the problem ards - mortality 30 - 60% etiology - unknown therapy - largely supportive mechanical...

Ventilatory Management of Ventilatory Management of Patients with ARDSPatients with ARDS

Arthur S. Slutsky, MDArthur S. Slutsky, MDSt. Michael’s HospitalSt. Michael’s HospitalUniversity of TorontoUniversity of Toronto

The ProblemThe Problem• ARDS - mortality 30 - 60%

• Etiology - unknown

• Therapy - largely supportive»mechanical ventilation

Lung injury

How do you ventilate the ARDS patient without aggravating/causing further injury?

OverviewOverview

• Review mechanical ventilation outcome trials in patients with acute lung injury/ARDS» Focus is RCTs with conventional ventilation

• Non-conventional methods of ventilation will be covered in a subsequent talk» High frequency ventilation» Partial liquid ventilation

Factors Aggravating Lung InjuryFactors Aggravating Lung Injury

Collapse-Recruitment- effects on surfactant- recruitment/de-recruitment

0 5 10 15 20

Over-Distention- gross barotrauma- diffuse alveolar damage

Biotrauma

Regional expansion

Pulmonaryedema

Avoid Collapse/Recruitment

N Engl J Med 1998;338:347-54

Avoid Over-Distention

Vt Reduction for Prevention of Vt Reduction for Prevention of VILI in ARDSVILI in ARDS

Brochard et al AJRCCM 1998;158:1831-38

N Engl J Med 1998;338:355-61

ARDSnetARDSnet

NIH NHLBI ARDS Clinical Trials NetworkNIH NHLBI ARDS Clinical Trials Network

N Engl J Med 2000;342:1301-1308

Ventilation with Low Tidal Volumes Ventilation with Low Tidal Volumes for ALIfor ALI

Ventilator ProceduresVentilator Procedures

12 ml/kg Group (Control)

• Initial Vt = 12 ml/kg PBW

• If Pplat > 50 cmH20, reduce Vt by 1 ml/kg.

• Minimum Vt = 4 ml/kg

• If Pplat < 45 cmH20 and

Vt < 11 ml/kg, increase Vt by 1 ml/kg.

6 ml/kg Group

• Initial Vt = 6 ml/kg PBW.

• If Pplat > 30 cmH20, reduce Vt by 1 ml/kg.

• Minimum Vt = 4 ml/kg.

• If Pplat < 25 cmH20 and

Vt < 5 ml/kg, increase Vt by 1 ml/kg.N Engl J Med 2000;342:1301-1308

Ventilator Procedures Ventilator Procedures

Oxygenation goal:

PaO2 = 55-80 mmHg or SpO2 = 88-95%

PEEP 5 5 8 8 10 10 … 18 20-24

FiO2 .3 .4 .4 .5 .5 .6 ... 1.0 1.0

N Engl J Med 2000;342:1301-1308

28 Day Survival28 Day Survival

0

0.2

0.4

0.6

0.8

1

0 7 14 21 28Days after study entry

Proportion Surviving

12 ml/kg

6 ml/kg

N Engl J Med 2000;342:1301-1308

Why are there such large differences among the trials?

Amato vs 3 Negative TrialsAmato vs 3 Negative Trials

• More effective ventilatory strategy

• Worse strategy for the Control group

5

10

15

PVLControlPEEPPEEP

(cm H(cm H220)0)

PEEP Differences Among StudiesPEEP Differences Among Studies

0

10

20

30

40

50

PVLControl%%

BarotraumaBarotrauma

Why are there Different Results Among Trials of Low Stretch Ventilation?

• Power of the studies

• Treatment of hypercapnia

• Development of Auto-PEEP

• Greater separation of key variables among

studies

Greater Differences between Control and Greater Differences between Control and Intervention ArmsIntervention Arms

NIH

VVT

, T, m

l/kg

ml/k

g

ALVEOLI Trial: HypothesisALVEOLI Trial: Hypothesis

In ALI/ARDS patients receiving

volume-and-pressure limited mechanical ventilation,

higher PEEP will result in better clinical outcomes.

ARDSNet Investigators (Brower et al, ATS 2002)

Ventilator ProtocolVentilator Protocol

Arterial Oxygenation: SpO2 = 88 - 95% PaO2 = 55 - 80 mm Hg

ARDSNet Investigators (Brower et al, ATS 2002)

Lower PEEP/Higher FiO2

FiO2 .3 .4 .4 .5 .5 .6 .7 .7 .7 .8 .9 .9 .9 1.0PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24

Ventilator ProtocolVentilator Protocol

Arterial Oxygenation: SpO2 = 88 - 95% PaO2 = 55 - 80 mm Hg

ARDSNet Investigators (Brower et al, ATS 2002)

Lower PEEP/Higher FiO2

FiO2 .3 .4 .4 .5 .5 .6 .7 .7 .7 .8 .9 .9 .9 1.0PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 18-24

Higher PEEP/Lower FiO2

FiO2 .3 .3 .4 .4 .5 .5 .5-.8 .8 .9 1.0 PEEP 12 14 14 16 16 18 20 22 22 22-24

PEEPPEEP

** ** **** **Low PEEP

High PEEP

6

8

10

12

14

16

0 1 2 3 4 7Study day

PEEPcm H2O

Study DayARDSNet Investigators (Brower et al, ATS 2002)

Plateau PressurePlateau Pressure

* * *

Pplat

cm H2O

High PEEP

Low PEEP

Study Day

Mortality Before Discharge HomeMortality Before Discharge Home

Low PEEP High PEEP

P=0.56

ARDSNet Investigators (Brower et al, ATS 2002)

Mor

talit

y, %

ALVEOLI SummaryALVEOLI Summary

• 550 patients • Trial stopped for “futility” No significant differences in:

» Mortality» Ventilator-free days» ICU-free days

Baseline CharacteristicsBaseline Characteristics

APACHE III# hospital days# Organs failedTidal volumeCstatPaO2/FiO2

Age

Low PEEP High PEEP P

92 + 2 96 + 2 0.18

4.1 + 0.4 3.8 + 0.3 0.54

1.0 + 0.1 1.0 + 0.1 0.75

8.2 + 0.1 8.1 + 0.1 0.33

32 + 1 35 + 2 0.14

149 + 4 137 + 4 0.056 48 + 1 54 + 1 0.0003

ARDSNet Investigators (Brower et al, ATS 2002)

Mortality DifferenceMortality DifferenceAttributable to Higher PEEPAttributable to Higher PEEP

10% 0% 10%

Favors Lower PEEP

Favors Higher PEEP

Mortality Difference

Adjusted

Unadjusted

(95% Confidence Intervals)

ARDSNet Investigators (Brower et al, ATS 2002)

Why is Higher PEEP not better in ALVEOLI study?Why is Higher PEEP not better in ALVEOLI study?

• Beneficial effects of Higher PEEP counteracted by adverse effects?

• Recruitment maneuvers are needed?

• “Lower PEEP” was sufficient to protect against injury from ventilation at low end-expiratory volumes?

• Lower tidal volume and Pplat limit reduced injury from ventilation at low end-expiratory volumes?

Prone Position in Patients with ARDSProne Position in Patients with ARDS

Gattinoni et al N Engl J Med 2001:345:568-73

• Methods: Multi-center RCT trial with 304 patients» Prone or supine position for at least 8 h/day for 10 days

Problems:- Duration of prone ventilation: 7 hrs/d - Delayed use: 24% with decubiti on entry- 10 day duration (but daily variation)- Underpowered - No ventilation or weaning protocols

Post-hoc analysis: survival in lowest P/F

Prone Position in Patients with ARDSProne Position in Patients with ARDS

Gattinoni et al N Engl J Med 2001:345:568-73

Prone Ventilation TrialsProne Ventilation Trials

• Mancebo et al (In Preparation)» Prone ventilation 20 h/day» 133 patients » Supine mortality: 59 %» Prone mortality: 44%

p=0.12p=0.12

ConclusionsConclusions• Very strong animal data that ventilator-induced lung

injury is a real and important entity

• Low tidal volume strategy with 6 ml/kg (predicted body weight) decreases mortality compared to 12 ml/kg

• Increasing PEEP as per ARDSNet investigators yields ambiguous results

• Prone position may be advantageous

Partial Liquid Ventilation in Adult Partial Liquid Ventilation in Adult Patients with Acute Lung InjuryPatients with Acute Lung Injury

Kacmarek R, Wiedemann H, Lavin P, Wedel MK, Kacmarek R, Wiedemann H, Lavin P, Wedel MK, Tütüncü AS, Lemaire F, Slutsky ASTütüncü AS, Lemaire F, Slutsky AS

28-Day Mortality28-Day Mortality

26.3% 15.0% 19.1%

0.064p 0.39

Low PLV CMVHigh PLV n=99 n=107 n=105

mortality

Multicenter

Prospective

Randomized

Controlled

Pivotal Efficacy Trial

LiquiVentLiquiVent ®® LVAD-007-INT LVAD-007-INT

Inclusion CriteriaInclusion Criteria

Primary risk factor for ARDS/ALI

Acute, bilateral infiltrates on CXR

Impaired oxygenation

– P/F ratio 200 on FIO2 0.5 and PEEP 5

– 70 < P/F < 300 on FIO2 0.5 and PEEP 13

Baseline: DemographicsBaseline: Demographics

Low PLV CMVHigh PLV

Age (years) 45 ± 14 46 ± 1245 ± 13

Sex (M/F) 60/39 64/4360/45

Weight (kg) 79 ± 21 83 ± 2277 ± 19

IBW (kg) 64 ± 11 65 ± 1165 ± 11

Height (cm) 169 ± 11 171 ± 10170 ± 10

28-Day Mortality28-Day Mortality

0.4

Perc

ent M

orta

lity 0.3

0.2

0.1

0.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Study Day

Low dose

High dose

CMV

Mortality ComparisonMortality Comparison

• Trial • Ventilation• Strategy

• 28-Day• Mortality

• 15.0%

• 19.7%ARDSnet "low stretch" arm

age < 65 yrs(n=350)

PLV-007CMV arm

age < 65 yrs(n=107)

• TV 6ml/kg/IBW

• PEEP 9 cmH20

EIP 28 cmH20

TV 9 ml/kg/IBWPEEP 14 cmH20EIP 28 cmH20

Independent Predictors of MortalityIndependent Predictors of Mortality

• Age• APACHE III• Pplat• Pplat missing• # organ failures• # hosp days before enrollment• A-a DO2

From ARDSnet # 1 Lower Tidal Volume Study Group: NEJM 342: 1301-1308, 2000

I. Power I. Power

0

20

40

60

80

100 PVLControl

Mor

talit

y %

Mor

talit

y %

• All 3 studies tend to have lower mortality in Control arm» 288 patients in total

PaC

OPa

CO

2

2 (m

mH

g)(m

mH

g)

NIH

III. Treatment of HypercapniaIII. Treatment of Hypercapnia

IV. Development of Auto-PEEPIV. Development of Auto-PEEP

12

13

14

15

0 1 2 3 4Study Day

Lite

rs p

er

6 ml/kg12 ml/kg

Min

ute

Vent

ilatio

n

How does one Avoid Collapse/Recruitment?How does one Avoid Collapse/Recruitment?

• Recruitment maneuvers

»variations of “sigh”; stacked breaths

• Operate on deflation limb of pressure-volume curve

• High level of PEEP

• Pressure-volume curve to assess inflection point

How do you avoid overdistention?How do you avoid overdistention?

• Allow higher values for PaCO2

• Minimize peak pressures/tidal volumes

• Prone position

• Use pressure-volume curve to identify dangerous zones