Presented by Dr.

Kunal Lala

 Severe,

acute lung injury involving diffuse alveolar damage, increased microvascular permeability and non cardiogenic pulmonary edema Acute refractory hypoxemia Annual incidence 75/100,000 in the US High mortality- 40%-60% First described in 1967

 Acute

onset of respiratory failure Bilateral infiltrate on CXR PAOP (Formerly PCWP) <18 or absence of left atrial htn, PaO2/FiO2 < 200 (Pao2/Fio2 <300 signifies ALI)

Direct Lung Injury:

a) Pneumonia (puemocystic carinii, h.infuenzae, falciparum) b) Aspiration of gastric contents (Mendelsons syndrome) c) near drowning d) Pulmonary contusion,penetrating lung injury e) inhalation injury (toxic chemicals) f) reperfusion pulm edema after lung transplant g) pulmonary embolism- air embolism, fat embolism, amniotic fluid embolism

 Indirect

lung injury

a) sepsis b) severe trauma w/ shock hypoperfusion c) drug over dose d) cardiopulmonary bypass e) acute pancreatitis f) multiple blood transfusions

 1.

Exudative (acute) phase 0- 7 days 2. Proliferative phase 7 21 days 3. Fibrotic phase - >21 days

Exudative Stage Activation of inflammatory mediators and cellular components resulting in damage to capillary endothelial and alveolar epithelial cells Tight normal alveolar barrier disrupted Influx of protein rich edema fluid and inflammatory cells into air spaces Dysfunction of surfactant & pulmonary vascular injury

Proliferative phase Beginning of recovery Most pts. get relieved of MV in this phase Signs of lung recovery occur organisation of alveolar exudates, shift from neutrophil to lymphocytes, proliferation of type 2 pneumocytes Early fibrotic changes begin

Fibrotic phase Edema of early stage & inflammatory exudates get converted to extensive alveolar ducts and interstitial fibrosis Architecture disruption leading to emphysematous changes and large bullae formation Fibro-proliferation in pulm. micro circulation leads to PAH

CBC, RFT, LFTs, Pancreatitic enzymes, Electrolytes - ABG - Blood cx, urine cx - BNP (low BNP may point to ARDS) - TTE/TEE - CXR - CT (Heterogenesity in lung Invmt.) - Bronchoscopy/BAL - CVP, PCWP - CRP
-

 Factors

whose presence can be used to predict the risk of death at the time of diagnosis of acute lung injury and the acute respiratory distress syndrome include a)chronic liver disease b)non-pulmonary organ dysfunction, c)sepsis, d)advanced age.

 patients

with ALI/ARDS at 10 centers, 861

patients Patients randomized to tidal volumes of 12 mL /kg or 6 ml/kg(volume control, assist control, plat Press = 30 cm H2O) 22% reduction in mortality in patients receiving smaller tidal volume

 Tidal

Volume
rate

PaCO2 Respiratory PaO2/FIO2 Plateau PEEP

6ml/kg 43 12 30 7 160 68 26 7 9.2 3.6

12ml/kg 36 9 17 7 177 81 34 9 8.6 4.2

pressure

 Calculated

predicted body weight(pbw) male: 50+2.3[height(inches)-60] female: 45.5+2.3[height(inches)-60] Mode: Volume assist-control Change rate to adjust minute ventilation(not>35/min) PH goal 7.30-7.45 Plateau press<30cm h20 PaO2 goal: 55-80mmhg or SpO2 88-95% FiO2/PEEP combination to achieve oxygenation goal.

 PEEP/FiO2

relationship to maintain adequate

PaO2/SpO2 PaO2 goal: 55-80mmHg or SpO2 88-95% use FiO2/PEEP combination to achieve oxygenation goal
FIO2 PEEP
0.3 5 0.4 5 0.4 8 0.5 8 0.5 10 0.6 10 0.7 10 0.7 12 0.7 14 0.8 14 0.9 14 0.9 16 0.9 18 1.0 2024

 Greatest

Lung strain PC IRV(I:E 2:1), least w/ PC (I:E 1:2) and intermediate w/ VC (I:E 1:2) No difference in gas exchanged, hemodynamics, and plateau pressure No difference in outcome w/ ARDS pts randomized to pressure control vs volume cycled PC(n=37), VC(n=42).
Edibam et al Am J Resp Crit Care Med 2003 Esteban et al , Chest 2000

 Low

Vt (6ml/kg) to prevent overdistention Increase respiratory rate to avoid very high level of hypercapnia PaCO2 allowed to rise Usually well tolerated May be beneficial Potential Problems: tissue acidosis, autonomic dysregulation, CNS effect, and circulatory effects

120pts randomized to low Vt or high Vt a) 25%mortality w/ low tidal volume b) 45% mortality w/ high tidal volume 20% had restricitve defect and 20% had obstructive defect 1 yr after recovery About 80% had DLCO reduction 1 yr after recovery Standardized tested showed health-related quality of life lower than normal No difference in long-term outcomes between tidal volume group
Orme Am J respir Crit Care Med 2003

 Total-2786

pts. Non-septic pts. Included trauma,aspiration,multiple tyransfusion etc. Results: sepsis related ards more common in women, diabetes and had higher apache-III score & <PaO2/FiO2 compared to non septic group Conclusion: Increased 60 day mortality and lower successful extubation rate in sepsis associated ards.

Chau-Chyun Sheu, MD, David C. Christiani, MD, FCCP and others.

 ARDS

Net ALVEOLI Trial Canadian LOVS Trial European Express Trial Aggressive PEEP to maximize oxygenation and lung mechanics Vs. Conservative PEEP- minimal amount required to provide adequate oxygenation Conclusion: No extra benefit with high PEEP group compared to conservative PEEP group.

 By

ARDS net Conservative Fluid management therapy associated with Improved lung function and decreased duration of mechanical ventilation

Two meta analysis of short course (< 48hr) of high dose methyl pred. (30mg/kg/d) in early sepsis and ARDS found no evidence of beneficial effects.
- LEFERING et al CCM 1995, CRONIN l et al., CCM 1995

In a Recent Randomized control trial prolonged administration of methyl pred. in patients with unresolving ARDS was a/w improved LIS, MODS, mortality
JAMA 1998 Vol. 280 ; 159 165.

Randomized double blind, placebo controlled trial 24 pat. with severe ARDS who failed to improve LIS by 7th day of mech. ventil. 16 received methyl pred. while 8 rec. placebo 4 pat. whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to alternate treatment.

SIGNIFICANT IMPROVEMENT IN : LIS (1.7 v 3.0) Pao2/Fio2 (262 v 148) MODS score (.7 v 1.8) Successful Extubation (7 v 0) mortality (0 v 62 %) No signif. differences in nosocomial episode PROTOCOL
Day (mg/kg/d) 1-14 15-21 22-28 29-30 31-32 2.0 1.0 0.5 0.25 0.125 Dose (Methy. Pred.)

HOW STEROIDS ARE BENEFICIAL : i. Inhibit transcriptional activation of various cytokines. ii. Inhibit synthesis of phospholipase A2 : cycloxygenase. iii. Reduced prod. of prostanoids, PAF iv. fibrinogenesis

 Research

paper produced in Indian Society of Critical Care Medicine by M.S Hari, A.Trikha, R. Madan, H.L Kaul Responders were who showed a impv. In PaO2/FiO2 by 15% and decrease in PASP by 15% Optimum dose of NO in ARDS is 3-10ppm PaO2 impv. was independent of Pulmonary haemodynamic changes Comparision to other studies: Treggiari and Venzi et al. and Lowson et al. showed optimum dose at 10ppm. Bigatellow and Rossaint at al. showed a dose dependent improvement in PaO2/FiO2

Rh GM-CSF used to stimulate leucocyte production from bone marrow. Originally obtained from lung tissue Initial research shows its role in Surfactant homeostasis and Alveolar Macrophage function Administration can lead to Better lung repair and lung immunity Treatment trial to see reduction in mechanical ventilation is going on in University of Michagan Health System, Ann Arbor, Michagan
Paine R III, Morris SB, Jin H, et al. Impaired functional activity of alveolar macrophages from GMCSF-deficient mice. Am J Physiol Lung Cell Mol Physiol. 2001;281:L1210-L1218. Paine R III, Wilcoxen SE, Morris SB, et al. Transgenic overexpression of granulocyte macrophagecolony stimulating factor in the lung prevents hyperoxic lung injury. Am J Pathol. 2003;163:23972406

In ARDS Fibrin deposition intra-alveolar and interstitial. Local procoagulant activity and reduced fibrinolysis. Procoagulant Fibrinolysis TF (VIIa) Fibrinolytic inhibitors PAI1 ; PAI-2,

alfa-2 antiplasmin
urokinase and tPA

1) 2) 3) 4) 5) 6) 7)

Fibrin Inhibit surfactant atelactasis + Fibrinonectin Matrix on which fibroblast aggregate +N Fibroblast proliferation Potent chemotactic (Neutrophil recruitment) Lung vasculature PAH Heparin- showed impvt. in animal studies. Human data lacking Antithrombin 3 Kybersept trial, 2314 pat. with severe sepsis No reduction in 28 days all cause mortality but excess rate of bleeding events in pat. receiving concomitant heparin prophylaxis.

nactivates Va & VIIa limit thrombin generation. ii) Inhibit PAI-1 activity - fibrinolysis. iii) Anti-inflam. - cytokines, inhibit apoptosis. In the PROWESS study APC administ. Improved survival. 28 days absolute risk reduction in mortality 6.1%. 19.4% reduction in relative risk. Risk of bleeding (3.5% vs 2.0%) Faster resolution of respiratory dysfun. ventilatory free days (14.3 vs 13.2 days) Administration of rh activated protien-c may be helpful in sepsis related ards. Trial going on by University of California, San fransisco
i)
Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709.

 Decreases

airway resistance Decreases pulmonary edema beta cell receptor stimulation leads to Na-K ATPase pump activation and basolateral alveolar epithelial cells decreases odema.
McAuley DF, Frank JA, Fang X, Matthay MA. Clinically relevant concentrations of beta2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury. Crit Care Med. 2004;32:1470-1476

Albumin plus Furosemide therapy Helpful in Hypo-oncotic ALI patients Partly due to antioxidant activity Further study required

Martin GS, Mangialardi RJ, Wheeler AP, Dupont WD, Morris JA, Bernard GR. Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med. 2002;30:2175-2182.
Quinlan GJ, Mumby S, Martin GS, Bernard GR, Gutteridge JM, Evans TW. Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury. Crit Care Med. 2004;32:755-759.

Prostaglandins Extracorporeal oxygen therapy- No mortality benefit Prone ventilation- difficult, requires specialization found to improve oxygenation, mortality benefit unknown Surfactant replacement therapy beneficial if used within 48 hrs- delayed benefits none- mortality benefits none Mitogen for type-II pneumatocyte (enhanced repair) 1. Hepatocyte growth factor 2. Keratinocyte growth factor.

 Measurement

of c-reactive protein within 48hrs of onset of disease Higher levels were associated with increased survival, low organ failure scores and decreased mechanical ventilation

Ednan K. Bajwa, MD, MPH, Uzma A. Khan, MD James L. Januzzi, MD,Michelle N. Gong, MD, MS,B. Taylor Thompson, MD and David C. Christiani, MD, MPH, FCCP

Treatment strategy is one of low volume and high frequency ventilation(ARDSNet protocol) Search for and treat the underlying cause Ensure adequate nutrition and place on GI/DVT prophylaxis Prevent and treat nosocomial infx Consider short course of high dose steroids in pts w/ severe dzthat is not resolving.

THANK YOU

Parameter Finding Value Rx.Torax Hypoxemia no alveolar consolidation 0 PaO2/FIO2 > 300 0 alveolar consolidation de 1 quadrant 1 PaO2/FIO2 225 - 299 1 alveolar consolidation de 2 quadrant 2 PaO2/FIO2 175 - 224 2 alveolar consolidation de 3 quadrant 3 PaO2/FIO2 100 - 174 3 alveolar consolidation de 4 quadrant 4 PaO2/FIO2 < 100 4 PEEP Compliance PEEP <= 5 cm H2O 0 compliance >= 80 mL/cm H2O 0 PEEP 6 - 8 cm H2O 1 compliance 60 - 79 mL/cm H2O 1 PEEP 9 - 11 cm H2O 2 compliance 40 - 59 mL/cm H2O 2 PEEP 12 - 14 cm H2O 3 compliance 20 - 39 mL/cm H2O 3 PEEP >= 15 cm H2O 4 compliance <=19 mL/cm H2O 4

0 score 0: no lung injury score 0.1 - 2.5: mild-to-moderate lung injury score > 2.5: severe lung injury (ARDS)