Dr. AKHILESH.K M.DAssistant Professor

Pulmonary MedicineAIMS,KOCHI

Direct insultCommon

Aspiration pneumonia

Pneumonias

Less common

Inhalation injury

Pulmonary contusions

Fat emboli

Near drowning

Reperfusion injury

Indirect insultCommon

Sepsis

Severe trauma

ShockLess common

Acute pancreatitis

Cardiopulmonary bypass

Transfusion-related

Disseminated

intravascular coagulation

Burns

Drug overdose

Insult (direct or indirect)

Activation of inflammatory cells

& mediators

Damage to alveolar capillary membrane

Increased permeability of alveolar capillary membrane

Influx of protein rich edema fluid and inflammatory cells into air spaces

Dysfunction of surfactant

Causative Factors in ARDS

PRIMARY

INJURY

HOST

RESPONSE

CONSEQUENCES

OF THERAPY

1

• TREATMENT OF CAUSE

• e.g. antibiotics for pneumonia

2

• SUPPORTIVE THERAPY (5P’s)

• Perfusion, Position, Protective lung ventilation, Protocol

weaning, Preventing complications

3

• PHARMACOLOGICAL TREATMENT

• Steroids, vasodilators, surfactant, anti inflammatory

Fluid and hemodynamic management

Prone positioning

ECMO/ECCO2 removal

Pharmacotherapy

ARDS characterised by increased alveolar-capillary permeability

Increased extravascular lung water with secondary consequences◦ Decreased compliance – increased WOB

◦ Increased shunt and worsening gas exchange

◦ Pulmonary hypertension

Strategies to limit pulmonary edema and accelerate its resorption◦ Limited evidence on therapeutic benefit

Compared a liberal Vs conservative fluid management strategy in ALI / ARDS subjects

Simultaneously compared PAC versus CVC based fluid management

Used a complex 2*2 factorial table design Studied the effect on mortality, gas exchange, organ

failure and need for MV

N Eng J Med 2006; 354: 2564-75

Used four basic input varaiables except in

shock or in patients on vasopressors for guiding management instructions

MAP

Urine Output

Effectiveness of circulation

Intravascular pressures(CVP or PAOP)

OUTCOME:

No significant difference in 60 day mortality between conservative (25.5%) and liberal (28.4%) strategy

More ventilator free days in conservative strategy(14.6+-0.5 Vs 12.1 +-0.5)

Decreased ICU stay (13.4+-0.4 Vs 11.2+-0.4)

Did not worsen incidence of shock , number of days in shock, Organ failures, rate of use of dialysis

CVC is better for monitoring as PVC is associated with more complications rate

CVP(mm of

Hg)

PAOP(Optional)

Average Urine Output

< 0.5 ml/kg/hr

Average Urine Output

> 0.5 ml/kg/hr

(MAP should be > 60 mm and subject should not be needing vasopressorsfor last 12 hours)

> 8 > 12 FrusemideReassess in 1 hour

FrusemideReassess in 4 hours

4 - 8 8 - 12 Fluid bolus as fast as possibleReassess in 1 hour

FrusemideReassess in 4 hours

< 4 < 8Fluid bolus as fast as possible

Reassess in 4 hours

No interventionReassess in 4 hours

Chest 2007; 131; 913-920

Start off with 20 mg bolus and 3 mg/hr infusion (or last known effective dose)

Double each subsequent dose until goals achieved(intravascular pressure target or reversal of oliguria)

Maximum dose of 160 mg bolus and 24 mg/hr infusion

Maximum daily dose 620 mg

May add dobutamine if subject has heart failure

Avoid diuretic therapy if patient has renal failure or dialysis dependence

(Oliguria with s.creatinine > 2mg/dl or other urinary indices of ARF)

Improves oxygenation without improving overall outcome

Critical Care 2011, 15:R125

Concept: To give rest to the lung and let them get recovered from the injury by using extracorporeal gas exchange temporarily

No significant difference between

conventional and ECCo2 removal method

Used in severe lung disease which warrant

high flow ECMO with full support of oxygenation and CO2 removal

Reliance on patient’s lung to provide oxygenation at high airway pressure eliminate the possibility of “Lung rest”

Deliver fresh gas(4-8 L/ mt) through a modified ET tube

at a point just above carina.

This additional gas remove CO2 rich gas from trachea

and smaller airways there by reduce anatomic dead

space.

: Tracheal erosions,O2 toxicity ,hemodynamic

instability,barotrauma

TGI improves PCO2 but no significant change in PaO2.No

change in airway pressure and hemodynamic variables

in ventilated patients(Chest 1995; 107:1416-19)

May be tried

Beneficial

UselessLate usage

harmful

Use early, low dose, infusion

Chest 2007; 131: 954–963

N Engl J Med 2006;354:1671-84

JAMA 1998; 280: 159-65

Multiple Early Works

Except for glucocorticoids, no pharmacologic therapy has yet been shown to

decrease the mortality of ARDS independent of treating the

underlying cause

Crit Care Clin 2011; 27; 589–607

Paul E. Marik, G. Umberto Meduri, Patricia R.M.Rocco, Djillali Annane

Early Steroid therapy (≤ 3 d of mechanical ventilation)

appeared more strongly associated with mortality than

late administration. Patients receiving steroids had more

acquired pneumonia and a trend to a longer duration of

ventilation. Ajrccm Vol. 183, No. 9 (2011), pp. 1200-1206.

Inflammation is central to the pathogenesis of ARDS

Persisting inflammation has a role in progressive ARDS

Steroids have effects and multiple sites of the inflammatory pathway

CIRCI occurs in ARDS

Predispose to infections; delayed recognition

Inappropriate glycemic control

Neuromuscular weakness and GI bleed

Suppression of endogenous cortisol; rebound inflammation

Unequivocally beneficial in steroid responsive ARDS etiologies◦ AIP

◦ PCP

Steroids may be beneficial in early ARDS

Small dose infusion of methyl prednisolone

Prolonged tapering

Aggressive surveillance for infection

Trophic feeding (20 Kcal/hr )Vs full enteric feeding(80 kcal/hr) for 6days in 1000 patients of newly diagnosed ARDS without obviousmalnutrition.

Despite the full enteric feeding group receiving many more calories(1300 kcal/day vs 400), there were no differences in important clinical outcomes (ventilator- free days at 28 days, 60 day mortality, or

infections).

Those receiving full enteric feedings had more gastrointestinal intolerance

Draw back: Duration of study was too short for a definitive conclusion for adverse events. Larger studies needed

Conclusion: Trophic feeding equal to full enteral feedingBut SCCM and canadian critical care society advise full enteral feeding whenever

possible

Many of the patients enrolled For trophicfeeding group enrolled in Omega trial.

Found out that Omega 3 fatty acid is not helping ; even harm full , increase mortality

Abandoned mid way.

Statins reduce healthy volunteers’ inflammatory response to

inhaled or injected lipopolysaccharide.

80 mg of simvastatin or placebo to 60 patients with ARDS, for up to 14 days.

There were no differences in mortality (30%), ventilator-free days or ICU/hospital stay.

one-third of the treated group who were left to analyze after 14 days had significantly lower SOFA organ dysfunction scores.

They also had a non-statistically significant improvement in hemodynamics at day 14 (0 of 9 [simvastatin] vs. 3-4 of 10 [placebo]

requiring vasopressors or inotropes, p=0.05-0.09)

Significantly lower IL-8 in BAL fluid. No adverse events were noted. Larger trials are underway to explore this further.(n=60).

Patients with High GM CSF in BAL fluid have more Survival

GM CSF maintains homeostasis in lung, maturation of alveolar macrophage, growth of Alveolar epithelial cell ;the cell got destroyed in ARDS

Did not increase ventilator free days

No Statistically significant difference in 28 day mortality between GM CSF group and placebo group.

Paine R 3d et al. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med 2012;40:90-97.

Surfactant of possible therapeutic use :

Class Origin Example

1. Natural Amniotic Human amniotic fluid surfactant

2. Modified - Bovine Infasurf, alveofact

Natural BLESS, Survanta

- Procine Curosurf

3. Synthetic Exosurf, ALEC, KL4

Surfactant, Venticute

DOSE

Sufficient dose should reach alveolar environment

TIMING

• As early as possible [<48 hr]

• Little benefit at 3 to 5 days [Fibrosis already set]

SURFACTANT REPLACEMENT Improved lungs function , compliance , oxygenation.

Surfactant in infants with RDS is found to be

effective in improving gas exchange, decrease C- PAP requirement, lessen barotrauma and increased survival

In adults Surfactant therapy trials are having disappointing results.

AJRCCM 2011;183:1055-1061.

Inhaled NO selectively vasodilates pulmonary vessels that

subserve ventilated alveoli , divert blood flow to these alveoli

and away from areas of shunt

Lower PVR,PAP

Does not improve survival , only transient improvement in

oxygenation, costly.

Inhaled prostacyclin – Less costly . May improve oxygenation

as much as inhaled NO

(Chest 1995; 107:1107-15)

Stimulate removal of fluid from flooded alveoli by

stimulating sodium pump and promote transport of Na+

out of alveoli

BALT1 trial(2006): iv Albuterol in ARDS reduced their

plateau pressures by 6 cm H2O

Seemed to substantially reduce their “lung water”

(measured by thermodilution)

Increased rate of Supraventricular arrythmias

BALT2 Trial( 2012):Continuous infusion of iv salbutamol

or placebo for 7 days.Increased mortality in B agonist

group( 34% Vs 23%)

Smith FG et al. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012;379:21-27.

ARDS Net folks randomized 282 patients with ARDS to

receive either 5 mg of nebulized albuterol or placebo

every 4 hours for 10 days (or until 24 hours after being

extubated).

The trial was stopped early

There was no difference in the number of ventilator-free

days (1′ endpoint), nor in survival to hospital discharge

(2′ endpoint).

Attempts to elevate the intravascular oncotic pressure

Decreases transudation into pulmonary interstitium

Mobilises EVLW into circulation

Can worsen intravascular volumes

Combined with diuretics

37 mechanically ventilated subjects

Serum proteins < 5 g/dl

Albumin(25%) 25 grams Q 8 hourly with continuous infusion of frusemide for 5 days◦ targeted to diuresis, weight loss and

serum proteins

No mortality benefit

Improvement in P/F ratio, diuresis and weight loss, duration of MV

Cost effectiveness questionableCrit Care Med 2002: 30: 2175-2182

Retrospective matched, case control studySubjects with ALI and elevated IAP

Treated with high PEEP, hyperoncotic albumin and frusemide

http://www.annalsofintensivecare.com/content/2/S1/S15

Not an RCTHuge diuretic doses

Huge magnitude of difference - ? Biological plausibility

Control group - ? Standard therapyMultiple interventions - ? synergistic

Basic understanding about thepathogenesis is essential indeveloping newer strategiesfor management of ARDS

Most of The trials in nonventilatory strategies giveconflicting results

practical use of thesemodalities are controversial

Cost effective strategies suitable to resource poor

countries need to be developedto apply them in practical use