndrome (i.e. neonatal respiratory distress
syndrome) is initiated because the immature fetal lungs
are unable to replenish spent surfactant
 in the adult the cycle differs in that it's initiated by a
variety of causes that damage the delicate alveolar
epithelium
 When fully developed, the pathological changes are those
of hyaline membrane disease
 high mortality rate, around 50% overall
Definition
 diffuse pulmonary injury associated with noncardiogenic
pulmonary edema and resulting in severe respiratory
distress and hypoxemic respiratory failure
 pathologic hallmark is diffuse alveolar damage - damage
to the alveolar epithelium and pulmonary capillary
endothelium
o followed by increased permeability to plasma into the
lung interstitium and the alveolar spaces
o A fluid, which has a high protein content, leaks into the
alveolar spaces (noncardiogenic pulmonary edema)
 Hypoxemia from intrapulmonary shunting manifests
clinically as cyanosis refractory to oxygen therapy
EPIDEMIOLOGY
~ No differences in the incidence between males and
females appear to exist
PATHOGENESIS OF DIFFUSE ALVEOLAR DAMAGE
~ Injury to these type 1 alveolar pneumocyte and capillary
endothelial cell underlies the development of diffuse
alveolar damage
Necrosis of type I alveolar pneumocyte and capillary
endothelial cell
 earliest stage of the disorder
 type I alveolar epithelial cells show cytoplasmic blebbing
 necrosis  denudation of the basement membrane
 Cyanosis of the lips and nailbeds may occur
 Examination of the lungs may reveal bilateral rales.
 Patients developing ARDS are critically ill, often with
multisystem organ failure
HISTOLOGIC CHANGES OF DIFFUSE ALVEOLAR DAMAGE
Exudation
 Lasts 1 week - lungs are heavy
 widespread collapse of alveoli, intense congestion of the
capillaries, interstitial edema and distension of the
lymphatics
 At the air/tissue interface, respiratory movements deposit
a fibrin-rich exudate mixed with necrotic epithelial debris
and compact it into a thin layer that covers an otherwise
denuded epithelial basement membrane leading to the
formation of hyaline membranes
Increase in alveolar and pulmonary capillary
permeability
 escape of protein-rich exudates into the interstitium and
alveoli
 loss of the surface-active alveolar lining film
 pulmonary collapse
Inflammatory cascade
 Protein-rich exudate engulfs the alveoli  activated
neutrophils and macrophages follow  inflammatory
cascade is initiated
 surfactant is markedly inactivated
Alveolar collapse
 Surfactant depletion leads to alveolar collapse because of
increased surface tension
 closing lung volume decreases below the patient's
functional residual capacity
Small vessel thrombosis
 injury to endothelial cells induces platelets to aggregate,
and a procoagulant cascade may arise, leading to small
vessel thrombosis
Impairment of oxygen-diffusing capacity
 widened interstitial space between the alveolus and the
vascular endothelium decreases oxygen-diffusing capacity
Respiratory muscle fatigue
 decrease in lung compliance increases the work of
breathing  leads to respiratory muscle fatigue
 respiratory failure ensues
ARDS
 Development of acute dyspnea and hypoxemia within 1248 hours to days of an inciting event
o such as trauma, sepsis, drug overdose, massive
transfusion, acute pancreatitis, or aspiration
 patients initially note dyspnea with exertion
 ARDS often occurs in the context of sepsis, associated
hypotension and peripheral vasoconstriction with cold
extremities may be present
Regeneration
 Healing by resolution: involves fibrinolysis and permits
the lungs to return to normal
 Healing by repair: involves fibrosis and leaves the lungs
permanently scarred
 stem cell concerned in epithelial regeneration is the type
II alveolar epithelial cell - proliferate and then
differentiate into type I cells
 atelectatic induration - regenerating epithelial cells bridge
mouths of collapsed alveoli so that these air spaces never
re-expand and there is permanent shrinkage of the lung
Repair
 pulmonary lesions can produce scarring and even
honeycombing
o Honeycombing suggests extensive lung fibrosis with
alveolar destruction
o can result in a cystic appearance on gross pathology
 During organization, interstitial connective tissue cells
proliferate and as in any scarring, myofibroblasts are
involved at an early stage
o Promotes early closure of wound, but largely results in
harmful distortion of the bronchioloalveolar
architecture and shrinkage of the lungs
 Fibroblasts also proliferate and lay down collagen, leading
to the development of interstitial fibrosis
 fibrosis by accretion - incorporating the alveolar collagen
into the interstitium
 Survivors of ARDS may suffer from debilitating fibrotic
lung disease
ETIOLOGY
Shock
 state of prolonged hypotension, generally attributable to
trauma, hypovolemia, cardiac failure, sepsis or anaphylaxis
 Hypotension leads to inadequate tissue perfusion and if
this is not corrected, multiorgan failure
 In shock, the alveolar walls are hypercellular due to the
accumulation of neutrophils
 “shock lung” - sequestration of neutrophils in the
pulmonary microvasculature vascular
 Endotoxin activates these cells within the systemic
circulation so that they lose their normal deformability
and aggregate into micro-emboli with the result that they
cannot traverse the alveolar capillaries
o arrest there is promoted by endothelial intercellular
adhesion molecules
 Trapped in the alveolar capillaries, activated neutrophils
damage the alveolar wall by producing reactive oxygen
radicals and releasing enzymes
Blood Transfusion
 Patients with major trauma necessitating blood
transfusion or transfusion of packed red blood cells are at
increased risk for ARDS
 Leukocyte antibodies are the likely cause of lung injury
in these patients
Fat Embolism
 Pulmonary fat embolism invariably accompanies bony
injury
 Major fat embolism is accompanied by progressive
hypoxemia, confusion and petechial hemorrhages
 Histological changes of adult respiratory distress
syndrome result from a chemical vasculitis caused by the
toxic effects of free fatty acids released by the action of
pulmonary lipase on neutral fats
Cardiopulmonary Bypass
 entails oxygenation and circulation of the blood by
extracorporeal devices, so permitting major heart surgery
 Early days of such surgery – usual for patients to develop
fatal respiratory insufficiency in the postoperative period
o Postperfusion lung
 synthetic materials with which blood comes into contact
during the bypass procedure are able to activate
complement
o mediated by Hageman factor (factor XII) and the
alternative pathway
 Aggregation of neutrophils  sequestration in the lungs
and damage results from their release of lysosomal
enzymes and active radicals
Oxygen Toxicity
 Oxygen toxicity is thought to be due to the intracellular
production of active oxygen radicals
 Under normal conditions oxygen is largely reduced to
water by cytochrome oxidase and any active radicals
produced are eliminated by superoxide dismutase,
catalase and other antioxidants
 However, these defense mechanisms may prove
inadequate when active radicals are produced in excess
PROGNOSIS
 only 30-40% of patients die
 Survivors of ARDS frequently have significant functional
impairment even 1 year after discharge
o spirometry and lung volumes normalize within 6
months
o Diffusing capacity remains mildly diminished at 1
year
o abnormal 6-minute walking distances at 1 year
o health-related quality of life is significantly below
normal
o only 49% return to work
 No patient remains oxygen-dependent at 12 months