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