Prediction and Prevention of ARDS

Ognjen Gajic M.D.

Professor of Medicine

Attending Intensivist

Mayo Clinic

Rochester MN, USA

Multidisciplinary Epidemiology and Translational Research in

Intensive Care and Perioperative Medicine (METRIC - PM)

@ gajic.ognjen@mayo.edu

Leaver, S. K et al. BMJ 2007;335:389-394

Acute Respiratory Distress Syndrome: ARDS

Background

• Despite improved understanding of ARDS, the clinical impact has been limited to improvements in

• Mechanical ventilation, fluid management, sedation, rehabilitation

• Mechanistic treatments uniformly negative • When applied late in the course of illness?

• Surprisingly little research has been done on the prevention and early treatment of ARDS

Substantial amount of problems related to critical illness can be prevented!

• Minimizing diagnostic error

• Timely resuscitation

• Avoidance of iatrogenic complications

• Patient centered care

• Including palliative

Potentially Preventable Complications of Critical Illness

• Stress ulcer bleeding

• Pulmonary embolism

• Ventilator associated pneumonia and other nosocomial infections

• Why not ARDS?

911 Emergency Room

ICUOperating room Recovery room

Hospital ward Rapid response team

Bad

Outcome

Good

Outcome

Conventional Clinical Trial Enrollment

Window for Early Treatment & Prevention

Golden Hours: Chaos Theory of Critical Illness

ARDS Pathogenesis: “Multiple hit” Hypothesis

ARDS Onset in Relationship to Health Care Contact: Population-Based Cohort

©2010 MFMER | slide-8

Shari et al Resp Care 2011

©2010 MFMER | slide-9

Timing of ARDS Onset: Multicenter Cohort

Gajic et al Am J Resp Crit Care Med 2011

Epidemiology: Predisposing Conditions

% ALI development according to predisposing

conditions

0

5

10

15

20

25

30

Sm

oke

inha

latio

n 7/

27

Sho

ck 7

2/40

3

Asp

iratio

n 35

/212

Aor

tic sur

gery

21/

127

Lung

con

tusion

27/

190

Car

diac

sur

gery

55/

541

Acu

te a

bdom

en 2

7/29

5

Traum

atic b

rain in

jury

45/

495

Pne

umon

ia 1

02/1

234

Mul

tiple fr

actu

res 26

/332

Sep

sis 12

4/18

15

Thora

cic

surg

ery 7/

175

Spine

sur

gery

16/

486

Pan

crea

titis 9

/325

Gajic et al Am J Resp Crit Care Med 2011

Risk Modifiers

• Chronic alcohol use• Absence of diabetes mellitus• Smoking• Hypoalbuminemia• Acidosis• Obesity• Silent aspiration• Multiple “hits”

• VILI• FIO2

• RBC, Platelet & FFP transfusion• Fluid overload

Gajic et al Am J Resp Crit Care Med 2011

4 5 6 7 8 9 1011 1314 16 1819

Vt m L/ kg PBW

4 5 6 7 8 9 1011 1314 16 1819

Vt m L/ kg PBW

NOT SAFE

NOT SAFE

Ventilator settings % ARDS Mortality

33%

9.6%

28.3%

18%

2nd Hit Risk Modifiers: Large Tidal Volumes

• Lung Injury

• MortalityNeto et al JAMA 2012

Walkey et al. J Crit Care Volume 27, Issue 3, June 2012

450 mL

350 mL

✚

0

1

2

3

4

5

6

7

8

9

10

RBC (0, 1 to 4, >4 Units) FFP (0, 1 to 4, >4 Units) Platelet (0, 1, >1 Units)

Ad

juste

d O

dd

s R

ati

o f

or

AL

I/A

RD

S

Unadjusted odds ratio (95%CI) Adjusted* odds ratio (95%CI)

RBC 1.28 (0.88 to 1.84) 1.39 (0.79 to 2.43)

FFP 3.25 (2.09 to 5.03) 2.48 (1.29 to 4.74)

Platelet 5.99 (2.48 to 15.38) 3.89 (1.36 to 11.52)

Khan, H, Yilmaz M, Belshar, J, Winters J, Moore SB, Afessa B, Hubmyr RD, Gajic O. Chest 2007

** **

2nd Hit Risk Modifiers: Transfusion

O +

2871982739

879

O +

28719827

39879 Trash

Why transfusion? Donor sample collection:

Cooler

HLAI

HLAII

GIF

IL8

LysoPC

TRALI

BAG

Gajic et al. Am J Respir Crit Care Med 2007; 176: 886.

• Consecutive transfused ICU patients

• Prospective, nested case-control study design

Variable Adjusted Odds Ratio P-Value

Number of units 1.11 (0.99,1.25) 0.086

Number of units from female donors 1.51 (1.08, 2.12) 0.016

Amount of male plasma (L) 1.60 (0.76,3.37) 0.215

Amount of female plasma (L) 5.09 (1.37,18.85) 0.015

Amount of plasma from female donors with at least one pregnancy (L)

9.48 (1.38,65.35) 0.022

Number of pregnancies among donors 1.19 (1.05,1.34) 0.007

Number of HLA class I + units 1.70 (0.94,3.09) 0.098

Number of HLA class II + units 3.08 (1.15,8.25) 0.025

Number of GIF + units 4.85 (1.32,17.86) 0.018

2nd hit exposures: alloimmunized donor plasma

Gajic et al AJRCCM 2007

Prevention of transfusion related ALI : AABB Recommendations

Transfusion-Related Acute Lung Injury. Association Bulletin #06-07 (November 3, 2006) Bethesda,

MD: AABB, 2006

TRALI Deaths Reported to FDA

FDA report 2010

Annual incidence of TRALI at two US academic centers

0

1

2

3

4

5

2006 2007 2008 2009

TRALIIncidence

(per 104 units

transfused)

Year

Toy P, Gajic O at al. Blood 2011

P=0.002

Change in plasma procurement

Incidence and Mortality of TRALI in UK

Chapman et al Transfusion 2009

Change in plasma procurement

OR 95%CI p value

Delayed resuscitation 3.55 1.52 - 8.63 0.004

Delayed antibiotics 2.39 1.06 - 5.59 0.039

Respiratory rate (per SD) 2.03 1.38 - 3.08 <0.001

Chemotherapy 6.47 1.99 - 24.9 0.003

Alcohol abuse 2.09 0.88 - 5.10 0.098

Transfusion 2.75 1.22 - 6.37 0.016

Aspiration 3.48 1.22 - 10.78 0.024

Diabetes mellitus 0.44 0.17 - 1.07 0.076

Isceman et al. 2008 CCM

Additional 2nd Hit ALI Risk Modifiers

• 71 of 160 patients with septic shock (44%) developed ALI

What is the most highly associated variable with ARDS in US Descendents?

TenHoor et al Chest 2001

Ahmed at al ATS 2012

Exposures Cases Controls OR (95% CI) P value

Infection control (among those with suspected or proven infection N=151 pairs)

Inadequate empiric antimicrobial, N (%) 61(40.4) 30 (19.9) 2.9(1.7-5.2) <0.001

Time to adequate antimicrobial in hours

M(IQR)

7.6(3.0-25.4) 3.9 (2.4-8.4) 1.3 (1.1-1.5) <0.001

Hospital acquired aspiration and aspiration surrogates

Hospital acquired aspiration 51 (12.3) 1 (0.2) 51 (7.1-369) <0.001

Head of bed elevation *(≥30 ) 16 (61.5) 17 (65.4) 0.8 (0.4-2.4) 0.81

Documented intubation difficulty 32 (7.7) 10 (2.4) 3.2(1.5-6.5) <0.001

Mechanical ventilation parameters N=29 pairs

TVPBW Median (IQR) 9 (7.3,10.8) 7.7(6.9,8.5) 1.7(1.1-2.6) 0.025

TV>10 ml/kg PBW N (%) 14 (48.3) 6 (23.1) 7(0.8-56.8) 0.068

Adverse events (surgical and medical misadventures) N=828 **

Accidental cut, perforation or hemorrhage, 27 (6.5) 4(1.0) 12.5(3.0-52.8) <0.001

Instrument or apparatus failure, N (%) 8 (1.9) 3 (0.7) 5.3 (3.2-8.8) <0.001

Dosage failure, N (%) 113(27.3) 35 (8.5) 3.5(0.7-16.8) 0.118

Other and unspecified N (%) 57 (13.8) 8 (1.9) 8 (3.6-17.6) <0.001

Any adverse event N (%) 131 (31.6) 47 (11.4) 6.2(4.0-9.7) <0.001

Blood product transfusion for one or more unit infused N (%)

Red blood cells 163(39.4) 49 (11.8) 1.4 (1.3-1.6) <0.001

Platelet 51 (12.3) 11 (2.7) 2.0 (1.4-2.9) <0.001

Fresh frozen plasma 85 (20.5) 15 (3.6) 1.4 (1.2-1.6) <0.001

Secular Changes in Critical Care Delivery

Li et al Am J Resp Crit Care 2011

Incidence of ARDS in Olmsted County, Minnesota: Combined Effect?

Li et al Am J Resp Crit Care 2011

• Community-Acquired ARDS • Hospital-Acquired ARDS

Li et al Am J Resp Crit Care 2011

Frey et al AJRCCM 2009

Barriers to prevention of ALI/ARDS

• Need to identify those at high risk for development of ARDS early during their hospital presentation

• Under-utilization and practice variation in proven clinical practices that may influence development and outcome of ARDS

• Lack of safe and effective pharmacologic therapies to prevent ARDS

Mount Sinai School of Medicine

Temple University School of Medicine

The Johns Hopkins University

University of Medicine and Dentistry of New Jersey

Denver Health Medical Center

Hospital of the University of Pennsylvania

Brigham and Women's Hospital

Mayo Clinic Rochester

U of Michigan University Hospital

University of Washington, Harborview Medical Center

Parkland Health and Hospital System Dallas, Texas

University of Illinois at Chicago

Wake Forest University Health Sciences

Mayo Clinic Jacksonville

Bridgeport Hospital, Yale New Haven Health

Massachusetts General Hospital

Akdeniz University Hospital, Turkey

Beth Israel Deaconess Medical Center

Miami Valley Hospital

Emory University, Atlanta

Uludag University School of Medicine, Turkey

University of Missouri - Columbia

Infrastructure for Emergency Critical Care Research

• The first USCIIT Group study in 22 hospitals who joined USCIITG-LIPS1

• Researchers in emergency medicine, trauma surgery, anesthesiology and pulmonary/critical care medicine

http://www.usciitg.org/

Lung Injury Prediction Score (LIPS)

Barriers to prevention of ALI/ARDS

• Need to identify those at high risk for development of ARDS early during their hospital presentation

→ LIPS: Lung Injury Prediction Score

• Under-utilization and practice variation in proven clinical practices that may influence development and outcome of ARDS

• Lack of safe and effective pharmacologic therapies to prevent ARDS

CLIP Element Best Practices

Adequate empiric antimicrobial treatment and source control

According to suspected site of infection, health care exposure, and immune suppression

Lung protective mechanical ventilation Tidal volume <6-8 mL/kg predicted body weight and plateau pressure <25 cm H2O; PEEP≥5 cm H2O, minimize FIO2 (target O2sat 88-92% after early shock)

Aspiration precautions Rapid sequence intubation supervised by experienced providers, elevated head of the bed, oral care with chlorhexidine, gastric acid neutralization

Early reassessment of noninvasive ventilation (to prevent delayed intubation)

Early reassessment of the work of breathing 30 minutes into the onset of noninvasive ventilation

Fluid management:

- Early fluid administration in septic shock

-Limiting fluid overload after resuscitation

- Resuscitation according to institutional protocol and IHI sepsis bundle

- Modified ARDSnet FACCT protocol after early shock (first 12 hours)

Restrictive transfusion Hemoglobin target >7 g/dL in the absence of active bleeding and/or ischemia; avoid FFP and platelet transfusion in the absence of active bleeding

Appropriate handoff of patients at risk Structured handoff such as SBAR

Checklist for Lung Injury Prevention: CLIP

"Based on your expert opinion and the input of your peers,

should this item be included in CLIP?"

0% 25% 50% 75% 100%

Use noninvasive techniques to target

resuscitation

Consider early neuromuscular

blockade

Ensure safe rapid sequence intubation

Provide gastric acid suppression

Determine goals of care

Use a structured handoff tool

Provide early mobilization

Minimize inspired oxygen

concentration

Perform oral decontamination with

chlorhexidine

Reassess noninvasive ventilation early

Provide goal-directed sedation

Limit unnecessary platelet transfusions

Provide acute volume resuscitation in

septic shock

Consider permissive hypercapnia

Limit unnecessary plasma transfusions

Limit fluid overload after acute

resuscitation

Assess readiness for extubation daily

Limit unnecessary RBC transfusions

Elevate the head of bed in ventilated

patients

Ensure adequate empiric antimicrobial

coverage and source control

Use lung-protective ventilation

Delphi

Litell et al ATS 2012

Preliminary Data from Six Hospitals

Lee JM et al ATS 2012

Most respondents (67.5%) identified no barriers. Only barriers identified were:

• Local culture/practices on restrictive transfusion and fluid

management

• Pharmacy delays in timely antibiotic delivery

• Physician resistance to change old habits

• Lack of knowledge on restrictive transfusion, NIPPV use,

low tidal volume strategies, oral hygiene, and use of PEEP

• Misperception of low tidal volume & minimal FiO2

intolerance by patients

• Lack of experience with rapid sequence intubation

• Poor communication – verbal handoff; no standard

protocol; “too busy”; turnover mostly given by study

investigators rather than providers; poor turnover from

outside institutions

Barriers to CLIP Implementation

Lee JM et al ATS 2012

Barriers to prevention of ALI/ARDS

• Need to identify those at high risk for development of ARDS early during their hospital presentation

→ LIPS: Lung Injury Prediction Score

• Under-utilization and practice variation in proven clinical practices that may influence development of ARDS or outcomes of patients at risk for ARDS

→ CLIP: Checklist for Lung Injury Prevention

• Lack of safe and effective pharmacologic therapies to prevent ARDS

Membrane Injury

Mechanical stress

Inflammation

Coagulation

+

ARDS

CLIP:Checklist for Lung Injury Prevention

• Standardized

care delivery

LIPS:Lung Injury Prediction

Score

• Identifying patients

at risk of ARDS

Emergency department

Operating room

LIPS-ALung Injury Prevention Study with Aspirin (ongoing)

LIPS-BLung Injury Prevention Study with inhaled Budesonide

LIPS-HLung Injury Prevention Study with inhaled Hypertonic saline

$$_

QALY

50 year old with worsening shortness of breath

• Chief Complaint:• 50 year old with two days history

of cough, hemoptysis, worsening shortness of breath and markedly elevated heart rate

• Past History:• Hepatitis C

• Previous substance abuse on Methadone

• Seizure disorder

• Paroxysmal A fib, s/p ablation, on chronic Coumadin

Anxious, Increased work of breathing with accessory

muscles,

Bronchial breath sounds over R lung

Weak, irregular radial pulse, warm skin, brisk capillary refill

Ultrasound: hyperdynamic LV/RV, collapsing IVC; B lines

RUL, no effusion

Temperature : 38.4 C

Lung Injury Prediction Score (LIPS)

Shock (2) + Pneumonia (1.5) +

Sepsis (1) +Tachypnea (1.5) +

Acidosis (1.5) = 7.5

CLIP Element Clinically Supported Practices

Adequate empiric antimicrobial treatment and source control

According to suspected site of infection, health care exposure, and immune suppression

Lung protective mechanical ventilation Tidal volume <6-8 mL/kg predicted body weight and plateau pressure <25 cm H2O; PEEP≥5 cm H2O, minimize FIO2 (target O2sat 88-92% after early shock)

Aspiration precautions Rapid sequence intubation supervised by experienced providers, elevated head of the bed, oral care with chlorhexidine, gastric acid neutralization

Fluid management:

- Early fluid administration in septic shock

-Limiting fluid overload after resuscitation

- Resuscitation according to institutional protocol and IHI sepsis bundle

- Modified ARDSnet FACCT protocol after early shock

Restrictive transfusion Hemoglobin target >7 g/dL in the absence of active bleeding and/or ischemia; avoid FFP and platelet transfusion in the absence of active bleeding

Appropriate handoff of patients at risk Structured handoff such as SBAR

Checklist for Lung Injury Prevention: CLIP

Rapid sequence intubation

Lung protective ventilation

Goal directed fluid resuscitation

Blood and sputum culture

Cefepime 2 gr IV

Levofloxacine 750 mg IV

Hydrocortisone 50 mg IV

Furosemide

Spontaneous awakening and breathing trial

Short monitoring after extubation

De-escalation to oral antibiotics, steroid taper and transfer

Golden Hours!

Safar P. Critical care medicine – Quo Vadis? Crit Care Med 1974; 2:1–5.

Hillman K, Cur Opinion Crit Care 2010

• “The most sophisticated intensive care becomes unnecessarily expensive terminal care…”

Peter Safar

The father of critical care (ABCs) whose lifelong goal was to "save the hearts and brains of those too young to die."

gajic.ognjen@mayo.edu

Multidisciplinary Epidemiology and Translational

Research in Intensive Care

CLIP

Scientific Advisory board

Ancillary studies and publications committee

LIPS 1 LIPS A LIPS B LIPS C

US Critical Illness and Injury Trials Network (USCIIT)

USCIITG- Prevention of Organ Failures (USCIITG-PROOF) Study Group

USCIITG-PROOF Administrative Council

LIPS 1

Executive

Committee

LIPS A

Executive

Committee

LIPS B

Executive

Committee

LIPS C

Executive

Committee

CLIP

Executive

Committee

LIPS 1 Group LIPS A Group LIPS B Group LIPS C Group CLIP Group

PROOF Resources and Support (depending on funding the support may extend beyond the specific study)

Data coordinating center

Clinical coordinating center

Biospecimen coordinating center

LIPS 1 Ancillary

Studies

LIPS A Ancillary

Studies

LIPS B Ancillary

Studies

LIPS C Ancillary

Studies

CLIP Ancillary

Studies

Lung Injury Prevention Studies (LIPS) Kidney Injury Prevention Studies (KIPS)…

KIPS 1 KIPS A KIPS B

Protective effects of anti-platelet agents in the LIPS study cohort

• 3855 patients analyzed after excluding surgical patients

• ASA protective against ALI in univariate analysis

• On multivariate analysis adjusted for propensity to receive ASA OR of 0.70 (0.48- 1.03) p= 0.072

Kor et al. CCM 2011

Conclusions

• ARDS may be viewed as a potentially preventable complication of critical illness or injury

• Early identification of patients at risk (ED, OR, first hours in the ICU)

• To avoid “second hit” exposures

• Facilitate mechanistic studies and ARDS prevention trials

• ABCs of ARDS prevention• Mechanistic treatments may have a better chance to

work early in the course of illness (early treatment and prevention of ALI)

• “Patients do not die of their disease. They die of the physiologic abnormalities of their disease”

Sir William Osler

(1849-1919)

Prognosis

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Su

rviv

ing

0 20 40 60 80 100 120 140 160 180

Days

6 months - 39%

M Yilmaz ,R Iscimen,MT Keegan,NE Vlahakis ,B Afessa ,RD Hubmayr, O Gajic Six months survival of patients with acute

lung injury: prospective cohort study Crit Care Med 2007

MORTALITY:

ICU - 17%

Hospital - 27%

Follow up of ICU Survivors

Katz J N et al. Chest 2011;139:658-668

Platelets and platelet-neutrophil interactions in sepsis and ALI

Protective effects of anti-platelet agents in patients at risk for Acute Lung Injury

Erlich et al. Chest 2010

• ALI in anti-platelet group: 12.7%

• ALI in patients without anti-platelet agents: 28.1%

• Unadjusted OR: 0.37, 95% CI: 0.16 to 0.84; p = 0.02

Emergency Room Visit

Planned Hospital Admission

LIPS score ≥ 4R

and

om

izat

ion

Aspirin 325mg load followed by

81 mg PO/NG once daily

vs.

Placebo

Standardized Practice:Checklist for Lung Injury Prevention (CLIP)

Ou

tco

me

Ass

essm

en

t

• ∆ PaO2/FiO2

• ∆ SaO2/FiO2

• ∆ LIS

• ALI/ARDS

• ∆ Mortality

• Length of Stay

• Duration of ventilation

Inclusion Criteria

Age < 18 years

Current anti-platelets

Bleeding Diathesis

Planned surgery

Allergy to aspirin

No consent

Exclusion Criteria

Bas

elin

e P

lasm

a

Day

3P

lasm

a

Clinical Outcomes

Physiologic Outcomes

Plasma Evaluation• Thromboxane B2

• 15-epi lipoxins

• IL-6, PAI-1, RAGE

< 12 hours 7 days

• Acute onset (7 days)

• Diffuse injury to the blood-gas barrier• Alveolar flooding, inflammation and change in surfactant properties

• Bilateral infiltrates c/w edema• Not explained by effusions, lobar atelectasis or nodules

• In the absence of left atrial hypertension (as the principal cause)

• In the absence of predisposing condition needs objective (ECHO) exclusion

• Incidence ~100/106/year• High mortality (~40%), morbidity, decreased long-term quality of life

and high cost

• USA: each year ~200,000 patients, 75000 deaths, 3.5 million hospital daysGoss et al 2003. Ware et al 2000. Bachofen et al 1982 Rubenfeld 2005 and 2012

ARDS: “Lung Attack”

ARDS Treatment

• Mechanical ventilation• Lung protective (avoid overdistension, atelectasis, and

oxygen toxicity)

• Treatment of underlying condition• Infection

• Avoiding fluid overload• Diuretics/dialysis

• Adjunctive treatment options• Corticosteroids

• Supportive care• Sedation, nutrition, VTE and stress ulcer prophylaxis,

physical therapy, spontaneous breathing trials

Membrane Injury

Inflammation

Coagulation

Oxidative

stress

Mechanical

Chemical

Biological

$$_

QALY

ARDS Pathogenesis

Capillary stress failure

Acid aspiration

Direct – SARS, Influenza, RSV, PCP

Indirect – SIRS, reperfusion, IL2, TRALI

+

Adherence to Lung Protective Mechanical Ventilation

• Height and gender are known to be better predictors of lung size than is actual body weight

10

20

% T

LC

*

10 20

Vt mL/kg predicted body weight

10

20

% T

LC

*

10 20

Vt mL/kg actual body weight

Holets SR, Hubmayr RD. How to set the ventilator 2006

ARDS Prevention: Avoidance of Unnecessary Transfusion?

Gentle Reminder (“Nudge”) for RBC Transfusion

Rana R, Afessa B, Whalen F, Keegan M, Nuttall G, Evenson L, Hubmayr R, Winters J, Moore S, Gajic O. Crit Care Med 2006

Results of QI Intervention

• ~1000 less transfusions in three months

• Decrease in transfusion related complications

• 6.1% vs 2.7%, p=0.015

Rana R, Afessa B, Whalen F, Keegan M, Nuttall G, Evenson L, Hubmayr R, Winters J, Moore S, Gajic O. Crit Care Med 2006

Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, Rana R, St Sauver JL, Afessa B, Hubmayr

RD Crit Care Med. 2004 Sep;32(9):1817-24

2nd Hit Risk Modifiers: Ventilator Settings

Creating Ambient Intelligence

SHOCK

ALIAKI

DIC

Nurses, physicians, families

Any checklist to help standardize

clinical management of patients

at risk for ARDS must be

adaptable to:

• Different institutions

• Multiple clinical teams in

different areas of the hospital

• Different and changing clinical

conditions of the patients

The Checklist