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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)
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."
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