ARDS

ARDS&

Lung Protective Strategy

By Dr RAHUL VARSHNEY

Ventilator associated lung injury

Post-perfusion lung or pump lung

Shock lung

Adult hyaline membrane disease

Adult respiratory insufficiency syndrome

A. K. A

History

• Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome(ARDS) are common problems in the intensive care unit (ICU) and cancomplicate 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 respiratorydistress syndrome of neonates. However, with the recognition that ALI/ARDScan occur in children, the term acute has replaced adult in the nomenclature inrecognition of the typical acute onset that defines the syndrome.

• In practice, ALI/ ARDS remains largely underdiagnosed and often expertpractitioners disagree on the diagnosis, which perpetuates inappropriate orinadequate treatment

Epidemiology

• The wide variety of causes and coexisting disease processes has also madeidentification of cases difficult, both at the clinical and administrative codinglevel.

• The National Institutes of Health first estimated the incidence at 75 per 100,000population 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 publichealth problem that will be encountered frequently by all physicians who carefor critically ill patients.

Definition

• 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 ARDSaccording to the severity of gas exchange abnormality. Despite some controversy, these criteriawere generally accepted and used to guide research study design and enrolment for nearly twodecades.

• However, in 2012 a new consensus conference proposed the “Berlin Definition” whicheliminates the distinction between “acute lung injury” and ARDS, and rather categorizes ARDSby severity based on the degree of hypoxemia (mild, moderate, severe). The three categories areassociated with increasing mortality. In contrast to the previous American-European Conferencedefinition, 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 DEFINITION OF

ACUTE RESPIRATORY DISTRESS SYNDROME

Risk Factors

ALI/ARDS can occur as a result of either DIRECT or INDIRECT injury to the lungs

Risk factor…

• 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 isclinically useful

• Patients with direct lung injury may be more likely to have improved lungmechanics with the application of PEEP.

• However, in the largest cohort of patients studied to date, there was no difference inmortality 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/ARDSappear to have a systemic illness with inflammation and organ dysfunction notconfined to the lung

Risk factor…

• Sepsis is the MC cause of indirect lung injury, with an overall risk of progression to ALI or ARDS ofapproximately 30% to 40%.

• In addition to sepsis itself being a risk factor for development of ARDS, the site of infection may alsoinfluence the risk of lung injury.

• Severe trauma with shock and multiple transfusions also can cause indirect lung injury. Although theother causes of indirect lung injury are less common, many, such as blood transfusions, arecommonplace 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 predisposingdisorders.

• Secondary factors like chronic lung disease, chronic or acute alcohol abuse, increasing age, transfusionof 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 thedevelopment of ARDS. Several studies have shown that patients with diabetes are less likely todevelop ARDS.

Cause of Lung Injury

NHLBI ARDS Clinical Trials Network. N Engl J Med. 2004.

Aspiration15%

Transfusion5%

Other10%

Pneumonia40%

Sepsis22%

Trauma8%

Aspiration

Transfusion

Other

Pneumonia

Sepsis

Trauma

• Complex and remains incompletelyunderstood.

• Microscopically, lungs from afflictedindividuals in the early stages show diffusealveolar damage with alveolar flooding byproteinaceous fluid, neutrophil influx intothe alveolar space, loss of alveolarepithelial cells, deposition of hyalinemembranes on the denuded basementmembrane, and formation of microthrombi.

Pathophysiology

Pathophysiology…

• Alveolar flooding occurs as a result of injury to the alveolar-capillary barrier and is a majordeterminant of the hypoxemia and altered lung mechanics that characterize early ALI/ARDS.Flooding is characteristically with a protein-rich edema fluid, owing to the increasedpermeability of the alveolar capillary barrier, in contrast to the low-protein pulmonary edemathat results from hydrostatic causes such as congestive heart failure or acute myocardialinfarction.

• Migration of neutrophils into the alveolar compartment play an important role in the initialinflammatory response in ARDS.

• Surfactant dysfunction

• Activation of coagulation cascade and impaired fibrinolysis.

• Alteration in balance between endogenous oxidants and

anti oxidants.

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 toincreased permeability pulmonary edema due to capillary stress failure and sustained elevationsof circulating plasma cytokines.

• In the injured lung, even tidal volumes that are well tolerated in the normal lung can lead toalveolar over-distension in relatively uninjured areas because the lung available for distributionof the administered tidal volume is greatly reduced and because of uneven distribution ofinspired gas.

• In addition to alveolar over-distension, cyclic opening and closing of atelectatic alveoli cancause lung injury even in the absence of alveolar over-distension.

• The combination of alveolar over-distension with cyclic opening and closing of alveoli isparticularly harmful and can initiate a pro-inflammatory cascade.

Pathophysiology…

Positive pressure ventilation may injure the lung

via several different mechanisms

VILI

Alveolar distension

“VOLUTRAUMA”

Repeated closing and opening

of collapsed alveolar units

“ATELECTRAUMA”

Oxygen toxicity

Lung inflammation

“BIOTRAUMA”

Multiple organ dysfunction syndrome

Pathophysiology…

Diagnosis

• 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 appropriate patients.

• 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 severalperspectives. New definitions are easy to apply and facilitate rapid identification and appropriatetreatment of patients with ALI/ARDS

• Although not strictly part of these definitions, an underlying cause of lung injury should besought. In the absence of an identifiable underlying cause, particular attention should be given tothe possibility of other causes of pulmonary infiltrates and hypoxemia, such as hydrostaticpulmonary edema

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

significant shortcomings.

• 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.

Diagnosis…

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

endotracheal intubation.

Circulating bio-markers.

Invasive techniques for diagnosis eg

• Broncho-alveolar lavage for culture and cytological examination.

• Open lung biopsy

Clinical Course

Early ALI/ARDS

• 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.

Radiographic infiltrate

• Bilateral

• Patchy or diffuse

• Fluffy or dense

• Pleural effusion

• Areas of alveolar filling and consolidation occurpredominantly in dependent zones, while non-dependent regions can appear relatively spared. Evenareas that appear spared in conventional radiographicimages may have substantial inflammation whensampled using bronchoalveolar lavage or using FDG-PET scanning.

Hypoxemia

• 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.

ARDS

Fibro-proliferative

stage

Resolution phase

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

Resolution PhaseFor 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 fromthe distal airway and alveolar spaces into the lung interstitium.

Soluble and insoluble protein must also be cleared from the airspaces. Soluble proteinprobably 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 cellendocytosis and transcytosis.

The denuded alveolar epithelium in ALI/ARDS must be repaired. The alveolar epithelial typeII cell serves as the progenitor cell for repopulating the alveolar epithelium.

Resolution of neutrophilic inflammation may be predominantly via neutrophil apoptosis andphagocytosis by macrophages.

The resolution of fibrotic changes is also not well understood. However, substantial remodelingis necessary to restore a normal or near-normal alveolar architecture. In patients with advancedfibrosis, this process likely takes place over many months.

treatment

• Standard supportive therapy

Treat predisposing factors

Fluid and haemodynamic management

Nutrition

• Mechanical VentilationLung 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 beundertaken. Appropriate treatment for any precipitating infection such as pneumonia iscritical to enhance the chance of survival.

• In the immunocompromised host or patients without predisposing risk factors, invasivediagnostic evaluation including bronchoscopy may be warranted to look for evidence ofopportunistic infections or alternative specific causes of ARDS.

• In a patient with sepsis and ALI/ARDS of unknown source, an intra-abdominal processshould be considered. Timely surgical management of intra-abdominal sepsis isassociated with better outcomes.

• In some patients, the cause of lung injury will not be specifically treatable (such asaspiration of gastric contents) or will not be readily identifiable.

Fluid and haemodynamic management

• For decades there was disagreement as to the best fluid-management strategyin patients with ARDS.

• Proponents of a liberal fluid strategy reasoned that increased circulatingvolume would preserve end-organ perfusion and protect patients from thedevelopment of non-pulmonary organ failures.

• Others supported a conservative fluid strategy in an attempt to reducecirculating volume, thereby reducing the driving force for pulmonary edemaformation. 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.

nutrition

• The enteral route is preferred to the parenteral route and is associated with fewerinfectious complications.

• 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 withALI/ARDS.

• Until the results of the ARDS Network study become available, the goals of nutritionalsupport in any critically ill patient include providing adequate nutrients for the patient’slevel of metabolism and treating and preventing any deficiencies in micro- ormacronutrients.

• There is still no compelling evidence to support the use of anything other than standardenteral 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/kgpredicted body weight, plateau pressure < 30 cm H2O) with a higher tidal volume (12mL/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 the6 mL/kg—a 22% reduction.

Ventilator-free days and organ failure–free days were also significantly improved in thelow-tidal-volume group. These findings were truly remarkable, since no prior largerandomized clinical trial of any specific therapy for ALI/ARDS has ever demonstrated amortality benefit.

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Days after Randomization

Lower tidal volumes

Survival

Discharge

Traditional tidal values

Survival

Discharge

ARDS Network. N Engl J Med. 2000.

ARDS Network: Improved Survival with Low VT

High vs low peep

• PEEP by avoiding repetitive opening and collapse ofatelectatic lung units, could be protective against VILI.

• High PEEP should make the mechanical ventilation lessdangerous than low PEEP.

• The recruitment is obtained essentially at end-inspiration,and the lung is kept open by using PEEP to avoid end-expiratory collapse.

• PEEP, by preserving inspiratory recruitment andreestablishing end-expiratory lung volume, has been shownto prevent surfactant loss in the airways and avoid surfacefilm collapse.

• There has never been a consensus regarding the optimumlevel 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 acuteexacerbation 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 hypoxemicrespiratory failure who were not already intubated, NIV failed in 30% of patients butfailed in 51% of patients with ARDS.

• One group of patients in whom NIV is particularly appealing is those patients who areimmunosuppressed for various reasons and are at highest risk for nosocomial infections.Encouraging results have now been reported in a variety of patients with acuterespiratory failure and immunosuppression.

Pharmacological therapy

• Glucocorticoids therapy, as some believe, might hasten the resolution of late fibro-proliferative ALI/ARDS. Compared to patients treated with placebo, those treated withmethylprednisolone had an increase in the number of shock-free days and ventilator-free daysby day 28, as well as improvements in oxygenation; but they did not have improved survivaland 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 nothave 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 timewindow for corticosteroid administration, between early acute injury and established post aggressivefibrosis.

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 theirdisease marked by fibrotic lung disease or fibrosing alveolitis with alveolar collagen andfibronectin accumulation.

Patient selection: Severe ARDS/ 7 days of mechanical ventilation/ No evidence of untreatedinfection

Treatment protocol: Methylprednisolone

In patients with un-resolving ARDS, prolonged administration of methylprednisolone wasassociated 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.

Pharmacological therapy…

Rescue therapy

In patients who do not respond to conventional treatment with low-tidal-volumeventilation and remain persistently hypoxemic, there are several unproven rescuetherapies 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 inhaledprostacyclin.

Although none have shown improved mortality, its use has been associated withimprovements in oxygenation.

Ventral

Dorsal

Dorsal

Ventral

Mechanism of Prone Positioning

While selecting ventilatory

strategy

REMEMBER THE CONCEPT

Buy Time – Doing Least Harm

Complications

Barotrauma occurs when air dissects out of the airways or alveolar space into surroundingtissues, leading to pneumothorax, pneumo-mediastinum, pneumatocele, or subcutaneousemphysema.

In 861 patients enrolled in the ARDS Network trial, approximately 10% of patients developedsome form of barotrauma regardless of whether they were in the 6 or 12 mL/kg tidal volumearm.

Further, PEEP level was the only factor that predicted

the development of barotrauma in a multivariate analysis.

Barotrauma

Nosocomial pneumonia

There is yet no consensus regarding the appropriate wayto diagnose nosocomial pneumonia in the mechanicallyventilated patient.

Clinical criteria commonly used in the diagnosis includefever, elevated white blood cell count, purulent secretions,and pulmonary infiltrates. However, these signs are oftenpresent in patients with ALI/ARDS even in the absence ofnosocomial pneumonia.

Regardless of the methods used for diagnosis, early,appropriate, empirical therapy is the mainstay of treatmentfor nosocomial pneumonia.

MULTISYSTEM ORGAN DYSFUNCTION

Multisystem organ dysfunction is a common complication in ALI/ARDS. Organdysfunction may result from the underlying cause of ALI/ARDS, such as sepsis, oroccur independently.

Given the simultaneous occurrence of multiple organ failures, it is often difficult todetermine the exact cause of death in ALI/ARDS patients, and survival ultimatelydepends on the successful support of the failing organs

NEUROMUSCULAR WEAKNESS

Patients with ALI/ARDS are at high risk for developing prolonged muscle weaknessthat persists after resolution of pulmonary infiltrates and can complicate weaning frommechanical ventilation and rehabilitation. This clinical syndrome is commonly calledcritical illness polyneuropathy.

Prolonged muscle weakness is most common in critically ill patients who are treatedwith glucocorticoids.

Neuromuscular blockade has also been implicated, and for this reason, the use ofneuromuscular blockade should be reserved for those patients who are unable to beadequately oxygenated or who have problematic dyssynchrony with the mechanicalventilator despite deep sedation.

Outcome and Prognosis

• In the ARDS Network study of 861 patients with ALI/ARDS, aggregate mortality tohospital discharge was 31% in the 6 mL/kg tidal volume arm and 40% in the 12 mL/kgtidal 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 thosewith multiple trauma (11%).

• The low-tidal-volume strategy was effective at reducing mortality across all causes ofALI/ARDS.

• ALI/ARDS survivors frequently have long-term functional disability, cognitivedysfunction, 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 spirometryhad 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 musclewasting 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 ofdepression and anxiety

Outcome and Prognosis…

Thank You