ARDS is a widespread acute inflammatory lung injury with various degrees of intensity that occurs in response to a pulmonary or systemic insult and invariably leads to abnormalities in gas exchange (predominantly hypoxemia) and in pulmonary mechanics. It is a prototypical disease of reduced lung compliance that causes acute respiratory failure in both children and adults. In effect, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide with the blood across a thin layer of the lungs' microscopic air sacs known as alveoli. The syndrome is associated with a death rate between 20 and 50% .

1. 1
Baghdad University
College of Medicine
Respiratory Distress Syndrome
Fatima Omer Hamad
CLS – Pathology
Module

2. 2
Contents:
1.Introduction to ARDS …..…………………...………4
2.Search board and Discussion
 Signs and Symptoms ………………………..…. 4
 Causes ………………………………………...… 5
 Risk factors …………………….……………..... 6
 Pathogenesis ………………………………….… 7
 Lung endothelial injury ………………...……... 8
 Alveolar endothelial injury ……………………. 8
 Respiratory distress syndrome of newborn ….. 9
 Diagnosis …………………………………...….. 10
 Prognosis ……………………………………… 11
 Resolution …………………..…..…………...… 12
 Treatment …………………..…….………....… 13
3.Respiratory distress syndrome of the premature and
newborn ………………………………………….… 14
4.Summary ……………………………………...…… 16
5.References …………………………………….…… 17
6.Figures' references …………………………..……. 21

3. 3
Acute respiratory distress syndrome (ARDS)
ARDS is a widespread acute inflammatory lung injury with various
degrees of intensity that occurs in response to a pulmonary or systemic insult
and invariably leads to abnormalities in gas exchange (predominantly
hypoxemia) and in pulmonary mechanics. It is a prototypical disease of
reduced lung compliance that causes acute respiratory failure in both
children and adults.[1,2]
In effect, ARDS impairs the lungs' ability to exchange oxygen and
carbon dioxide with the blood across a thin layer of the lungs' microscopic
air sacs known as alveoli.The syndrome is associated with a death rate
between 20 and 50%. [3]
The risk of death varies based on severity, the person's age, and the
presence of other underlying medical conditions. Although the terminology
of "adult respiratory distress syndrome" has at times been used to
differentiate ARDS from "infant respiratory distress syndrome" in
newborns, the international consensus is that "acute respiratory distress
syndrome" is the best term because ARDS can affect people of all ages.[4]
The acute respiratory distress syndrome (ARDS) was described
originally in 1967 by the late Dr. Thomas L. Petty and coworkers.[5]
Most
patients require endotracheal intubation and positive pressure ventilation.
There are several clinical disorders associated with the development of
ARDS, including sepsis, pneumonia, aspiration of gastric contents, and
major trauma.[6]
The pathology of ARDS in the lung was first described in
1977 by Bachofen & Weibel in a seminal publication. [7]
Acute respiratory distress syndrome (ARDS) is a common and
devastating condition which can affect all adult patients - eg, medical,
surgical and obstetric patients. It occurs when non-cardiogenic pulmonary
oedema (secondary to acute damage to the alveoli) leads to acute respiratory
failure. Although the terms ARDS and ALI are used interchangeably, the
American-European Consensus Conference Committee describes them as
different entities - ALI having less severe hypoxaemia than ARDS.[8]

4. 4
Signs and symptom of ARDS
The signs and symptoms of ARDS often begin within two hours of an
inciting event, but can occur after 1–3 days. Signs and symptoms may
include shortness of breath, fast breathing, and a low oxygen level in the
blood due to abnormal ventilation.[9][10]
The presence of all or some of these symptoms does not necessarily
indicate RDS. All of these characteristics are non-specific signs of
respiratory distress in a premature baby. In other words, these
characteristics are also typical of other types of breathing problems such as
lung infection.[11]
Fig(1): The normal lungs appear dark as they contain more air. The lungs with
respiratory distress syndrome look quite dense and white due to the collapse of the lung
tissue. The amount of air in the lungs is very small.

5. 5
Causes of ARDS
Diffuse compromise of the pulmonary system resulting in ARDS
generally occurs in the setting of critical illness. ARDS may be seen in the
setting of severe pulmonary (pneumonia) or systemic infection (sepsis),
following trauma, multiple blood transfusions (TRALI), severe burns, severe
inflammation of the pancreas (pancreatitis), near-drowning or other
aspiration events, drug reactions, or inhalation injuries.[12]
Some cases of
ARDS are linked to large volumes of fluid used during post-trauma-
resuscitation.[13]
 SIRS and sepsis (most common cause)[14][15]
 E.g., secondary to trauma, infection or peritonitis
 Shock[16]
 Massive transfusion[16]
(See “TRALI” for details)
 Acute Pancreatitis
 Hematopoietic stem cell transplantation
 Medication (e.g., salicylic acid, tricyclic antidepressants, bleomycin)
 Recreational drug overdose (e.g., cocaine)
Fig(2): A chest x-ray of transfusion-related acute lung injury which lead to ARDS.

6. 6
Risk Factors
Multiple conditions may cause ARDS . Sepsis remains the most
common cause of ARDS, with 46% of the cases triggered by pulmonary
entities. Mortality also varies according to the cause. Particularly, mortality
in patients with ARDS due to severe trauma (injury severity score > 15) is
24.1%, whereas mortality in patients with severe sepsis with a pulmonary
source is 40.6% .
Common risk factors for acute respiratory distress syndrome acute
lung injury: [17]
 Direct
 Pneumonia
 Aspiration of gastric contents
 Inhalation injury
 Pulmonary contusion
 Pulmonary vasculitis
 Drowning
 Fat embolism
 Reperfusion pulmonary edema after lung transplantation or
pulmonary embolectomy
 Indirect
 Nonpulmonary sepsis
 Major trauma
 Pancreatitis
 Severe burns
 Noncardiogenic shock
 Drug overdose
 Multiple transfusions (>15 units blood in 24 h) or transfusion-related
acute lung injury
 Neurogenic pulmonary edema
 Amniotic fluid embolism
 Following bone marrow transplantation

7. 7
Pathogenesis
The pathogenesis of ALI/ARDS can best be understood by focusing on (a) the
factors that are responsible for the accumulation of protein-rich and neutrophilic
pulmonary edema in the lung interstitium and in the distal air spaces of the lung and
(b) the mechanisms that impair the removal of pulmonary edema fluid and
inflammatory cells from the lung. The protein-rich edema fluid in ARDS is
associated with large numbers of neutrophils; monocytes; denuded epithelial cells;
and proinflammatory markers including cytokines, proteases, oxidants, and
procoagulant factors (Figure 3). [18]
Fig(3): (a) The normal alveolus and (b) the injured alveolus in the acute phase of acute lung injury
and the acute respiratory distress syndrome. In the acute phase of the syndrome (b), there is
sloughing of both the bronchial and alveolar epithelial cells; protein-rich hyaline membranes form
on the denuded basement membrane.

8. 8
Lung Endothelial Injury :
Lung vascular injury is the most important initial cause of
ALI/ARDS. There is considerable evidence that an increase in lung vascular
permeability occurs primarily at the level of lung microcirculation, which in
turn results in the accumulation of protein-rich pulmonary edema, even in
the presence of normal lung vascular pressure [19][20]
Injury to the lung
endothelium can occur by several mechanisms, although neutrophil-
dependent lung injury is probably the best-documented pathway. [21][22]
Alveolar Epithelial Injury :
Although lung endothelial injury is a prerequisite for the
development of protein-rich pulmonary edema in ARDS, injury to the lung
endothelium alone is usually not sufficient to cause the syndrome of ARDS in
the absence of some degree of injury to the lung epithelium.[23]
Alveolar edema developed in this model only when epithelial function
was impaired by instillation of live bacteria. In addition to experimental
evidence that epithelial injury is required for ARDS, the classic pathologic
studies by Bachofen & Weibel in 1977 documented that patients with ARDS
demonstrate both lung endothelial and alveolar epithelial injury.[24]
Fig (4)

9. 9
Respiratory distress syndrome of newborn
Respiratory distress syndrome of newborn, or increasingly surfactant
deficiency disorder (SDD),[25]
and previously called hyaline membrane
disease (HMD), is a syndrome in premature infants caused by developmental
insufficiency of pulmonary surfactant production and structural immaturity
in the lungs. It can also be a consequence of neonatal infection.[26][27]
It can
also result from a genetic problem with the production of surfactant
associated proteins. IRDS affects about 1% of newborn infants and is the
leading cause of death in preterm infants .The syndrome is more frequent in
infants of diabetic mothers and in the second born of premature twins.[28]
Signs and symptoms :
The signs of NRDS are often noticeable immediately after birth
and get worse over the following few days. They can include:[29]
 blue-coloured lips, fingers and toes
 rapid, shallow breathing
 flaring nostrils
 a grunting sound when breathing
Risk factors of (IRDS) :
The risk factor of infant respiratory distress syndrome include : [30]
 Premature delivery.
 Male infants.
 Infants delivered via caesarean section without maternal labour.
 Hypothermia.
 Perinatal asphyxia.
 Maternal diabetes.
 Family history of IRDS.

10. 10
Diagnosis :
The diagnosis is made by the clinical picture and the chest x-ray, [31]
To confirm the diagnosis, the medical team may want to take X-rays of the
premature baby’s chest. An X-ray of a preemie with RDS will likely
show:[11]
 small lung volume
 air bronchograms or air in the airways of the lung that are black in
comparison to the surrounding white areas that do not contain air
 granular-looking areas on the lung where the lung resembles white salt
and black pepper being sprinkled on the film. The more pepper, the
more aeration; the more salt, the more collapse or fluid.
ARDS is a likely diagnosis in the presence of both typical causes and therapy-
resistant hypoxemia. The diagnosis is further supported by characteristic findings
on chest x-ray that are not explained by underlying cardiac disease.[32]
Fig(5): voluminous right lung with diffuse congestion on pleural aspect as well as the cut surface.
Chronic complications of respiratory distress syndrome
include the following :[33]
 Bronchopulmonary dysplasia (BPD)
 Retinopathy of prematurity (ROP)
 Neurologic impair

11. 11
Prognosis :
Overall mortality is 50-75%. and prognosis varies with age of patient,
cause of ARDS (pneumonia 86%, trauma 38%), and number of organs
involved (three organs involved for >1 week is invariably fatal).[34]
In most cases, survivors' lung function returns almost to normal within 6-12
months. However, some may have persistent reduced vital capacity and even
obstructive lung disease, although these are usually asymptomatic.[35]
Interestingly, patients with ALI have reduced exercise capacity up to two
years after the episode (despite normal lung function) and there is evidence
to suggest long-term neurocognitive impairment.[26, 35]
Acute complications of respiratory distress syndrome include the
following: [33]
 Alveolar rupture
 Infection
 Intracranial hemorrhage and per ventricular leukomalacia
 Patent ducts arteriosus (PDA) with increasing left-to-right shunt
 Pulmonary hemorrhage
 Necrotizing enter colitis (NEC) and/or gastrointestinal (GI) perforation
 Apnea of prematurity
 In cases with simultaneous multi-organ failure, the mortality rate can rise
to over 50%.[37]
Fig(6): Diffuse alveolar damage (DAD)

12. 12
Resolution :
Resolution of ALI requires effective and synchronous (a) reabsorption of alveolar edema,
(b) repair of the epithelial and endothelial barriers, and (c) removal of inflammatory cells
and exudate from the distal airspaces (Figure 7). Resolution of ALI and repair of alveolar
structures may — like the initiation of alveolar damage — depend on a precise balance of
inflammatory interactions and molecular signaling. For example, hyaluronan fragments
found in the serum of ALI patients trigger release of chemokines by macrophages but also
interact with Toll-like receptors to deliver signals that limit epithelial apoptosis and
promote reestablishment of epithelial integrity in experimental lung injury. [38]
Reabsorption of alveolar edema (Figure 7A) occurs through vectorial transport of sodium
and chloride across alveolar epithelial type I and II cells to create a mini–osmotic gradient
to reabsorb water [39–41]
. This process is impaired in ALI and ARDS because of apoptosis
and necrosis of alveolar epithelium [42,43]
and defects in transcellular ion transport induced
by proinflammatory cytokines, oxidants, and hypoxia [39, 44–47].
Effective reabsorption of edema fluid from the air spaces requires reestablishment of an
effective epithelial barrier [48,49]
. Reepithelialization occurs initially by proliferation of type
II cells [43]
, and the traditional view is that type II cells are the main source of new alveolar
epithelial cells [50]
. Nevertheless, there is new evidence that progenitor cells may exist in
strategic niches in bronchoalveolar junctions and that the alveolar epithelium can be
activated to regenerate the epithelial and endothelial barriers (51–54). For example, α6β4-
expressing progenitor cells have been identified that account for a substantial fraction of
the type II cells that reepithelialize the injured alveolar barrier (Figure 7C and ref. 55).
There may also be a human c-kit+
lung stem cell capable of renewing all lung cells [56]
,
although this hypothesis is controversial and requires validation. There has been progress
in understanding how inflammation is resolved through clearance of alveolar neutrophils,
monocytes, and necrotic debris including the contributions of lipid mediators such as
lipoxin A4, resolvin E1, and other antiinflammatory pathways (Figure 7B and refs. 57, 58).
Macrophages remove apoptotic neutrophils and monocytes via molecular mechanisms that
have recently been more clearly identified [59–61]
. A deficiency of alveolar macrophages
worsens influenza-related pneumonia and lung injury in mice, leading to an increase in
neutrophils and neutrophil extracellular traps [62]
.
Fig(7): Resolution of ALI requires removal of alveolar edema fluid, removal of the acute
inflammatory cells, and repair of the injured alveolar epithelium.

13. 13
Treatment :
Respiratory Distress Syndrome (RDS) is characterized by surfactant
deficiency in the premature baby’s lung. The condition is generally
progressive in that the breathing difficulties experienced by the baby begin
immediately at birth and worsen over time. The severity of RDS and its
progression have to do with the maturity of the lung. As with most
conditions affecting premature babies, the more premature the baby, the
more likely RDS is to be severe. Treatment of RDS may include surfactant
replacement therapy and supplemental oxygen delivered by one of these
ventilation methods:[11]
 continuous positive airway pressure (CPAP)
 conventional mechanican ventilation (CMV)
 high frequency oscillation (HFO)
 high frequency jet ventilation (HFJV)
Fig(3): The first X-ray was taken before surfactant was administered. The lungs look
quite dense and white due to the collapse of the alveoli. The amount of air in the lungs is
very small. The second X-ray was taken after the administration of surfactant. The lungs
appear darker as they now contain more air.

14. 14
Respiratory distress syndrome (grade 1-4) of the premature
and newborn (IRDS) :
Stage 1 : Fig (4)
slight reticular (slight granular)
decrease in transparency of the lung,
no certain difference to normal
finding.
Stage 2 : Fig (5)
Soft decrease in Transparency with an
aerobronchogram, which overlaps the
heart (= always a sign of an alveolar lung
reaction!).
Stage 3 : Fig (6)
like stage 2, but with gradual stronger
decrease in transparency, as well as a
blurry diaphragm and heart.

15. 15
Stage 4 : Fig (7)
White lung: practically homogenic lung
opacity.
Fig (8): Synopsis of the changes in Stages I – IV

16. 16
Summary :
 RDS is associated with a death rate between 20 and 50%.
 Sepsis is the most common cause of ARDS.
 Acute respiratory distress is a common and often serious emergency.
 The lungs with respiratory distress syndrome look quite dense and white due to
the collapse of the lung tissue.
 IRDS is more frequent in infants of diabetic mothers and in the second born of
premature twins.
 The diagnosis of RDS is made by the clinical picture and the chest x-ray.
 Multiple conditions may cause ARDS.
 the more premature the baby, the more likely RDS is to be severe.
 The signs and symptoms of ARDS often begin within two hours of an inciting
event, but can occur after 1–3 days.
 categorises of ARDS could be mild, moderate or severe.
 In cases with simultaneous multi-organ failure, the mortality rate can rise to
over 50%.
 ARDS can be caused by any major direct or indirect injury to the lung.

17. 17
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