Ventilator associated lung injury
Post-perfusion lung or pump lung
Adult hyaline membrane disease
Adult respiratory insufficiency syndrome
A. K. A
• Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome
(ARDS) are common problems in the intensive care unit (ICU) and can
complicate a wide spectrum of critical illnesses.
• First described by Ashbaugh in 1967, the syndrome was initially termed
“adult respiratory distress syndrome” to distinguish it from the respiratory
distress syndrome of neonates. However, with the recognition that ALI/ARDS
can occur in children, the term acute has replaced adult in the nomenclature in
recognition of the typical acute onset that defines the syndrome.
• In practice, ALI/ ARDS remains largely underdiagnosed and often expert
practitioners disagree on the diagnosis, which perpetuates inappropriate or
• The wide variety of causes and coexisting disease processes has also made
identification of cases difficult, both at the clinical and administrative coding
• The National Institutes of Health first estimated the incidence at 75 per 100,000
population in 1977.
• Some studies suggest a decline in the incidence of ARDS over time.
• Regardless of the exact incidence, it is clear that ALI/ARDS is a major public
health problem that will be encountered frequently by all physicians who care
for critically ill patients.
• In order to better standardize the definition of ARDS for epidemiologic and research purposes,
in 1994 a joint American– European Conference proposed criteria for characterizing ARDS
according to the severity of gas exchange abnormality. Despite some controversy, these criteria
were generally accepted and used to guide research study design and enrolment for nearly two
• However, in 2012 a new consensus conference proposed the “Berlin Definition” which
eliminates the distinction between “acute lung injury” and ARDS, and rather categorizes ARDS
by severity based on the degree of hypoxemia (mild, moderate, severe). The three categories are
associated with increasing mortality. In contrast to the previous American-European Conference
definition, the Berlin Definition of ARDS was empirically evaluated using patient-level meta-
analysis, and is thus better validated as a research and descriptive tool.
COMPARISON OF THE AMERICAN-EUROPEAN CONSENSUS CONFERENCE AND BERLIN
ACUTE RESPIRATORY DISTRESS SYNDROME
ALI/ARDS can occur as a result of either DIRECT or INDIRECT injury to the lungs
• Direct cause appear to account for approx. half of all the cases.
• It is not clear whether the distinction between direct and indirect lung injury is
• Patients with direct lung injury may be more likely to have improved lung
mechanics with the application of PEEP.
• However, in the largest cohort of patients studied to date, there was no difference in
mortality between those with direct (pulmonary) and indirect (extra-pulmonary)
causes of lung injury.
• Regardless of the underlying cause of ALI/ARDS, most patients with ALI/ARDS
appear to have a systemic illness with inflammation and organ dysfunction not
confined to the lung
• Sepsis is the MC cause of indirect lung injury, with an overall risk of progression to ALI or ARDS of
approximately 30% to 40%.
• In addition to sepsis itself being a risk factor for development of ARDS, the site of infection may also
influence the risk of lung injury.
• Severe trauma with shock and multiple transfusions also can cause indirect lung injury. Although the
other causes of indirect lung injury are less common, many, such as blood transfusions, are
commonplace events in the ICU setting.
• The MC cause of direct lung injury is pneumonia, which may be of bacterial, viral, or fungal origin.
• The risk of developing ALI/ ARDS increases substantially in the presence of multiple predisposing
• Secondary factors like chronic lung disease, chronic or acute alcohol abuse, increasing age, transfusion
of blood products, lung resection and obesity may also increase the risk.
• Emerging evidence has suggested that some at-risk patients may actually be protected from the
development of ARDS. Several studies have shown that patients with diabetes are less likely to
Cause of Lung Injury
NHLBI ARDS Clinical Trials Network. N Engl J Med. 2004.
• Complex and remains incompletely
• Microscopically, lungs from afflicted
individuals in the early stages show diffuse
alveolar damage with alveolar flooding by
proteinaceous fluid, neutrophil influx into
the alveolar space, loss of alveolar
epithelial cells, deposition of hyaline
membranes on the denuded basement
membrane, and formation of micro
• Alveolar flooding occurs as a result of injury to the alveolar-capillary barrier and is a major
determinant of the hypoxemia and altered lung mechanics that characterize early ALI/ARDS.
Flooding is characteristically with a protein-rich edema fluid, owing to the increased
permeability of the alveolar capillary barrier, in contrast to the low-protein pulmonary edema
that results from hydrostatic causes such as congestive heart failure or acute myocardial
• Migration of neutrophils into the alveolar compartment play an important role in the initial
inflammatory response in ARDS.
• Surfactant dysfunction
• Activation of coagulation cascade and impaired fibrinolysis.
• Alteration in balance between endogenous oxidants and
Ventilator Induced Lung Injury
• There are several mechanisms by which mechanical ventilation can injure the lung.
• Ventilation at very high volumes and pressures can injure even the normal lung, leading to
increased permeability pulmonary edema due to capillary stress failure and sustained elevations
of circulating plasma cytokines.
• In the injured lung, even tidal volumes that are well tolerated in the normal lung can lead to
alveolar over-distension in relatively uninjured areas because the lung available for distribution
of the administered tidal volume is greatly reduced and because of uneven distribution of
• In addition to alveolar over-distension, cyclic opening and closing of atelectatic alveoli can
cause lung injury even in the absence of alveolar over-distension.
• The combination of alveolar over-distension with cyclic opening and closing of alveoli is
particularly harmful and can initiate a pro-inflammatory cascade.
Positive pressure ventilation may injure the lung
via several different mechanisms
Repeated closing and opening
of collapsed alveolar units
Multiple organ dysfunction syndrome
• Diagnostic uncertainty in ALI/ARDS is a major barrier to initiation of appropriate therapy and
one of the main reasons why clinicians fail to initiate lung-protective ventilation in clinically
• There are no specific clinical or laboratory studies that can reliably identify ARDS.
• The standardization of definitions for ALI and ARDS has been helpful from several
perspectives. New definitions are easy to apply and facilitate rapid identification and appropriate
treatment of patients with ALI/ARDS
• Although not strictly part of these definitions, an underlying cause of lung injury should be
sought. In the absence of an identifiable underlying cause, particular attention should be given to
the possibility of other causes of pulmonary infiltrates and hypoxemia, such as hydrostatic
Based solely on clinical criteria
There is no reference to pathogenesis or underlying cause
Presence or absence of multi-organ dysfunction is not specified.
Bilateral infiltrates has major prognostic significance and is a Hallmark,
radiographic findings are not specific for ALI/ARDS
However, it should be noted the nature of
ALI/ARDS is such that any definition will have
• One more potential limitation of the consensus definition is the need for arterial blood gas
sampling to calculate a Pao2/Fio2 ratio. Recent work has shown good correlation between
the Spo2/Fio2 ratio (measured by pulse oximetry) and the Pao2/Fio2 ratio, with an Spo2/Fio2
ratio of 235 corresponding to a Pao2/Fio2 ratio of 200, and an Spo2/Fio2 ratio of 315
correlating to a Pao2/Fio2 ratio of 300. These calculations are valid only when the Spo2 is less
than 98%, because the oxy-haemoglobin dissociation curve is flat above this level.
• Oxygen saturation is a non-invasive, continuously available measurement; use of the
Spo2/Fio2 ratio may improve the ability of clinicians to diagnose ARDS.
Alternate methods of Diagnosis
To Increase sensitivity and specificity of clinical definitions for ALI/ARDS.
Pulmonary edema fluid to plasma protein ratio, if measured early after
Invasive techniques for diagnosis eg
• Broncho-alveolar lavage for culture and cytological examination.
• Open lung biopsy
• Radiographic infiltrates
• Hypoxemia and Increased work of breathing
• Increased pulmonary vascular resistance Pulmonary HTN RV Failure
Late Fibro-proliferative ALI/ARDS
Resolution of ALI/ARDS.
• Patchy or diffuse
• Fluffy or dense
• Pleural effusion
• Areas of alveolar filling and consolidation occur
predominantly in dependent zones, while non-
dependent regions can appear relatively spared. Even
areas that appear spared in conventional radiographic
images may have substantial inflammation when
sampled using bronchoalveolar lavage or using FDG-
• Relatively refractory to supplemental oxygen.
• The increased work of breathing in the acute phase of ALI/ARDS is due to decreased
lung compliance as a result of alveolar and interstitial edema combined with increased
airflow resistance and increased respiratory drive.
• Many patients with ARDS also develop evidence of increased pulmonary vascular
resistance leading to pulmonary hypertension and RV failure. The prevalence of
pulmonary hypertension in patients presenting to the hospital with ARDS may be as
high as 92%, and as many as 10% of patients with ARDS may have right ventricular
(RV) failure defined by hemodynamic measurements.
Late fibro-proliferative stage
Radiographically, linear opacities develop, consistent with the evolving fibrosis.
Histologically, pulmonary edema and neutrophilic inflammation are less prominent. A severe fibro-
proliferative process fills the airspaces with granulation tissue that contains extracellular matrix rich in
collagen and fibrin, as well as new blood vessels and proliferating mesenchymal cells.
Clinically, the late fibro-proliferative phase of ALI/ARDS is characterized by continued need for
mechanical ventilation, often with persistently high levels of PEEP and Fio2. Lung compliance may fall
even further, and pulmonary dead space is elevated.
If it has not developed in the acute phase, pulmonary hypertension may occur now owing to
obliteration of the pulmonary capillary bed, and right ventricular failure may appear
For complete resolution of ALI/ARDS to occur, a variety of processes must be reversed:
Alveolar edema is actively reabsorbed by the vectorial transport of sodium and chloride from
the distal airway and alveolar spaces into the lung interstitium.
Soluble and insoluble protein must also be cleared from the airspaces. Soluble protein
probably diffuses by a paracellular route into the interstitium, where it is cleared by lymphatics.
Insoluble protein probably is cleared by macrophage phagocytosis or alveolar epithelial cell
endocytosis and transcytosis.
The denuded alveolar epithelium in ALI/ARDS must be repaired. The alveolar epithelial type
II cell serves as the progenitor cell for repopulating the alveolar epithelium.
Resolution of neutrophilic inflammation may be predominantly via neutrophil apoptosis and
phagocytosis by macrophages.
The resolution of fibrotic changes is also not well understood. However, substantial remodeling
is necessary to restore a normal or near-normal alveolar architecture. In patients with advanced
fibrosis, this process likely takes place over many months.
• Standard supportive therapy
Treat predisposing factors
Fluid and haemodynamic management
• Mechanical Ventilation
Lung protective ventilation
Non Invasive ventilation
• Pharmacological therapies
• Rescue therapy
Treatment of predisposing factors
• First and foremost, a search for the underlying cause of ALI/ARDS should be
undertaken. Appropriate treatment for any precipitating infection such as pneumonia is
critical to enhance the chance of survival.
• In the immunocompromised host or patients without predisposing risk factors, invasive
diagnostic evaluation including bronchoscopy may be warranted to look for evidence of
opportunistic infections or alternative specific causes of ARDS.
• In a patient with sepsis and ALI/ARDS of unknown source, an intra-abdominal process
should be considered. Timely surgical management of intra-abdominal sepsis is
associated with better outcomes.
• In some patients, the cause of lung injury will not be specifically treatable (such as
aspiration of gastric contents) or will not be readily identifiable.
Fluid and haemodynamic management
• For decades there was disagreement as to the best fluid-management strategy
in patients with ARDS.
• Proponents of a liberal fluid strategy reasoned that increased circulating
volume would preserve end-organ perfusion and protect patients from the
development of non-pulmonary organ failures.
• Others supported a conservative fluid strategy in an attempt to reduce
circulating volume, thereby reducing the driving force for pulmonary edema
formation. There is some clinical evidence to support this approach.
Currently, the recommended strategy is to aim to achieve the lowest intravascular
volume that maintains adequate tissue perfusion as measured by urine output, other organ
perfusion, and metabolic acid-base status, using CVP monitoring to direct therapy. If organ
perfusion cannot be maintained in the setting of adequate intravascular volume,
administration of vasopressors and/or inotropes should be used to restore end-organ
perfusion. Once shock has resolved, patients should be managed with a conservative fluid
strategy, with the goal of driving the CVP below 4 to keep each patient’s fluid balance net
zero over their ICU stay.
• The enteral route is preferred to the parenteral route and is associated with fewer
• The ARDS Network is currently conducting a randomized trial of trophic (10 mL/h,
well below caloric requirements) versus full-calorie enteral feeds in patients with
• Until the results of the ARDS Network study become available, the goals of nutritional
support in any critically ill patient include providing adequate nutrients for the patient’s
level of metabolism and treating and preventing any deficiencies in micro- or
• There is still no compelling evidence to support the use of anything other than standard
enteral nutritional support, with avoidance of overfeeding, in patients with ALI/ARDS.
Lung protective ventilation
In 2000, the NIH ARDS Network published the findings of their first randomized,
controlled, multi-center clinical trial in 861 patients.
The trial was designed to compare a lower-tidal-volume ventilatory strategy (6 mL/kg
predicted body weight, plateau pressure < 30 cm H2O) with a higher tidal volume (12
mL/kg predicted body weight, plateau pressure <50 cm H2O).
In this trial, the in-hospital mortality rate was 40% in the 12 mL/kg group and 31% in the
6 mL/kg—a 22% reduction.
Ventilator-free days and organ failure–free days were also significantly improved in the
low-tidal-volume group. These findings were truly remarkable, since no prior large
randomized clinical trial of any specific therapy for ALI/ARDS has ever demonstrated a
Days after Randomization
Lower tidal volumes
Traditional tidal values
ARDS Network. N Engl J Med. 2000.
Improved Survival with Low VT
High vs low peep
• PEEP by avoiding repetitive opening and collapse of
atelectatic lung units, could be protective against VILI.
• High PEEP should make the mechanical ventilation less
dangerous than low PEEP.
• The recruitment is obtained essentially at end-inspiration,
and the lung is kept open by using PEEP to avoid end-
• PEEP, by preserving inspiratory recruitment and
reestablishing end-expiratory lung volume, has been shown
to prevent surfactant loss in the airways and avoid surface
• There has never been a consensus regarding the optimum
level of PEEP for a given patient with ARDS.
In ALI and ARDS patients, higher PEEP strategy was associated with:
• PaO2/FiO2 higher the first seven days post randomization
• Plateau pressure higher the first three days post randomization
• VT lower the first three days post randomization
• No difference in RR, PaCO2, or pH
• No difference in mortality rate
• No difference in organ failures or barotrauma
• No difference in IL-6, ICAM-1, surfactant protein-D
“Lower PEEP” (or lower tidal volume) was sufficient to protect against injury from
“Atelectrauma” (ventilation at low end-expiratory volumes)?
High vs low peep…
Non Invasive ventilation
• NIV has been highly successful in avoidance of intubation in patients with acute
exacerbation of COPD. NIV is commonly used in pediatric patients with ALI/ARDS,
The role for NIV in adults with ALI/ARDS is still unclear.
• In one large multi-center study of 354 of 2770 patients with acute hypoxemic
respiratory failure who were not already intubated, NIV failed in 30% of patients but
failed in 51% of patients with ARDS.
• One group of patients in whom NIV is particularly appealing is those patients who are
immunosuppressed for various reasons and are at highest risk for nosocomial infections.
Encouraging results have now been reported in a variety of patients with acute
respiratory failure and immunosuppression.
• Glucocorticoids therapy, as some believe, might hasten the resolution of late fibro-
proliferative ALI/ARDS. Compared to patients treated with placebo, those treated with
methylprednisolone had an increase in the number of shock-free days and ventilator-free days
by day 28, as well as improvements in oxygenation; but they did not have improved survival
and had higher rates of re-intubation, perhaps due to neuromuscular weakness.
Corticosteroid Therapy in ARDS:
Better late than never?
High-dose corticosteroids in early ARDS
• Do not lessen the incidence of ARDS among patients at high risk
• Do not reverse lung injury in patients with early ARDS/worse recovery
• Have no effect on mortality/even increase mortality rate
• Significantly increase the incidence of infectious complications
High-dose corticosteroids for Unresolving ARDS of 7 days duration who do not
have uncontrolled infection
• Patient selection: Lack of clinical improvement rather than use of only the LIS
• Aggressive search for and treatment of infectious complications is necessary.
• Several questions remain: Timing, dosage, and duration of late steroid therapy in ARDS/Appropriate time
window for corticosteroid administration, between early acute injury and established post aggressive
Kopp R et al., Intensive Care Med 2002
Brun-Buisson C and Brochard L, JAMA 1998
Effect of Prolonged Methylprednisolone
in Unresolving ARDS
Rationale: Within seven days of the onset of ARDS, many patients exhibit a new phase of their
disease marked by fibrotic lung disease or fibrosing alveolitis with alveolar collagen and
Patient selection: Severe ARDS/ 7 days of mechanical ventilation/ No evidence of untreated
Treatment protocol: Methylprednisolone
In patients with un-resolving ARDS, prolonged administration of methylprednisolone was
associated with improvement in lung injury and MODS scores and reduced mortality.
Meduri GU et al., JAMA 1998
recombinant human activated protein C
Site-inactivated recombinant factor VIIa
HMG-CoA reductase inhibitors (statins)
Peroxisome proliferator–activated receptors modulators.
In patients who do not respond to conventional treatment with low-tidal-volume
ventilation and remain persistently hypoxemic, there are several unproven rescue
therapies that may be tried to improve oxygenation in the acute setting:
• Extracorporeal membrane oxygenation (ECMO)
• High-frequency oscillatory ventilation (HFVO)
• prone positioning
• pulmonary vasodilator, such as inhaled nitric oxide (iNO) or inhaled
Although none have shown improved mortality, its use has been associated with
improvements in oxygenation.
Mechanism of Prone Positioning
While selecting ventilatory
REMEMBER THE CONCEPT
Buy Time – Doing Least Harm
Barotrauma occurs when air dissects out of the airways or alveolar space into surrounding
tissues, leading to pneumothorax, pneumo-mediastinum, pneumatocele, or subcutaneous
In 861 patients enrolled in the ARDS Network trial, approximately 10% of patients developed
some form of barotrauma regardless of whether they were in the 6 or 12 mL/kg tidal volume
Further, PEEP level was the only factor that predicted
the development of barotrauma in a multivariate analysis.
There is yet no consensus regarding the appropriate way
to diagnose nosocomial pneumonia in the mechanically
Clinical criteria commonly used in the diagnosis include
fever, elevated white blood cell count, purulent secretions,
and pulmonary infiltrates. However, these signs are often
present in patients with ALI/ARDS even in the absence of
Regardless of the methods used for diagnosis, early,
appropriate, empirical therapy is the mainstay of treatment
for nosocomial pneumonia.
MULTISYSTEM ORGAN DYSFUNCTION
Multisystem organ dysfunction is a common complication in ALI/ARDS. Organ
dysfunction may result from the underlying cause of ALI/ARDS, such as sepsis, or
Given the simultaneous occurrence of multiple organ failures, it is often difficult to
determine the exact cause of death in ALI/ARDS patients, and survival ultimately
depends on the successful support of the failing organs
Patients with ALI/ARDS are at high risk for developing prolonged muscle weakness
that persists after resolution of pulmonary infiltrates and can complicate weaning from
mechanical ventilation and rehabilitation. This clinical syndrome is commonly called
critical illness polyneuropathy.
Prolonged muscle weakness is most common in critically ill patients who are treated
Neuromuscular blockade has also been implicated, and for this reason, the use of
neuromuscular blockade should be reserved for those patients who are unable to be
adequately oxygenated or who have problematic dyssynchrony with the mechanical
ventilator despite deep sedation.
Outcome and Prognosis
• In the ARDS Network study of 861 patients with ALI/ARDS, aggregate mortality to
hospital discharge was 31% in the 6 mL/kg tidal volume arm and 40% in the 12 mL/kg
tidal volume arm.
• The risk of in hospital mortality was highest in patients with sepsis (43%),
intermediate in those with pneumonia (36%) or aspiration (37%), and lowest in those
with multiple trauma (11%).
• The low-tidal-volume strategy was effective at reducing mortality across all causes of
• ALI/ARDS survivors frequently have long-term functional disability, cognitive
dysfunction, and psychosocial problems.
• Interestingly, pulmonary function frequently returns to normal or near normal in survivors.
• In a report of 1-year follow-up in 109 survivors from ARDS, lung volumes and spirometry
had returned to normal by 6 months.
• However, carbon monoxide diffusing capacity was persistently low at 12 months.
• Six-minute walk distances were persistently low at 12 months, largely due to muscle
wasting and weakness rather than pulmonary function abnormalities.
• Survivors of ALI/ARDS have been reported to have reduced health-related quality of life.
• In addition to physical and social difficulties after ARDS, survivors have high rates of
depression and anxiety
Outcome and Prognosis…