Under the Guidance of

Dr. Rajmani Assistant Professor

Department of Medicine
J.L.N. Medical College, Ajmer (Raj.)

REFERANCE
Harrisons Principle of Internal Medicine 17th Edition, 2008.
API of General Medicine 2008. The Washington Manual of Medical Therapeutics 32th edition 2007. Wikipedia Images from various internet sites

 Acute respiratory distress

Cyanosis refractory to oxygen therapy Decreased lung compliance Diffuse infiltrates on chest radiograph

Difficulties:
lacks specific criteria
controversy over incidence and mortality

 1988: four-point lung injury score

Level of PEEP PaO2 / FiO2 ratio

Static lung compliance

Degree of chest infiltrates

1994: consensus conference simplified the definition

 Severe lung injury characterized by noncardiogenic pulmonary edema, decreased lung compliance, refractory hypoxemia
1994 Consensus Definition
Acute onset (<2 weeks) Bilateral infiltrates on chest x-ray PCWP 18mmHg or lack of evidence of left atrial hypertension

Acute lung injury if PaO2/FiO2 300

ARDS if PaO2/FiO2 200

 Incidence of acute lung injury (ALI): up to 80 cases per 100,000 person-years Incidence of acute respiratory distress syndrome (ARDS): up to 60 cases per 100,000 person-years Approx 10% of ICU beds in US In India study from Mumbai ,respiratory failure due to ARDS occurred in 26% patients with severe malaria ,with a nearly 90% mortality.

 Pneumonia (40-50%)
Sepsis (31%) Aspiration (9%)

Trauma (20%)
Pulmonary contusion Multiple fractures

 Preexisting lung disease

Chronic alcohol use Low serum pH

Sepsis
40% of patients with sepsis develop ARDS

Differential diagnosis
Pulmonary edema from left heart failure BOOP or COP Hypersensitivity pneumonitis

Diffuse alveolar hemorrhage

Leukemic infiltrate Acute eosinophilic pneumonia Lupus pneumonitis Drug-induced pulmonary edema and pneumonitis

Acute interstitial pneumonia

Pulmonary alveolar proteinosis

Acute major pulmonary embolus

Sarcoidosis Interstitial pulmonary fibrosis

EXUDATIVE

PROLIFERATIVE

FIBROTIC

EDEMA HYALINE MEMBRANES

INTERSTITIALS INFLAMMATION INTERSTITIAL FIBROSIS

FIBROSIS

DAY

0-7

14

21..

11

 Alveolar-capillary barrier is formed by microvascular endothelium and alveolar epithelium

Under normal conditions epithelial barrier is much less permeable than endothelium

Epithelium is made up of type I and II cells

Type I cells are injured easily and Type II cells are more resistant

 In ALI/ARDS damage to either one occurs resulting in increased permeability of the barrier
influx of protein-rich edema fluid into the alveolar space Injury of Type I cells results loss of epithelial integrity and fluid extravasations (edema)

Injury of Type II cells then impairs the removal of the edema fluid

 Dysfunction of Type II cells also leads to reduced production and turnover of surfactant which leads to alveolar collapse

If severe injury to epithelium occurs disorganized/insufficient epithelial repair occurs resulting in fibrosis
In addition to inflammatory process, there is evidence that the coagulation system is also involved

Alveolar Filling

Expansion of interstitium with macrophages and inflammation

Hyaline Membranes

 Rapid onset respiratory failure in patient at risk for ARDS Hypoxemia refractory to oxygen Chest x-ray resembles cardiogenic pulmonary edema
Bilateral infiltrates worse in dependent lung zones, effusions Infiltrates may be asymmetric

A representative computed tomographic scan of the chest during the exudative phase of ARDS in which dependent alveolar edema and atelectasis predominate.

Proliferative Phase
With intervention (mechanical ventilation) there is clearance of alveolar fluid
Soluble proteins are removed by diffusion between alveolar epithelial cells

Insoluble proteins are removed by endocytosis and transcytosis through epithelial cells and phagocytosis through macrophages

 Type II cells begin to differentiate into Type I cells and reepithelialize denuded alveolar epithelium

Further epithelialization leads to increased alveolar clearance

 After acute phase, some pt will have uncomplicated course and rapid resolution

Some pts will progress to fibrotic lung injury

Such injury occurs histologically as early as in 5-7 days

 Intense inflammation leads to obliteration of the normal lung architecture

Alveolar space is filled with mesenchymal cells and their products

Reepithelialization and new blood vessel formation occurs in disorganized manner

Fibroblasts also proliferate, collagen is deposited resulting in thickening of interstitium

Fibrosing alveolitis and cyst formation

 Impaired gas exhange leading to severe hypoxemia - ventilation-perfusion mismatch, increase in physiologic deadspace
Decreased lung compliance due to the stiffness of poorly or nonaerated lung Pulm HTN 25% of pts, due to hypoxic vasoconstriction, Vascular compression by positive airway compression, airway collapse and lung parenchymal destruction

 Pts are critically ill

develop rapidly worsening tachypnea, dyspnea, hypoxia requiring high conc of O2 Occurs within hours to days ( usually12-48 hours) of inciting event Early clinical features reflects precipitants of ARDS Physical exam shows cyanosis, tachycardia, tachypnea and diffuse rales and other signs of inciting event

ARDS Clinical

Chest X-ray:

Bilateral pulmonary infiltrates, diffuse, symmetric or asymmetric, evolve rapidly, with maximal severity within the first 3 days Initially, the infiltrates may have a patchy peripheral distribution but soon progress to diffuse bilateral involvement with ground glass changes or frank alveolar infiltrates For patients who begin to improve and show signs of resolution, improvement in radiographic abnormalities generally occurs over 10-14 days

CXR
During the exudative phase, chest radiographs reveal a progression from diffuse interstitial infiltrates to diffuse, fluffy, alveolar opacities . Although ARDS cannot reliably be distinguished from cardiogenic pulmonary edema on radiologic grounds, patients with ARDS often lack cardiomegaly, pleural effusions, and vascular redistribution. Reticular opacities may ensue, suggesting the development of interstitial fibrosis.

 A representative anteroposterior (AP) chest x-ray in the exudative phase of ARDS that shows diffuse interstitial and alveolar infiltrates, which can be difficult to distinguish from left ventricular failure.

ARDS Clinical

Clinical evaluation and routine chest radiography are sufficient in patients with ARDS
More sensitive than plain chest radiography in detecting pulmonary interstitial emphysema, pneumothorax, pleural effusions, cavitations and mediastinal lymphadenopathy CT scanning in ARDS reveals extensive heterogeneity of lung involvement.

 CT SCAN SHOWS:

ARDS

ABGs:
Initial respiratory alkalosis acidosis If sepsis, metabolic acidosis initially Hematological Renal Hepatic Cytokines( TNF-L , IL1,1L6,1L8)

ARDS

Hemodynamic monitoring with pulmonary artery catheter. a) helpful in separating cardiogenic from non-cardiogenic PE

b) mixed venous oxygen saturation (shunt)

c) appropriate fluid management Arterial Line CVP Bronchoscopy with BAL or protected specimen brush culture

 Treat underlying medical&surgical illness

Sepsis, aspiration & pneumonia etc

Minimizing procedure & their complications

Adequate nutrition
Supportive care DVT prophylaxis GI prophylaxis Medications

ARDS Management

Perform early clinical determination of respiratory difficulty

Perform objective assessment with arterial blood gas and chest radiograph
Provide supplemental oxygen, monitor saturation and investigate risk factors for ARDS

Determine the need for intubation and mechanical ventilation

Use low tidal volume, low plateau pressure, lung protective ventilator strategies Optimize fluid status, nutrition, pulmonary toilet and treat complications Consider transfer to tertiary centers for clinical trials and advanced techniques

ARDS

1) Conventional ventilation(invasive ventilation): aim : a) maintain oxygenation and avoid toxicity O2 sat 85%-90% on FiO2 <65% b) avoid complications of mechanical ventilation

PEEP

(8.3-13.2 cmH2O)

Low tidal volume (6ml/kg): inspiratory pressure< 30mm H2O Maintain pH around normal (HCO3) Pressure control ventilation?? Inverse I:E ratio Permissive hypercapnia
Pressur support Pressure regulated volume control ( PaCO2<75mmHg, pH>7.2) (autoPEEP,heavy sedation)

} weaning

ARDS management..

Algorithm for the initial management of ARDS. Clinical trials have provided evidence-based therapeutic goals for a step-wise approach to the early mechanical ventilation, oxygenation, correction of acidosis and diuresis of critically ill patients with ARDS.

Contraindications : Diminished level of consciousness Inadequate cough Vomiting or upper gastrointestinal bleeding Inability to properly fit the mask Poor patient cooperation

Hemodynamic instability
Prone position

ARDS Management

Partial Liquid ventilation Nitric oxide (Inhaled) ECMO (extra corporeal membrane oxygenation) HFOV Lung protective strategies.
Prone position

Low tidal volume

ARDS Management

Steroids Inotropic agents Aerosolized exogenous surfactant

Antioxidants
Sedation Fluids ( conservative therapy )

5) Nutrition
6) Surgical care

CONVENTIONAL VENTILATION
o o o o o Oxygen PEEP Inverse I:E ratio Lower tidal volume Ventilation in prone position

PEEP - Benefits
o To prevent end-expiratory collapse and maintain the alveoli open throught respiratory cycle so it.. o Increases transpulmonary distending pressure o Displaces edema fluid into interstitium o Decreases atelectasis o Decrease in right to left shunt o Improved compliance o Improved oxygenation

Prone Position
o o o o o Improved gas exchange More uniform alveolar ventilation Recruitment of atelectasis in dorsal regions Improved postural drainage Redistribution of perfusion away from edematous, dependent regions

Pressure-controlled Ventilation (PCV)

o Time-cycled mode o Approximate square waves of a preset pressure are applied and released by means of a decelerating flow o More laminar flow at the end of inspiration o More even distribution of ventilation in patients with marked different resistance values from one region of the lung to another

Pressure-controlled Inverse-ratio Ventilation

Conventional inspiratory-expiratory ratio is reversed (I:E 2:1 to 3:1) Longer time constant Breath starts before expiratory flow from prior breath reaches baseline auto-PEEP with recruitment of alveoli o Lower inflating pressures o Potential for decrease in cardiac output due to increase in MAP o o o o

Partial Liquid Ventilation (PLV)

o Ventilating the lung with conventional ventilation after filling with perfluorocarbon o perfluorocarbon o 20 times O2 and 3 times the CO2 solubility o Heavier than water o Higher spreading coefficient o Studies in animal models suggest improved compliance and gas exchange

High Frequency Oscillating Ventilator (HFOV)

o o o o Raise MAP Recruit lung volume Small changes in tidal volume Impedes venous return necessitating intravascular volume expansion and/or pressers

High Frequency Oscillating Ventilator (HFOV)

o In patients with potentially reversible underlying diseases resulting in severe acute respiratory failure that is unresponsive to conventional ventilation, high frequency ventilation improves gas exchange in a rapid and sustained fashion. o The magnitude of impaired oxygenation and its improvement after high frequency ventilation can predict outcome within 6 hours.

 Often used to help evaluate for cardiogenic pulmonary edema SUPPORT trial (retrospective study) first raised doubts about utility Two multicenter RCTs confirmed lack of mortality benefit of PA catheters in ARDS (ARDSnet FACTT) Monitoring CVP equally effective, so PAC not recommended in routine management

 861 patients randomized to Vt 10-12 mg/kg ideal body weight and plateau pressure 50cmH2O vs. Vt 6-8 mg/kg IBW and plateau pressure 30cm H2O
KEYS
Low tidal volumes 6-8mL/kg ideal body weight
Maintain plateau (end-inspiratory) pressures <30cm H20 Permissive hypercapnia and acidosis

Decreased mortality by 22%, increase ventilator free days.

 Titrate PEEP to decrease FiO2

Goal sat 88% with FiO2 <60%
Minimize oxygen toxicity

PEEP can improve lung recruitment and decrease end-expiratory alveolar collapse (and therefore right-to-left shunt) Can also decrease venous return, cause hemodynamic compromise, worsen pulmonary edema

ARDSnet PEEP trial of 549 patients show no difference in mortality or days on ventilator with high vs low PEEP

 Agents studied:
Corticosteroids Ketoconazole

Inhaled nitric oxide

Surfactant

No benefit demonstrated

 Earlier studies showed no benefit to early use steroids, but small study in 1990s showed improved oxygenation and possible mortality benefit in late stage
ARDSnet trial (Late Steroid Rescue Study LaSRS lazarus) of steroids 7+ days out from onset of ARDS 180 patients enrolled, RCT methylprednisolone vs placebo Overall, no mortality benefit
Steroids increased mortality in those with sx >14 days

 Ketoconazole
ARDSnet study of 234 patients, ketoconazole did NOT decrease mortality, duration of mechanical ventilation or improve lung function

Surfactant
Multicenter trial, 725 patients with sepsis-induced ARDS, surfactant had no effect on 30-day survival, ICU LOS, duration of mechanical ventilation or physiologic function

Inhaled Nitric oxide

177 patients RCT, improved oxygenation, but no effect on mortality of duration of mechanical ventilation
.

 Dry lungs are happy lungs

ARDSnet RCT of 1000 patients Conservative vs liberal fluid strategy using CVP or PAOP monitoring to guide, primary outcome: death. Conservative fluids
Improved oxygenation More ventilator-free days More days outside ICU No increase in shock or dialysis No mortality effects

ARDS

1) Related to ventilation :

(a) barotrauma
(i) pneumothorax (ii)pneumomediastinal

(b) subglottic stenosis 2) Related to IV lines and catheters : (a) sepsis (b) pneumothorax

3) Nosocomial infection- a significant potential complication 4) Renal failure : frequent complication 5) GI : illeus, stress gastritis 6) Anemia 7) Critical illness myopathy

ARDS

Recent Mortality 40%-61 %

Death mostly due to sepsis or MOF accounting for > 80% May be improving, as mortality in more recent studies in range 30-40% Nonetheless survivors report decreased functional status and perceived health 79% of patients remember adverse events in ICU
29.5% with evidence of PTSD

ARDS Prognosis

Advanced age(>75yrs have ~60% mortality vs <45 have~20% mortality Chronic liver disease , cirrhosis & alcohol abuse MOF ,Sepsis Chronic renal disease Chronic immunosuppression Increased APACHE Elevated levels of PCP-III (marker of pulmonary fibrosis in the BAL fluid) Early elevation in dead space
( within 24h of presentation)

 Extent of hypoxemia
The level of PEEP used in mechanical ventilation The respiratory compliance

Extent of alveolar infiltrates on chest radiography

Lung injury score

Functional Recovery in ARDS Survivors

The severity of hypoxemia at the time of diagnosis does not correlate with survival rates Radiographic abnormalities completely resolve within a year of recovery Patient usually recover their maximum lung function within 6 month. Survivals usually achieve a good functional status, though some pulmonary dysfunction and slightly decreased activity of life is common after one year of discharge from hospital Severe disease and prolonged duration of mechanical ventilation are predictors of persistent abnormalities in pulmonary

EVIDENCE-BASED RECOMMENDATIONS FO ARDS THERAPIES

ecommendation

Low tidal volume High PEEP or open lung prone position Recruitment maneuvers

A C C C

high frequency ventilation and ECMO

Minimize left atrial filling pressures Glucocorticoids B C

Surfactant replacement, inhaled nitric oxide, and other anti-inflammatory therapy (e.g.., ketoconazole,PGE1,NSAIDs)

A-recommended therapy based on strong clinical evidence from randomized clinical trials Brecommended therapy based on supportive but limited clinical data C-indeterminate evidence recommended as alternative therapy D-not recommended based on clinical evidence against efficacy of therapy

 ARDS is a clinical syndrome characterized by severe, acute lung injury, inflammation and scarring
Significant cause of ICU admissions, mortality and morbidity

Caused by either direct or indirect lung injury

Mechanical ventilation with low tidal volumes and plateau pressures improves outcomes So far, no pharmacologic therapies have demonstrated mortality benefit Ongoing large, multi-center randomized controlled trials are helping us better understand optimal management