Article
Abstract
Adults' Acute Respiratory Distress Syndrome (ARDS) is characterized
by serious acute respiratory failure caused by pulmonary oedema, which
in turn is subsequent to the alveolar-capillary barrier's increased
permeability.
Its first description, which dates back to 1967, referred to 12 patients
with acute dyspnoea, cyanosis refractory to oxygen treatment, reduced
lung compliance and widespread infiltrates detected by the chest X-ray.
From a morphological perspective ARDS is characterized by an exudative
phase, a proliferative phase and a fibrotic phase. This disease marks
progress from a phase characterized by a prevalence of neutrophils and
alveolar-interstitial oedema with eosinophil hyaline membranes, high
protein content in the exudates and mainly epithelial damage to a phase,
which numbers vascular thrombosis and endothelial damage with septal
and alveolar cell phlogosis and collagen deposits in interstitial and
alveolar spaces.
Treatment comprises two methods: targeted treatment (when possible)
and non targeted treatment (always feasible). Currently the best treatment
available for patients suffering from ARDS is supportive therapy as
to date no targeted treatment can restore the alveolar-capillary membrane's
normal permeability once the lung has been damaged.
Introduction
Acute Respiratory Distress Syndrome (ARDS) is a serious disease, which
strikes the lung bilaterally. Its first description dates back to 1967
and refers to 12 patients with acute dyspnoea, cyanosis refractory to
O2 treatment, reduced lung compliance and widespread infiltrates detected
by chest X-rays. (1)Initially called Adult Respiratory Distress Syndrome,
it is now defined Acute Respiratory Distress Syndrome (ARDS) because
it can also occur in children.
ARDS' incidence is hard to quantify due to name variations used when
referring to it in most epidemiological studies, which have been conducted.
The estimated incidence in the United States is about 150,000 –
200,000 cases a year. Most cases occur after the patient' s admission
to hospital. They are rarely observed in the Emergency Department and
generally involve direct pulmonary damage, such as the one resulting
from aspiration of gastric content, inhalation of toxic substances and
closed thoracic trauma, which cause the onset of ARDS from the moment
the patient is admitted to the Emergency Department.2, 3
The incidence is higher in adults rather than in children due to the
greater presence of predisposing factors, which strike the adult population,
such as for example sepsis and pancreatitis.
ARDS is not a specific lung disease; it is rather a serious lung dysfunction
caused by an underlying lung disease (sepsis, trauma, pneumonia).
| Tab. 1 |
 |
In 1988 the definition, which was at first free of
aetiological and physiopathological references, was modified and based
on four elements:
(1) phase (acute or chronic), (2) clinical-radiological score, (3) aetiology,
and (4) extrapulmonary organ dysfunction (5). However in this definition
the clinical-radiological score cannot be used to predict the outcome
during the first 24-72 hours. Hence in 1994 a consensus conference established
a new definition of ARDS characterized by (1) acute onset, (2) bilateral
infiltrates found in the chest X-ray, (3) pulmonary arterial wedge pressure
(PAWP) < 18 mmHg or the absence of clinical evidence of left atrial
hypertension, and (4) a PaO2/FiO2 ratio < 200. (Tab. 1)5
Lastly in recent years some authors have suggested dividing ARDS in
a lung form and in an extrapulmonary form. The latter can be observed
during extrapulmonary events, which cause the syndrome6. Though this
classification envisages different pathogenetic pathways, different
morphological and radiological aspects and different answers to ventilatory
strategies in the two forms of ARDS, it is still not clear if this division
can really improve the syndrome's outcome .
Aetiopathogenesis
ARDS' aetiology is only partly known. Current scientific knowledge sustains
many theories, but the precise mechanism is yet unknown. Generally this
syndrome's aetiology is caused by two mechanisms. The first is a direct
toxic stimulus, i.e. aspiration of gastric content, inhalation of toxic
substances or closed thoracic trauma. The second mechanism is more frequent,
but less known. Systemic insults (sepsis, trauma, multiple transfusions,
prolonged cardiopulmonary bypass and pancreatitis) cause the release
of many mediators [tumour necrosis factor – alpha (TNF-?), nitric
oxide (NO) and, polymorphonucleates (PNM)], which cause the lung damage
detected in ARDS (Tab. 2, Fig. 1)5. The reason why only some patients
suffering from these diseases develop ARDS has yet to be found. Recent
studies have highlighted that tabagism and alcoholism can facilitate
the development of ARDS when there is a triggering event. Previously
existing lung diseases (emphysema, asthma, chronic bronchitis) have
been identified both as causal factors and as relevant negative predictors
of the disease's outcome. (4)
| Tab. 2 |
 |
ARDS' acute phase is characterized by the flow of
oedematous fluid with a high protein content in alveolar spaces due
to the alveolar-capillary barrier's increased permeability. The degree
of alveolar epithelial damage is an important predictor of the outcome
and has many consequences: it contributes towards alveolar flooding
and hinders the removal of oedema, it reduces the surfactant's production
and turnover, it can predispose patients suffering from bacterial pneumonia
towards septic shock and it encourages the development of fibrosis.
A relevant role is played by neutrophil PMNs and neutrophil build up
is early and evident both in the alveoli and in BAL.
However ARDS can also occur in neutropenic patients and the administration
of GM-CSF does not improve the scene's gravity.
In ARDS the inflammatory reaction is started and maintained by a complex
network of cytokines (IL-8, IL-1, IL-10, MIF) and other product mediators
locally produced by various cell types.
Other reactions involve the coagulation system and surfactant.
 |
|
Fig.1:
Pathogenesis of alveolar damage in ARDS. |
Physiopatology
ARDS' physiopathology and anatomical and pathological picture are generally
distinguished in three stages, which are now well known and which follow
in a period of weeks or months.
Exudative stage: characterized by an excessive build up of fluid, proteins
and inflammatory cells from the alveolar capillaries, which settle down
in alveolar spaces. (Fig. 2)
 |
|
Fig.2:
ARDS’ exudative phase, which involves a loss of alveolar
epithelial cells and presents alveolar hyaline and neutrophil
membranes. |
Fibroproliferative phase (proliferative): during this
phase connective tissue and other structural elements settle in the
lung in response to the harmful stimulus and the lung appears densely
cellular when examined through microscopy. Besides alveolar breakage
with loss of air in the surrounding areas is frequent in this phase
when ARDS is subsequent to pneumonia.
Resolution and healing phase: in some patients the acute phase is followed
by a gradual improvement and resolution of the picture. Others instead
progress towards fibrosis, which can start early (5-7 days after the
diagnosis). Alveolar spaces fill up with mesenchymal cells, their products
and newly formed vessels. The fibrosing development is associated with
a worse prognosis and the early presence of procollagen III in BAL is
associated with more serious pictures and an increased risk of death.
Oedema is solved by active transport of Na+ and Cl- passively followed
by H2O through aquaporins on type I cells, while insoluble proteins
are removed by diffusion, epithelial cell endocytosis and macrophage
phagocytosis. Lastly re-epithelialization occurs through the action
of type II pneumocytes, which proliferate on the bare basal membrane,
stimulated by growth factors such as KGF and neutrophils are removed
through apoptosis. (Fig. 3)
Monitoraggio
del paziente con ARDS*.
|
| LIVELLO I Segni vitali/Vital signs Temperatura, frequenza cardiaca, frequenza respiratoria, pressione arteriosa sistemica Temperature, heart rate, breathing rate, systemic blood pressure. Peso/Weight Bilancio idrico (entrate ed uscite)/Fluid balance (intake and loss) Apporto calorico/Calory intake Esame obiettivo, con particolare enfasi a: cute (turgore perspiratio, enfisema), apparato respiratorio, (tipo di respirazione, esame del polmone), cardiovascolare (esame del cuore, polso periferico) addominale, neurologico (stato di coscienza) Physical examination with special emphasis on: skin (turgor and perspiration, emphysema), respiratory system (type of breathing, lung examination), cardiovascular system (heart examination, peripheral pulse), abdominal system and neurological system (state of consciousness). LIVELLO
II LIVELLO III (da Taylor RW: The adult respiratory distress syndrome. In Kirby RR, Taylor RW [eds]: Respiratory Fai/ure, pp 208-244. Chicago, Year Book MedicaI Publishers, 1986). (from Taylor RW: The Adult Respiratory Distress Syndrome. In Kirby RR, Taylor RW [eds]: Respiratory Failure, pp 208-244. Chicago, Year Book MedicaI Publishers, 1986). *Le diverse tecniche di monitoraggio sono state
divise in tre livelli arbitrari, che sono, grossolanamente, ordinati
in senso crescente per invasività e sofisticazione. Le
modalità esatte di monitoraggio selezionate e la frequenza
con la quale le misurazioni sono effettuate devono essere personalizzate. |
Clinical presentation
The acute or exudative phase is characterised by the rapid establishment
of respiratory failure in patients presenting risk factors for ARDS.
There is generally even considerable hypoxemia, which is refractory
to the administration of additional oxygen. Organ ischaemia induced
by hypoxia has been observed in some cases.
The X-ray detects irregular asymmetrical, bilateral infiltrates with
possible but infrequent pleural effusion. (Fig. 4)
The healing phase is characterized by a gradual resolution of hypoxemia
and by improved compliance. Usually any densification detected by X-rays
completely solves itself.
However in some cases the disease progresses towards fibrosing alveolitis
with persistent hypoxemia, increased alveolar dead space and a further
reduction in compliance. There can also be pulmonary hypertension. The
chest X-ray reveals linear opaque areas.
The basic diseases' picture and multiorgan failure syndrome, respectively
the triggering event and serious complication of ARDS, must be added
to the above.
 |
|
Fig.3:
Events characterising ARDS' resolution phas |
 |
Fig.4:
Widespread interstitial infiltrates in a patient suffering from
ARDS. |
Diagnosis
ARDS' diagnosis is based on a few factors:
a case history, which is compatible with the presence of possible causal
events. We must exclude chronic pulmonary diseases and the causes of
cardiogenic pulmonary oedema. However a heart attack caused by myocardial
infarction can, for example, be complicated by ARDS due to the aspiration
of gastric fluid.
Clinical signs of respiratory distress: tachypnoea, use of accessory
respiratory muscles with no signs of cardiac decompensation (galop,
orthopnea, jugular vein turgor), warm skin due to vasodilation and widespread
crepitations in the lung.
X-ray signs. The X-ray and CT scan of the chest show widespread patches
of interstitial and bilateral alveolar infiltrates in both lung fields,
which, compared to cardiogenic pulmonary oedema, mostly involve peripheral
and less parahilar regions. (Fig. 5)
Laboratory data: hypoxemia (PaO2 < 50 mmHg) refractory to O2 treatment,
hypocapnia (at least in the early phase), serious reduction in pulmonary
compliance and PCWP < 18 mmHg.
 |
Fig.5 |
Monitoring
ARDS patient monitoring resembles the monitoring process applied to
all critical patients. The most frequently used methods are listed in
tab. 3. Constant monitoring is essential to reduce or prevent possible
disastrous complications. The therapeutic course must be guided by careful
observation of all clinical cardiorespiratory and laboratory variables,
though their use is still controversial.
Treatment and managerial strategies
Since there is no specific treatment to stop inflammatory lung lesions
in ARDS, the management of Acute Respiratory Distress Syndrome generally
focuses on:
a) preventing iatrogenic lung lesions,
b) reducing water in lungs and,
c) maintaining tissue oxygenation.
Ventilation Treatment
Anyhow the treatment's cornerstone is mechanical ventilation with endotracheal
intubation. Tracheal intubation and mechanical ventilation must be considered
if respiratory frequency is > 30/min or if the need arises to apply
FiO2 > 60% through a face mask to maintain PO2 around 70 mmHg or
more for a few hours. As an alternative to intubation, a continuous
positive pressure mask applied to airways can effectively provide PEEP
to patients with mild or moderate ARDS. These masks are not recommended
for patients with a depressed state of consciousness due to the risk
of inhalation and they must be replaced by a ventilator if the patient
progresses towards a serious form of ARDS or if he shows signs of respiratory
muscle stress with an increased respiratory frequency and arterial PCO2.
It has by now been adequately proved how large tidal volumes used during
traditional mechanical ventilation (from 10 to 15 ml/kg) can damage
the lungs.7
Pathological modifications in ARDS are not evenly distributed throughout
the entire lung. On the contrary, regions of pulmonary infiltration
are alternated with regions where the pulmonary architecture remains
normal. In case of mechanical ventilation these normal lung regions
(which cannot exceed 30% of the lung) receive most of the tidal volume
administered. This over expands normal lung regions and is followed
by alveolar breakage, surfactant depletion and alveolar-capillary interface
lesions.8
Recognition of the risk of pulmonary lesions when large volumes of insufflation
and high pressure are used has led to an alternate strategy in which
peak inspiratory pressure is maintained below 35 cm H2O using 6 ml/kg
tidal volumes9. When such low inflation volumes are used, a positive
end expiratory pressure (PEEP), which ranges from 8 to 14 cm H2O, is
added to prevent atelectasis caused by compression and to limit the
collapse phase of airways. Besides this ventilation can cause CO2 retention,
but failing adverse effects hypercapnia is allowed to persist (permissive
hypercapnia).
Prone ventilation modifies the respiratory mechanism improving oxygenation
with a long-lasting effect. Instead there are no effects on the mortality
rate: clinical efficacy only postpones death, which is often unavoidable
in such serious patients. However an analysis conducted at a later date
on certain subgroups of patients selected on the basis of clinical seriousness
shows that mortality after ten days is lower in prone patients than
in those lying face upwards. But the difference fades after the patient's
discharge from the intensive care unit.10
The appropriate moment for weaning is marked by persistent signs of
improved respiratory functions (reduced need for O2 and PEEP), by improvements
noticed in chest X-rays and by the resolution of tachypnoea. It is generally
easy to wean patients with no previously existing lung diseases; weaning
difficulties can be a sign of an untreated infection or of a new localised
infection, hyperhydration, bronchospasm, anaemia, electrolyte alterations,
cardiac dysfunction or a bad nutritional state with subsequent weakening
of respiratory muscles. If these conditions are treated, weaning can
be achieved by using intermittent compulsory ventilation to reduce the
frequency of artificial respiratory acts, often with a certain amount
of supportive pressure or through increasingly long periods of spontaneous
respiration through a T-valve linked to the endotracheal tube. A low
PEEP (5 cm H2O) is usually maintained during the weaning phase.
Targeted Drug Treatment
Targeted drug treatment for ARDS focuses on the pathological lesion'
s regression and on reducing water in the lungs. Unfortunately there
are no significant reasons for optimism in this sense.
The synthetic surfactant prepared for aerosol treatment (Exosurf) has
proved effective in improving the result in neonatal forms of ARDS,
but it has not produced similar success in patients suffering from ARDS11.
As per our experience the synthetic surfactant directly administered
into the tracheobronchial tree has proved effective in treating ARDS.12
High dosage steroids have been taken into consideration due to their
capacity to reduce inflammatory lung lesions in ARDS. Unfortunately
the results obtained do not encourage the use of steroids in ARDS, at
least not in the early stages of the disease.13, 14
Considering that oxygen metabolites play a relevant role in neutrophil-mediated
tissue lesions and that this lesion can in turn play a relevant role
in the pathogenesis of ARDS, the information that studies have focused
on the possible use of antioxidants as specific ARDS treatment will
not come as a surprise.
Inhalation of nitric oxide can significantly improve pulmonary hypertension
and arterial oxygenation in patients suffering from an acute form of
ARDS without causing systemic hypotension. It has yet to be proved whether
nitric oxide improves survival and whether its protracted use encourages
lung damage caused by nitric oxide' s subproducts, i.e. the peroxynitrite
anion15. Its use to treat ARDS must, hence, be considered similar to
thrombolysis in pulmonary embolism and must be limited to patients in
extreme conditions, who suffer from acute hypoxemia and right ventricular
dysfunction and are refractory to traditional supportive methods.
A study has highlighted an improved survival rate in patients suffering
from ARDS and treated with N-acetylcysteine; however this study still
remains isolated for the moment.16
Ketoconazole helps prevent ARDS by inhibiting macrophages' formation
and release of the tumour necrosis factor. Its clinical advantages in
small preliminary studies must be confirmed in more extensive controlled
studies.17
Diuretic treatment can reduce water in the lungs by reducing hydrostatic
pressure in the capillaries and increasing colloidal osmotic pressure
(increased concentration of plasma proteins). While this strategy should
be effective in fluid-based hydrostatic oedema, the situation differs
when it comes to ARDS. Infiltration is in fact an inflammatory process
and diuretics do not reduce inflammation. Hence the fact that diuretics
have not proved to effectively reduce water in lungs in ARDS is not
amazing18. Considering the pathogenesis of ARDS, the use of diuretics
as a routine measure to reduce water in lungs does not seem to offer
any guarantees. The use of diuretics to minimize or cut down the fluid
overload seems to be a more reasonable measure, but only when the renal
excretion of water is altered (besides, the best way to prevent fluid
overload is to maintain an adequate output).19
Finally blood transfusion has been recommended to maintain haemoglobin
values over 10 g/dl; however there are no special grounds for this approach.
In fact considering blood transfusions' tendency to cause ARDS, it seems
cautious to avoid blood transfusions during ARDS. Anaemia need not be
corrected if there is no sign of inadequate tissue oxygenation.20
Extracorporeal Oxygenation
Extracorporeal membrane oxygenation (ECMO) is a prolonged cardiopulmonary
bypass system, which is obtained by intubating large extrathoracic blood
vessels; it is successfully used in the newborn who suffer from respiratory
failure resulting from aspiration of meconium, diaphragmatic hernia
or viral syndromes.21
The use of ECMO in the treatment of ARDS has produced controversial
results; in fact randomised prospective studies have proved no significant
reduction in the mortality rate of patients suffering from ARDS, while
extremely encouraging results have been observed when ECMO was used
at an early stage (less than 5 days of mechanical ventilation) and especially
in patients with acute injury induced lung damage.22
Evolution and prognosis
ARDS' evolution is variable and depends on the nature of the causal
process (and their reversibility), age, basic clinical condition and
lastly of an early accurate therapeutic intervention. In non-treated
and non-responsive cases the syndrome develops towards the multiorgan
failure syndrome with a 60% overall mortality rate. Factors, which influence
mortality number age and previously existing organ dysfunction.23
Some survivors develop fibrosis with signs and symptoms typical of obstructive
airways disease, while others generally completely recover normal respiratory
functions within 6-12 months after the acute episode.24, 25.
Francesco Rossi
Francesco Imperatore
Department of Experimental Medicine,
L. Donatelli” Pharmacology Division,
Faculty of Medicine and Surgery,
2nd University of Naples.