Acute Lung Injury and Adult Respiratory Distress Syndrome Marco Ranieri, MD Full Professor of...

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Acute Lung Injury and Adult Respiratory Distress Syndrome

Marco Ranieri, MDFull Professor of Anesthesiology

Department of Anesthesiology and Intensive Care Unit

University of Turin, S.Giovanni Battista Hospital, Turin,Italy

Cesare Gregoretti, MDChief of Anesthesiology and Intensive Care Unit,

M.Adelaide HospitalDepartment of Emergency and Anesthesiology CTO , Turin Italy

Slide 3

NAECC Definition

• The 1994 North American-European Consensus Conference (NAECC) criteria:

– Onset - Acute and persistent

– Radiographic criteria - Bilateral pulmonary infiltrates consistent with the presence of edema

– Oxygenation criteria - Impaired oxygenation regardless of the PEEP level, with a Pao2/Fio2 ratio 300 torr (40 kPa) for ALI and 200 torr (27 kPa) for ARDS

– Exclusion criteria - Clinical evidence of left atrial hypertension or a pulmonary-artery catheter occlusion pressure of 18 mm Hg.

Bernard GR et al., Am J Respir Crit Care Med 1994

Slide 4

NAECC Definition Limitations

• Permits inclusion of a multiplicity of clinical entities ranging from autoimmune disorders to direct and indirect pulmonary injury

• Does not

– address the cause of lung injury

– provide guidelines on how to define acute

– radiological criteria are not specific

– account for the level of PEEP used

– specify the presence of nonpulmonary organ system dysfunction

– include the pathways involved in producing lung injury

Atabai K and Matthay MA, Thorax 2000Abraham E et al., Crit Care Med 2000

Slide 5

Definition Updates

• Epidemiologic data based on the1994 NAECC definitions

• Assess severity of ALI/ARDS using scoring systems (e.g., Lung Injury Score (LIS), APACHE III or SAPS II)

• Review factors affecting prognosis

• Record:

– Etiology

– Mortality - cause and if death due to withdrawal of care

– Failure of other organs and covariates

– Follow-up information - recovery of lung function and quality of life

Artigas A et al., Am J Respir Crit Care Med 1998

Slide 6

ALI Stratification System (GOCA)

LetterLetter MeaningMeaning ScaleScale DefinitionDefinition

G

Gas exchange

Gas exchange

(to be combined with the numeric descriptor)

0

1

2

3

A

B

C

D

Pao2/Fio2 301

Pao2/Fio2 200 -300

Pao2/Fio2 101 – 200

Pao2/Fio2 100

Spontaneous breathing, no PEEP

Assisted breathing, PEEP 0-5 cmH2O

Assisted breathing, PEEP 6-10 cmH2O

Assisted breathing, PEEP 10 cmH2O

O Organ failure

A

B

C

D

Lung only

Lung + 1 organ

Lung + 2 organs

Lung + 3 organs

C Cause

1

2

3

Unknown

Direct lung injury

Indirect lung injury

A Associated diseases

0

1

2

No coexisting disease that will cause death within 5 yr

Coexisting disease that will cause death within 5 yr but not within 6 mo

Coexisting disease that will cause death within 6 mo

Artigas A, et al. Am J Respir Crit Care Med. 1998.

Slide 7

Epidemiology

• 1972 NIH ARDS (US): approximately 150,000 cases/yr

• 1989 - 2002 International multi-center ALI/ARDS cohort studies estimates of ALI/ARDS = 1.3 to 22 cases per 105 person.years

• 2003 ARDS Network Study incidence of ALI/ARDS in the US: 32 cases per 105 person.years (range 16 - 64)

• 2003 ARDS Network Study average number of cases of ALI per ICU bed per year (2.2) varied significantly from site to site (range 0.7 - 5.8)

Goss CH et al., ARDS Network, Crit Care Med 2003

Slide 8

ALI / ARDS Associated Disorders

Direct insult

Common• Aspiration pneumonia• Pneumonia

Less common• Inhalation injury• Pulmonary contusions• Fat emboli• Near drowning• Reperfusion injury

Indirect insult

Common• Sepsis• Severe trauma • Shock

Less common• Acute pancreatitis• Cardiopulmonary bypass• Transfusion-related TRALI• Diffuse intravascular coagulation-DIC • Burns• Head injury• Drug overdose

Atabai K, Matthay MA. Thorax. 2000.Frutos-Vivar F, et al. Curr Opin Crit Care. 2004.

Slide 9

Clinical Risk Factors

• Independent preditors with high mortality rates

Severity of the illness

Non-pulmonary organ dysfunction

Comorbid diseases

Sepsis

Liver dysfunction/cirrhosis

Age

• Other preditors

Late ARDS (>48 hrs after MV)

Organ Transplantation

HIV infection

Malignancy

Mechanisms of lung injury

Barotrauma

Right Ventricular dysfunction

High FiO2Atabai K, Matthay MA. Thorax. 2000.Ware LB. Crit Care Med. 2005.Ferguson ND, et al. Crit Care Med. 2005.

Slide 10

Plasma Biologic Markers

• Acute inflammation

• Endothelial injury

• Epithelial type II cell moleccules

• Adhesion molecule

• Neutrophil-endothelial interaction

• Procoagulant activity

• Fibrinolytic activity

Interleukin (IL-6, IL-8)

Von willebrand factor antigen

Surfactant protein-D

Intercellular adhesion molecule-1 (ICAM-1)

Soluble tumor necrosis factor receptors I and II (sTNFRI/II)

Protein C

Plasminogen activator inhibitor

Ware LB. Crit Care Med. 2005.

Slide 11

Mortality

• ARDS mortality - 31% to 74% (variability due to differences in population and ARD definitions)

• Death is mainly due to nonrespiratory factors

• Respiratory failure - cause of death in 9% to 16% of patients

• Deaths (within 72 hrs) due to underlying illness or injury

• Deaths (after 72 hrs) due to sepsis or multiorgan dysfunction

• Controversy around role of hypoxemia as a prognostic factor in adults. Some studies indicate both Pao2/Fio2 ratio and Fio2 were variables independently associated to mortality.

Frutos-Vivar F, et al. Curr Opin Crit Care. 2004.Vincent JL, et al. Crit Care Med. 2003.Ware LB. Crit Care Med. 2005.

Slide 12

First year Survivor Outcomes

• Persistent functional limitation

– Extrapulmonary diseases (primarily): Muscle wasting and weakness (corticosteroid-induced and critical-illness-associated myopathy) Entrapment neuropathy

– Heterotopic ossification

– Intrinsic pulmonary morbidity (5%): Bronchiolitis obliterans organizing pneumonia

– Bronchiolitis obliteransHerridge MS, et al. N Engl J Med. 2003.

Slide 13

Depression and Memory Dysfunction in Survivors

• ARDS survivors report a high prevalence of depression symptoms and a lower prevalence of memory dysfunction 6 to 48 months after ICU discharge.

Adhikari NKJ, et al CHEST 2009; 135:678–687

Slide 14

The ARDS Lungs

• Increase in lung density from alveolar edema and inflammation predominates in cephalic parts of the lungs

• Loss of aeration predominates in caudal and dependent lung regions in patients lying supine

• Consolidated alveoli predominates in caudal and dependent lung regions in patients lying supine

Slide 15

The ARDS Lungs

ARDS Focal Patchy Diffuse

Chest x-ray

(zero PEEP)

Focal heterogeneous loss of aeration in caudal and dependent lung region

Bilateral and diffuse x-ray densities respecting lung

apices

Bilateral and diffuse hyperdensities

“White lungs”

Chest CT scan

(zero PEEP)

Loss of aeration

Upper lobes normally aerated despite a regional excess of lung

tissue – Lower lobes poorly or non aerated

Lower lobes massively nonaerated – The loss of

aeration involves partially the upper lobes

Massive, diffuse and bilateral non- or poorly aerated lung

regions – No normally aerated lung region

Response to PEEP±

PEEP <10-12 cmH2O

++++

Lung recruitment curve

Open lung concept

Risk of overinflation of the aerated lung regions

++++±

Recruitment of non aerated lung unit

Low potential for recruitment High potential for recruitment

Rouby JJ, et al. Eur Respir J. 2003.Rouby JJ, et al. Anesthesiology. 2004.

Slide 16

The ARDS Lungs

Early phases of ARDSDirect insult of the lung

Primary pulmonary ARDS

“Indirect” insult of the lung

Secondary extrapulmonary ARDS

Pathologic changes

Lung tissue consolidation

Severe intra-alveolar damage

(Edema, fibrin, collagen

neutrophil aggregates, red cells)

Microvascular congestion

Interstitial edema

Alveolar collapse

Less severe alveolar damage

End-expiratory lung volume EELV

Static elastance of the total respiratory system Est,rs

Static elastance of the chest wall Est,w / Static lung elastance Est,L / /

Intra-abdominal pressure

Response to PEEPEst,rs [Est,L >> Est,w]

Stretching phenomena

Est,rs [Est,L Est,w]

Recruitment of previously closed alveolar spaces

Lung recruitment ± ++++

Gattinoni L, et al. Am J Respir Crit Care Med. 1998.

Slide 17

Healthy subjectIn normal healthy volunteers, the P/V curve explore the mechanical properties of the respiratory system

(lung + chest wall)

ARDS

Maggiore SS, et al. Eur Respir J. 2003. Rouby JJ, et al. Eur Respir J. 2003.

Respiratory Pressure/Volume (P/V) Curve

Slide 18

Reinterpreting the Pressure/Volume Curve in ARDS

• Measurement of the P/V curve in any given patient is not practical clinically.

• A single inflation P/V curve probably does not provide useful information to determine safe ventilator settings in ALI.

• The P/V curve for the whole lung is a composite of multiple regional P/V curves (considerable variation from the dependent to the nondependent lung; LIP from 50 to 30 cmH2O respectively).

Kunst PW et al., Crit Care Med 2000

Slide 19

Ventilator-induced Lung Injury(VILI)

• Lung injury from:

– Overdistension/shear

– Mechanotransduction

– Repetitive opening/closing

– Shear at open/collapsed lung interface

• Systemic inflammation and death from:

– Release of cytokines, endotoxin, bacteria, proteases and related multiple systemic organs damage

atelectrauma

volutrauma

Slide 20

Ventilator-induced Lung Injury (VILI)

• Three different pathologic entities:

– High-permeability type pulmonary edema

– Mechanical over-inflation/distortion of lung structures

– Lung inflammation “Biotrauma”

Rouby JJ, et al. Anesthesiology. 2004.

Slide 21


• High-permeability type pulmonary edema

– End-inspiratory lung volume >> inspiratory pressure

– Mechanisms altering the alveolar-capillary barrier permeability during MV involve:

• Increased transmural vascular pressure

• Surfactant inactivation

• Mechanical distortion and disruption of endothelial cells

• Regional activation of inflammatory cells

Rouby JJ, et al. Anesthesiology. 2004.Ricard JD, et al. Eur Respir J. 2003.

Slide 22


• Mechanical overinflation/distortion of lung structures

– Enphysema-like lesions, lung cysts, and bronchiectasis

more predominant in nondependent and caudal lung regions

– The degree of overinflation is dependent on:

• Tidal volume

• Plateau airway pressure

• Duration of mechanical ventilation

• Time exposed to an Fio2 > 0.6

Rouby JJ, et al. Anesthesiology. 2004.

Slide 23


• Lung inflammation “biotrauma”

– Lung overinflation / overstretching produces regional and systemic inflammatory responses generating or amplifying multiple-system organ failure.

– Factors converting shear stress applied to an injured lung include:

• Repetitive opening and collapse of atelectatic lung units

• Surfactant alterations

• Overinflation of health lung regions

• Loss of alveolo-capillary barrier function and Bacterial translocation

Rouby JJ, et al. Anesthesiology. 2004.Dreyfuss D, et al. Am J Respir Crit Care Med. 2003.

Slide 24


Ranieri VM et al. JAMA 2000

Slide 25

Ventilator-induced Lung Injury

Terragni P , et al. Am J Respir Crit Care Med. 2007

STRESS AND STRAIN

PLVT

FRC= *Elspec

Barotrauma Volotrauma

,Chiumello et al, Am J Respir Crit Care Med., 2008

The linkage is the specific elastance


Slide 28


STRESS INDEX

Ranieri VM et al., Anesthesiology , 2000

Slide 29

Positive-pressure Mechanical Ventilation

• To date , the only therapy that has been proven to be effective at reducing mortality in ALI/ARDS in a large, randomized, multi-center, controlled trial is a protective ventilatory strategy.

• Based on early 1990 research data SCCM and ACCP recommended reduction in tidal volume and limiting end-expiratory plateau pressure to < 30 cm H20

Terragni P. et al. Am J Respir Crit Care Med 2007


The best ventilatory strategy should be ideally adapted to the size of the aerated lung. The ARDSNet protocol may not be sufficient to minimize VILI in patients with ARDS.

Pplat: 25 – 26 cmH2O Pplat: 28 – 30 cmH2O

Terragni P., Am J Respir Crit Care Med, 2007

A B


Slide 32

Ventilatory Treatment Effect: Vt

Slide 33

ARDS Net Study 01 Hypothesis

• In patients with ALI/ARDS, ventilation with reduced tidal volume will limit “volutrauma” and improve survival.

• “Lung-protective strategies”

The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared

with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.

N Engl J Med 2000;342:1301-8.

Slide 34

ARDS Net Study 01 Low VT Trial

• Patients with ALI/ARDS (NAECC definitions) of < 36 hours

• Ventilator procedures – Volume-assist-control mode

– RCT of 6 vs. 12 ml/kg of predicted body weight-PBW Tidal Volume (PBW/Measured body weight = 0.83)

– Plateau pressure 30 vs. 50 cmH2O

– Ventilator rate setting 6-35 (breaths/min) to achieve a pH goal of 7.3 to 7.45

– I/E ratio:1.1 to 1.3

– Oxygenation goal: PaO2 55 - 80 mmHg/SpO2 88 - 95%

– Allowable combination of FiO2 and PEEP as follows:FiO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0 1.0 1.0 1.0

PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18 20 22 24

ARDS Network. N Engl J Med. 2000.

Slide 35

ARDS Net Study 01 Improved Survival with Low VT1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0180160140120100806040200

Pro

po

rtio

n o

f P

atie

nts

Days after Randomization

Lower tidal volumesLower tidal volumesSurvivalSurvivalDischargeDischarge

Traditional tidal valuesTraditional tidal valuesSurvivalSurvivalDischargeDischarge


Slide 36

ARDS Net Study 01 Main Outcome Variables

Low Vt Traditional Vt p Value

Death before discharge home and breathing without assistance (%)

31.0 39.8 0.007

Breathing without assistance by day 28 (%)

65.7 55.0 < 0.001

No. of ventilator-free days, days 1 to 28

12 11 10 11 0.007

Barotrauma, days 1 to 28 (%) 10 11 0.43

No. of days without failure of nonpulmonary organs or systems, days 1 to 28

15 11 12 11 0.006


Slide 37

ARDS Net Study 01 Median Organ Failure Free Days

0 7 14 21 28

Renal

Coagulation

Cardiovascular

Hepatic

CNS

Pulmonary

MOF Free Days

**

**

**

**

= 6 ml/kg= 12 ml/kg


Slide 38

ARDS Net Study 01 Additional Findings

– PaO2/FiO2 lower in 6 ml/kg low VT group

– High RR prevented hypercapnia with minimal auto-PEEP

– No difference in their supportive care requirements ~10% mortality reduction

– Less organ failures

– Lower blood IL-6 and IL-8 levels

ARDS Network. N Engl J Med. 2000. Parsons PE, et al. Crit Care Med. 2005.

Hough CL, et al. Crit Care Med. 2005. Cheng IW, et al. Crit Care Med. 2005.

ALI and ARDS patients - 6 ml/kg PBW tidal volume ventilation strategy was associated with:

Slide 39

Ventilatory Treatment Effect: Vt

• Strong rationale of using low Vt in ARDS.

Slide 40

Ventilatory Treatment Effect: PEEP

Slide 41

PEEP in ARDS

• PEEP could protective against VILI by avoiding repetitive opening and collapse of atelectatic lungs

• High PEEP should make the mechanical ventilation less dangerous than low PEEP.

• PEEP is used to avoid end-expiratory collapse.

• PEEP, has been shown to prevent surfactant loss in the airways and avoid surface film collapse.

Levy MM. N Engl J Med. 2004.Rouby JJ, et al. Am J Respir Crit Care Med. 2002.Gattinoni L, et al. Curr Opin Crit Care. 2005.

Slide 42

Amato M, et al. N Engl J Med. 1998.


• Significant prognostic factors responsible of the ventilatory treatment effect:

• APACHE II score

• Mean PEEP during the first 36 hours (with a protective effect)

• Driving pressures (PPLAT - PEEP) during the first 36 hours

VT ~ 6 ml/kg

PEEP ~13-16

VT~12 ml/kg

PEEP ~9

Slide 43

PEEP in ARDS

• “Optimal PEEP”- allows for optimization of arterial oxygenation without risking oxygen toxicity and VILI while lessening detrimental effect on hemodynamics, oxygen delivery, and airway pressures

• Recruitment potential varies largely among ALI/ARDS

• PEEP may increase PaO2 without any lung recruitment because of a decrease in and/or a different distribution of pulmonary perfusion.

Levy MM. N Engl J Med. 2004.Rouby JJ, et al. Am J Respir Crit Care Med. 2002.Gattinoni L, et al. Curr Opin Crit Care. 2005.

Slide 44

NIH-NHLBI ARDS Network: Hypothesis

• In patients with ALI/ARDS (NAECC definitions) of < 36 hours who receive mechanical ventilation with a VT of 6 ml/kg of PBW, higher PEEP may improve clinical outcomes.

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

Slide 45

NIH-NHLBI ARDS Network

• Volume-assist-control mode

• Tidal-volume goal: 6 ml/kg of predicted body weight PBW

• Plateau pressure 30 cm H2O

• Ventilator rate setting 6 - 35 (breaths/min) to achieve a pH goal of 7.3 if possible

• I/E ratio:1.1 to 1.3

• Oxygenation goal: PaO2 55 - 80 mmHg/SpO2 88 - 95%


Patients with ALI/ARDS (NAECC definitions of < 36 hours) ventilatory procedures:

Slide 46

Cause of Lung Injury

Transfusion5%

Trauma8%

Other10%

Aspiration15%

Pneumonia40%

Sepsis22%


Slide 47

FiO2-PEEP Step Comparison

0

4

8

12

16

20

24

PEEP

0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

FIO2Low PEEP group

High PEEP group


Slide 48

0.0

0.5

1.0

Pro

bab

ilit

y

0 10 20 30 40 50 60Days after Randomization

Lower PEEP, overall survival

Higher PEEP, overall survival

Higher PEEP, discharge

Lower PEEP, discharge


Clinical Outcomes

Slide 49

Main Outcome Variables

OutcomeLower-PEEP

groupHigher-PEEP

groupp value

Death before discharge home (%)

Unadjusted

Adjusted for difference in baseline covariance

24.9

27.5

27.5

25.1

0.48

0.47

Breathing without assistance by day 28 (%) 72.8 72.3 0.89

No. of ventilator-free days from day 1 to day 28 14.5 10.5 13.8 10.6 0.50

No. of days not spent in ICU from day 1 to day 28 12.2 10.4 12.3 10.3 0.83

Barotrauma (%) 10 11 0.51

No. of days without failure of circulatory, coagulation, hepatic, and renal organs from day 1 to day 28

16 11 16 11 0.82


Slide 50

Why is higher PEEP not better in this study?

• Beneficial effects of higher PEEP counteracted by adverse effects ?

• Need for recruitment maneuvers ?

• “Lower PEEP” (or lower tidal volume) was sufficient to protect against injury from “atelectrauma” (ventilation at low end-expiratory volumes)?

• “Higher PEEP” was administered indifferently to PEEP responders as well as to not responders


Slide 51


• No consensus regarding optimum level of PEEP for ARDS.

Slide 52

Ventilatory Treatment Effect: recruitment (RMs)

Slide 53

Recruitment Maneuvers (RMs)

•Scientific Knowledge on the Subject:

• Recruitment maneuvers lead to a significant increase in oxygenation

• This implies that nonaerated areas, once recruited, would resume mechanical properties similar or equal to those of the neighboring baby lung

•The effect of recruitment may not be sustained unless adequate PEEP is applied to prevent derecruitment

• Conflicting data exist regarding the safety and efficacy ofrecruitment maneuvers in patients with acute lung injury.Fan et al, . Am J Respir Crit Care Med. 2008

Grasso et al, Am J Respir Crit Care Med. 2009

Slide 54


•Proposed for improving arterial oxygenation and enhancing alveolar recruitment consisting of short-lasting increases in intrathoracic pressures

– Vital capacity maneuver (inflation of the lungs up to 40 cm H2O, maintained for 15 - 26 seconds) (Rothen HU. BJA. 1999; BJA 1993.)

– Intermittent sighs (Pelosi P. Am J Respir Crit Care Med. 2003.)

– Extended sighs (Lim CM. Crit Care Med. 2001.)

– Intermittent increase of PEEP (Foti G. Intensive Care Med. 2000.)

– Continuous positive airway pressure (CPAP) (Lapinsky SE. Intensive Care Med. 1999. Amato MB. N Engl J Med. 1998.)

– Increasing the ventilatory pressures to a plateau pressure of 50 cm H2O for 1-2 minutes (Marini JJ. Crit Care Med. 2004. Maggiore SM. Am J Respir Crit Care Med. 2003.)

Lapinsky SE and Mehta S, Critical Care 2005

Slide 55


• The open lung strategy aims at reopening (recruitment) of nonaerated lung areas in patients with acute respiratory distress syndrome to minimize tidal alveolar hyperinflation in the limited area of normally aerated tissue ("baby lung").

• Alveolar recruitment is not protective against hyperinflation of the baby lung because lung parenchyma is inhomogeneous during ventilation with the open lung strategy

Grasso et al, Am J Respir Crit Care Med. 2009

Slide 56


• Given the uncertain benefit of transient oxygenation improvements in patients with ALI and the lack of information on their influence on clinical outcomes, the routine use of RMs cannot be recommended or discouraged at this time.RMs should be considered for use on an individualized basis in patients with ALI who have life-threatening hypoxemia.

Fan et al . Am J Respir Crit Care Med. 2008

Slide 57


• Questions to be answered:

– Target to be reached after a RM? PaO2/FiO2 ratio, PaCO2, Elastance, FRC ??

– Optimal time to perform RMs

– Frequency of use

– Durations

– The recommended ventilatory mode

– The long-lasting effects of RMs on ABGs are contradictory.

Slide 58

High-frequency Oscillatory Ventilation

• Characterized by rapid oscillations of a reciprocating diaphragm, leading to high-respiratory cycle frequencies, usually between 3 and 9 Hz (180-540 b/m) in adults, and very low VT. HFOV is conceptually achieves many of the goal of lung-protective ventilation.

– Minimize tidal volume

– Maintains an “open lung” and optimizes lung recruitment

– Theoretically avoiding alveolar distension.

– Prevents gas trapping

– Leads to higher end-expiratory lung volumes and recruitment Chan KPW and Stewart TE, Crit Care Med 2005

Slide 59

High-frequency Oscillatory Ventilation

• Observational studies demonstrated that HFOV may improve oxygenation when used as a rescue modality in adults with severe ARDS failing CV.

• HFOV may be considered for patients with severe ARDS:

– FiO2 > 0.60 and/or SpO2 < 88% on CV with PEEP > 15 cm H2O, or

– Plateau pressures (Pplat) > 30 cmH2O, or

– Mean airway pressure 24 cm H2O, or

– Airway pressure release ventilation Phigh 35 cm H2O Higgins J et al., Crit Care Med 2005

Slide 60

Non-ventilatory Management Strategies of ARDS/ALI

• Fluid and hemodynamic management

• Prone position ventilation

• Inhaled nitric oxide

• Steroids

• Extracorporeal Membrane Oxygenation (ECMO)

• Other drug therapy

Slide 61

Fluid and Hemodynamic Management

Pathophysiology:

• Increases in capillary hydrostatic pressure

• Increased membrane permeability

• Diminished oncotic pressure gradient

Lewis CA and Martin GS, Curr Opin Crit Care 2004Klein Y, J Trauma 2004

Slide 62


Clinical Implications:

• Reductions in pulmonary capillary hydrostatic pressure/pulmonary artery occlusion pressure – CVP

• Hemodynamic monitoring to avoid tissue hypoperfusion

• Fluid restriction/negative fluid balance

• Diuretics

• Combination therapy with colloids and furosemide?Lewis CA and Martin GS, Curr Opin Crit Care 2004Klein Y, J Trauma 2004


Kaplan-Meier estimates the probability of survival to hospital discharge and of breathing without assistance during the first 60 days after randomization.

ARDS Net Group, Comparison of two Fluid-ManagementStrategies in Acute Lung Injury N Engl J Med 2006

Slide 64

Prone Positioning

• Limits the expansion of cephalic and parasternal lung regions

• Relieves the cardiac and abdominal compression

• Makes regional ventilation/perfusion ratios and chest elastance more uniform

• Facilitates drainage of secretions

• Potentiates the beneficial effect of recruitment maneuvers

Slide 65

Prone Positioning

• Absolute contraindications

• Burns or open wounds on the face or ventral body surface

• Spinal instability

• Pelvic fractures

• Life-threatening circulatory shock

• Relative contraindications

• Increased intracranial pressure

• Main complications

• Facial and periorbital edema

• Pressure sores

• Loss-displacement of the endotracheal tube, thoracic or abdominal drains, and central venous catheters

• Airway obstruction

• Hypotension

• Arrythmias

• Vomiting

Slide 66

Prone Positioning

• Improves arterial oxygenation

• No known difference in baseline features between responders and non responders.

• Oxygenation may return to the basal supine value

• Does not increase survival

• May reduce mortality and limit VILI.

• Duration ranges between six and 12 hours/day depends on the effects on arterial oxygenation

Gattinoni L et al., N Engl J Med 2001Slutsky AS. N Engl J Med 2001

Slide 67

Gattinoni L, et al. N Engl J Med. 2001.

Prone Positioning

Prone Positioning and Survival

• Enrollment:

• Oxygenation criteria

– PaO2/FiO2 200 with a PEEP 5 cm H2O

– PaO2/FiO2 300 with a PEEP 10 cm H2O

• Radiographic criteria - bilateral pulmonary infiltrates

• Pulmonary-capillary wedge pressure 18 mm Hg or the absence of clinical evidence of left atrial hypertension.

Slide 68

Prone Positioning

Prone Positioning and Survival

• Treatment protocol:

– After randomization, prone group patients were continuously kept prone for at least six hours per day for a period of 10 days.


Slide 69


Kaplan-Meier estimates of survival at six months

Prone Positioning

Prone Positioning

Mancebo J et al, Am J Respir Crit Care Med 2006

Kaplan-Meier estimates of intensive care unit survival for thesupine and the prone groups (up to 60 d).

Effects on survival when the prone group was targeted to receive continuous prone ventilation treatment for 20 h/d.

Prone – Supine Study II limits:

1. both ALI and ARDS patients 2. prone positioning limited to 6

hs/day for up to 10 days3. no modification of mechanical

ventilation setting while prone

Prone – Supine Study II perspective:

1. only ARDS patients2. prone positioning prolonged to 20

hs/day without 10-day limit3. protocol-guided lung protective

ventilation

PRONE – SUPINE STUDY I and II

Gattinoni et al, NEJM 2001

Prone Positioning

Slide 72

Inhaled Nitric Oxide

• Physiology of inhaled nitric oxide therapy

– Selective pulmonary vasodilatation (decreases arterial and venous resistances)

– Decreases pulmonary capillary pressure

– Selective vasodilatation of ventilated lung areas

– Bronchodilator action

– Inhibition of neutrophil adhesion

– Protects against tissue injury by neutrophil oxidants

Steudel W, et al. Anesthesiology. 1999.

Slide 73

Inhaled Nitric Oxide in ARDS

•Results of a Randomized Phase II Trial In patients with documented ARDS, iNO at 1.25, 5, 20, 40, or 80 ppm:

– Significant improvement in oxygenation compared with placebo over the first four hours of treatment

– Acute increased the PaO2 in 60% of the patients

– Acute increase in PaO2 and the magnitude of the change similar in each of the inhaled NO dose groups

– Tolerated in doses between 1.25 to 40 ppm

– Monitor closely NO2 concentrations and methemoglobin

– Decrease the intensity of mechanical ventilation needed to maintain adequate oxygenation and improved patient benefit at 5 ppm inhaled NO. Dellinger RP et al., Crit Care Med 1998

Slide 74

Low-dose Nitric Oxide ARDS

• Patients with documented ARDS and ALI (PaO2/FiO2 250) but without sepsis or other organ system failure, inhaled Nitric Oxide (iNO) at 5 ppm:

– Induces short-term improvements in oxygenation in first 24-48 hrs.

– Does not improve clinical outcomes or mortality

• Data do not support routine use of iNO in treatment of ALI or ARD

• iNO may be considered a salvage therapy in ALI or ARDS patients with life threatening hypoxemia despite optimization of conventional mechanical ventilation.

Taylor RW, et al. JAMA. 2004.

Slide 75

Prolonged Methylprednisolone in Unresolving ARDS

• Rationale:

– Within 7 days of ARDS onset of fibrotic lung disease or fibrosing alveolitis with alveolar collagen and fibronectin accumulation is exhibited

• Patient selection:

– Severe ARDS/ 7 days of mechanical ventilation with an LIS 2.5/No evidence of untreated infection

Meduri GU et al., JAMA 1998

Slide 76

Prolonged Methylprednisolone in Unresolving ARDS

• Treatment protocol: Methylprednisolone – Loading dose 2 mg/kg

– 2 mg/kg/24 hours from day 1 to day 14

– 1 mg/kg/24 hours from day 15 to day 21

– 0.5 mg/kg/24 hours from day 22 to day 28

– 0.25 mg/kg/24 hours on days 29 and 30

– 0.125 mg/kg/24 hours on day 31 and 32

• Results:

– Prolonged administration of methylprednisolone, in patients with unresolving ARDS, was associated with improvement in lung injury and MODS scores and reduced mortality.

Meduri GU et al., JAMA 1998

Slide 77

Corticosteroid Therapy in ARDS

•High-dose corticosteroids in ARDS of 7 days with infection

• 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 postagressive fibrosis.

Kopp R et al., Intensive Care Med 2002Brun-Buisson C and Brochard L, JAMA 1998

Slide 78

High dose Corticosteroid Therapy in ARDS

• High-dose corticosteroids in early ARDS

• No lessening of incidence of ARDS with high risk patients

• No reverse of lung injury in patients with early ARDS / worse recovery

• No effect on mortality / may increase mortality rate

• Significantly increase the incidence of infectious complicationsKopp R et al., Intensive Care Med 2002Brun-Buisson C and Brochard L, JAMA 1998

Extracorporeal Membrane Oxygenation (ECMO)

• An alternative treatment is extracorporeal membrane oxygenation (ECMO)

• It uses cardiopulmonary bypass technology to provide gas exchange so that ventilator settings can be reduced, which provides time for treatment and recovery.

Extracorporeal Membrane Oxygenation (ECMO)

Peel GJ et al , Lancet 2009

Kaplan-Meier survival estimates for survivalECMO=extracorporeal membrane oxygenation.

*Patients were randomly allocated to consideration for treatmentby ECMO, but did not necessarily receive this treatment.

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Slide 85

Other Drug Therapy

• Prostaglandin E1 (PGE1)

• Aerosolized prostacyclin (PGI2)

• Almitrine

• Surfactant

• Antioxidants

• Partial liquid ventilation

• Anti-inflammatory drugs

Slide 86

Combination of Approaches

• Combination of iNO and prone position (Papazian L, et al. Crit Care Med. 1998.)

• Combination of iNO and almitrine (Gallart L, et al. Am J Respir Crit Care Med. 1998.)

• Combination of prone position, iNO, and almitrine (Jolliet P, et al. Crit Care Med. 1997. Gillart T, et al. Can J Anaesth. 1998.)

• Combination of iNO and iv prostacycline (Kuhlen R, et al. Intensive Care Med. 1999.)

Slide 87

Conclusions

Positive pressure ventilation may injure the lung via several different mechanisms

VILI

Search for ventilatory “lung protective” strategiesSearch for ventilatory “lung protective” strategies

Alveolar distension“VOLUTRAUMA”

Repeated closing and openingof collapsed alveolar units

“ATELECTRAUMA”

Oxygen toxicity

Lung inflammation“BIOTRAUMA”

Multiple organ dysfunction syndrome

Slide 88

Recommendations in Practice

• Principle of precaution

• Limited VT 6 mL/kg PBW to avoid alveolar distension

• End-inspiratory plateau pressure < 30 cm H2O

• Adequate end-expiratory lung volumes utilizing PEEP and higher mean airway pressures to minimize atelectrauma and improve oxygenation

• Consider recruitment maneuvers

• Avoid oxygen toxicity: FiO2 < 0.7 whenever possible

• Monitor hemodynamics, mechanics, and gas exchange

• Address deficits of intravascular volume

• Prioritize patient comfort and safety

Slide 89

VILI: Remaining Questions

• Optimal tidal volume, Pplat, PEEP

• Role of recruitment maneuvers

• High-frequency ventilation

• Permissive hypercapnia

• Prone positioning

• ECMO

Acute Lung Injury and Adult Respiratory Distress Syndrome Marco Ranieri, MD Full Professor of...

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