Acute lung injury (ALI) and Acute respiratory distress syndrome (ARDS) Arthur P. Wheeler, MD Associate Professor of Medicine Director, Medical ICU Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University Commercial disclosures: none Research Support: NO1-HR-46054-64, NO1-16146-54

• • • • •

21 yo female WKU student Previously healthy Admitted with Gullian-Barre Day 5 aspiration-induced ARDS Ventilation – – – – –

Tidal volume 10 ml/kg FiO2 0.8 PEEP 15 PIP 70 cm H20 Adjustments made to normalize blood gases

• Day 23 bilateral tension pneumothoraces – Multiple (4+3) chest tubes – Large bilateral (R>L) cystic areas – Pneumomediastinum – Interstitial emphysema

• Day 52 air-hunger, suddenly sat upright – New seizure – Livedo reticularis right hemi-thorax, hand, and face – ECG: acute inferior myocardial infarction – Head CT: multiple new infarcts

• Day 70 autopsy: – Severe lung injury with prominent cystic changes, extensive fibrosis and foci of infection – Multiple myocardial infarcts, intact atrial septum – Multiple CNS infarcts c/w emboli Marini JJ Ann Intern Med 1989; 110: 699

Acute lung injury (ALI) Acute respiratory distress syndrome (ARDS) • Acute onset • Profound hypoxemia • Radiograph of pulmonary edema • No evidence of left atrial hypertension • “Stiff” or “small” lungs • Predisposing cause Bernard GR. Am J Resp Crit Care 1994; 149: 818

Causes of ALI Severe sepsis 26%

Aspiration 15%

Pneumonia 35%

Trauma 11%

Other 13%

ARDS Network N Engl J Med 2000; 342:1301

Drowning Pancreatitis Reperfusion Salicylate and narcotic OD Fat / amniotic fluid embolism Smoke / chemical inhalation

Mortality rate of ALI/ARDS 100

Mortality (%)

80 60 40 20 0 83

84

85

Milberg J JAMA 1995;273:306

86

87

88

89

90

91

92

93

Supportive care for all patients • • • • • • • • • •

DVT prophylaxis Gastrointestinal bleeding prophylaxis Elevate HOB to 30 degrees Hand washing Catheters inserted using full barrier precautions with chlorhexidine. Sedation and analgesia protocols. Reduction in transfusion thresholds. Standardized feeding protocols. Contrast nephropathy avoidance. Bedsore prevention program.

Causes of death Underlying injury / illness Multiple organ failure Severe sepsis

Montgomery AB Am Rev Respir Dis. 1985;132:485

Lung failure

Epithelial injury

Protein rich edema fluid

Inflammatoryhemorrhagic infiltrate

Increased vascular permeability

Adapted from Ware LB, N Engl J Med. 2000; 342:1334

Activated coagulation

ALI is heterogeneous Near normal Marginal Non-functional

Maunder R, JAMA 1986; 255:2463

Major questions in ALI in the 1990’s • What is the best way to ventilate the lung? • Does attenuating inflammation offer benefit? • What should be done with fluids?

ARDSnet

Mass General Philadelphia

Washington

Baltimore San Francisco

NHLBI Duke

Utah Denver

Michigan Vanderbillt

Cleveland

NIH NHLBI ARDS Clinical Trials Network

Ventilation

Airway pressures Peak inspiratory pressure (PIP)

Airway Pressure

Plateau pressure PEEP Time

Mechanisms of ventilation induced lung injury • Healthy animals developed lung injury if ventilated with PIP > 40 cm H2O “Barotrauma” – Kolobow Am Rev Resp Dis 135:312, 1987

• Identical pressures did not cause injury if lung expansion was restricted “Volutrauma” – Hernandez J Appl Physiol 1989 66:2364

• PEEP attenuated the injury of high pressure ventilation “Repetitive opening injury” – Webb Am Rev Resp Dis 1974; 110: 556

Ventilation can cause systemic inflammation: “biotrauma” 1200

600

1000

500

800

400

BAL IL-6 300 (pg/ml)

BAL TNF 600 (pg/ml)

200

400 200

100

0

0 Control MVHP

MVZP

HVZP

Tremblay J Clin Invest 1997; 99:944

Control MVHP

MVZP

HVZP

Inadequate Tidal Volume or PEEP

Large Tidal Volume or Inadequate PEEP

ALI Before Ventilation Consequences: • Atelectasis • Hypoxemia • Hypercapnia

TNF IL-6, etc

Consequences: • V/Q mismatch • Alveolar-capillary injury • “Barotrauma” • Inflammation

Tidal volume in practice 50 40 Percent of responders

30

Normal

Recommended

20 10 0 50 cmH20, reduce Vt •Minimum Vt = 4 ml/kg

6 ml/kg Group •Initial Vt = 6 ml/kg PBW. •If Pplat > 30 cmH20, reduce Vt. •Minimum Vt = 4 ml/kg

24 20 16

PEEP 12 8 4 0 0.3 0.4 0.4 0.5 0.5 0.6 0.7

0.7 0.8 0.9 0.9 0.9 1.0 1.0 1.0

FIO2

PaO2 = 55 - 80 mmHg or SpO2 = 88 - 95% Standardized weaning protocol

Macro-barotrauma is not the mechanism of injury 6ml/kg 12 ml/kg Requiring thoracostomy

13%

Not requiring thoracostomy

7%

ARDS Network N Engl J Med 2000; 342:1301

p

12%

0.932

9%

0.359

Effects of lower tidal volume Total respiratory rate

Tidal volume 14

30

12

26

Vt 10 (ml/kg PBW) 8

6 ml/kg 12 ml/kg

Breaths per 22 minute

18

6

14

4 0

1

2

3

0

4

1

Study Day

Plateau pressure

2 Study Day

3

4

Arterial PaCO2

35

45

cm water

30 25

PaCO2 40 (mm Hg)

20

35

15 0

1

2 Study Day

3

4

ARDS Network N Engl J Med 2000; 342:1301

30 0

1

2

Study Day

3

4

PaO2 / FiO2 180

*

* 160 P/F 140

6 ml/kg 12 ml/kg

120 0

1

2 Study Day

ARDS Network N Engl J Med 2000; 342:1301

3

4

Median ventilator free days 7 days p=0.005

ARDS Network N Engl J Med 2000; 342:1301

Hospital mortality 9 % ARR p=0.0054

Median organ failure free days CNS

*

Hepatic

*

Cardiovascular

*

Coagulation = 6 ml/kg = 12 ml/kg

*

Renal 0

7

14 Days

ARDS Network N Engl J Med 2000; 342:1301

21

28

6 mL/kg

12 mL/kg

0 -20

Percent change Day 0 to 3

-40 -60

IL-6

IL-8

IL-10

-80 -100

P=0.001 between groups Crit Care Med. 2005;33:1

Tidal volume as a risk factor for ALI Baseline Vt 2001

Risk of developing ALI

♂=10.4 mL/kg ♀=11.4 mL/kg

Gajic O. Crit Care Med 2004, 32:1817

OR 1.29 /mL Vt >6 PBW (1.12-1.51)

“Lung protective” ventilation V o l u m e

Add PEEP

Limit Distending Pressure

?

12 ml/kg PBW

Pressure

Hypothesis: In patients with ALI ventilated with 6 mL/kg, higher levels of PEEP will result in better clinical outcomes than lower levels of PEEP. N Engl J Med 2004; 351:327

Ventilation strategy •All given 6 mL/kg PBW tidal volume •Oxygenation: SpO2 = 88 - 95% or PaO2 = 55 - 80 mm Hg •Standardized weaning 24 20 16 PEEP 12 8 4 0 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.8 0.9 0.9 0.9 1.0 1.0 1.0 1.0

N Engl J Med 2004; 351:327

FIO2

Barotrauma 20

15

Low PEEP High PEEP P=0.51

Percent 10 267

270

5 0 New Barotrauma N Engl J Med 2004; 351:327

Physiology of higher / lower PEEP Pplat

Tidal volume 9

28

Low PEEP

Pplat (mm Hg)

High PEEP

Vt (ml/kg)

8 7 6

27 26 25 24 23

5 0

1

2

3

4

7

0

PEEP

16

1

2

3

4

7

FIO2

0.65

Low PEEP

0.60

High PEEP

14 12

FIO2

PEEP

0.55

10

0.50 0.45

8

0.40

6

0.35

0

1

2

3

Study day

4

7

0

N Engl J Med 2004; 351:327

1

2

3

Study day

4

7

Physiology of higher / lower PEEP PaCO2

210

50

190

45

PaCO2

P/F Ratio

PaO2 / FIO2 ratio

170

150

40 35

Low PEEP High PEEP

130

30 0

1

2

3

Study day

N Engl J Med 2004; 351:327

4

7

1

2 3 4 Study day

7

Hospital mortality 25% low vs 28% high p=0.48

Higher PEEP Lower PEEP

Median ventilator free days 14.5 low vs 13.8 high p=0.51

N Engl J Med 2004; 351:327

Median organ failure free days Renal

P=0.74

Coagulation

P=0.90

Hepatic

P=0.72

Cardiovascular

P=0.68

CNS

Low PEEP High PEEP

P=0.25

0 N Engl J Med 2004; 351:327

7

14

21

28

“Lower tidal volume with 6 cc per kilo decreased mortality from 40% to 31%. You twirl a knob, you’re ‘gonna save a life..OK…?”

Summary • Lower tidal volumes reduce death rates compared to “traditional” tidal volumes. • Patients on higher tidal volumes look more comfortable (until they die). • In the range tested higher PEEP is not “better” or “worse” than lower PEEP. • Lower tidal volumes may prevent ALI development.

Treating inflammation

Ketoconazole for Early Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome: A Randomized Controlled Trial The NIH NHLBI ARDS Network

JAMA 2000;283:1995-2002.

Crit Care Med. 2002;30:1-6.

RCT of Steroids for persistent ARDS • ARDS x 7 d with LIS > 2.5 • Randomized (2:1) to steroids vs. placebo – – – –

MPS 2 mg/kg load then 2 mg/kg/d x 14 d then 1 mg/kg/d x 7 d then 0.5 mg/kg/d x 7 d etc to 32 d

• Improvement = LIS by 1 • If no improvement at 10d, crossed over Meduri U. JAMA 1998; 280:159

24 randomized

Placebo 8

MPS 16

2 died 2 improved 4 cross-overs

16

Mortality outcomes Placebo

MPS

p value

• Intention to Rx 5/8 (62%)

2/16 (12%)

0.03

• As treated

5/20 (25%)

NS

2/4 (50%)

Meduri U. JAMA 1998; 280:159

• Randomized, blinded controlled trial of methylprednisilone vs. placebo for ALI persisting > 7 days – 2 mg/kg/day x 14 days; then 1 mg/kg/day x 7 days then tapered over 4 days. N Engl J Med. 2006 20;354:1671-84

Methylprednisilone vs. placebo results

N Engl J Med. 2006 20;354:1671

Summary • With the exception of human recombinant activated protein C for severe sepsis, no antiinflammatory strategy has improved mortality in ALI.

Fluid therapy and monitoring catheters

Is a PA catheter harmful or helpful ? • Prospective cohort study of the association between PAC (inserted ICU day 1) and survival, LOS, cost. • “Propensity score” to adjust for covariates. • PAC recipients matched with patients with same disease category and propensity score who did not get PAC.

Connors A, JAMA 1996; 276:889-897

Evidence the PAC may be harmful Relative Hazard of Death: Patients (n) All ARF MOF CHF Others*

(5735) (1789) (2480) (456) (1010)

Odds Ratio (95% CI) 1.21 1.30 1.32 1.02 1.06

(1.09-1.25) (1.05-1.61) (1.11-1.57) (0.55-1.89) (0.80-1.41)

p < 0.001 < 0.001 < 0.001 ns ns

* (severe COPD, cirrhosis, nontraumatic coma, etc)

Connors A. JAMA 1996; 276:889-897

Effectiveness of PAC in the initial care of the critically ill PAC (n=1008) Mortality (30-day) ICU LOS (days) Total Costs

37.5% 14.8 $49,300

Connors A. JAMA 1996; 276: 889-897

No PAC (n=1008) 32.8% 13.0 $35,700

p = 0.003 p < 0.001 p < 0.001

FACTT trial objectives To evaluate the mortality and morbidity effects of: • PAC versus CVC management and • “Fluid conservative” vs. “fluid liberal” management

FACTT: Factorial trial design Fluid Management C “Conservative” A (n = 500) T PAC H 250 patients (n = 500) E CVC T 250 patients E (n = 500) R

“Liberal” (n = 500) 250 patients 250 patients

FACTT: Treatment principles • Evaluate MAP, UOP, CI, exam and CVP or PAOP < every 4 hours • Hypotension: correct as fast as possible using any combination of any fluid and vasopressor. • Oliguria treatment: – Fluid - if CVP or PAOP low or low-normal – Furosemide - if CVP or PAOP high/high-normal • Ineffective circulation (low cardiac output) treatment: – Fluid - if CVP or PAOP low or low-normal – Dobutamine - if CVP or PAOP high/high-normal

FACTT: Treatment principles • If hypotension, oliguria and ineffective circulation are absent or resolved: – and CVP or PAOP is abnormally high give incremental furosemide. – and CVP or PAOP is within the “normal range” give fluid or diuretics to separate patients into two “normal” pressure ranges (liberal and conservative).

Intravascular Pressure (PAOP/CVP)

Low MAP

Acceptable MAP off vasopressors Low UOP Acceptable UOP low flow

nl flow

low flow

nl flow

>> Normal

Dobutamine Lasix

Lasix

Dobutamine Lasix

Lasix

> Normal

Dobutamine

Lasix

Dobutamine

Lasix

Fluid

Fluid

High normal Low normal

Vasopressor

Fluids

Fluid

Cons. Lasix

Fluid

Fluid

Fluid

Liberal

Fluid

Conservative fluid strategy Furosemide UOP < 0.5 ml/kg/h & CVP or PAOP low

MAP < 60 mmHg Low flow by exam or CI