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Lung protective ventilation strategy for the acute respiratory distress syndrome

  1. Nicola Petrucci*,
  2. Carlo De Feo

Editorial Group: Cochrane Anaesthesia, Critical and Emergency Care Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 3 SEP 2012

DOI: 10.1002/14651858.CD003844.pub4


How to Cite

Petrucci N, De Feo C. Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD003844. DOI: 10.1002/14651858.CD003844.pub4.

Author Information

  1. Azienda Ospedaliera Desenzano, Department of Anaesthesia and Intensive Care, Desenzano, Brescia, Italy

*Nicola Petrucci, Department of Anaesthesia and Intensive Care, Azienda Ospedaliera Desenzano, Loc. Montecroce, Desenzano, Brescia, 25015, Italy. n.petrucci@libero.it. nicola.petrucci.1@gmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 FEB 2013

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Characteristics of included studies [ordered by study ID]
Amato 1998

MethodsProspective, multi-centre, controlled, RCT.
Concealment of treatment allocation: yes.
Generation of allocation sequences: sealed envelopes and a 1:1 assignment scheme.
Intent to treat: yes.
Blinding of treatment: no.
Blinding of outcome assessment: not stated.


Participants53 adults > 14 and < 70 years old (2 centres).
Included: LISS ≥ 2.5, PaO2:FiO2 < 200, Pwedge < 16 mmHg.
Exclusion: Previous lung or neuromuscular disease, MV > 1 week, terminal disease, previous barotrauma, previous lung biopsy or resection, intracranial hypertension, uncontrollable and progressive acidosis, documented coronary insufficiency.
Time period of study: December 1990 - June 1995.


InterventionsTidal volume < 6 ml/kg (n=29) or tidal volume 12 ml/kg (n=24).
Plateau pressure < 20 mmHg (experimental arm) or unlimited (control arm).
PEEP 2 cmH2O above LIP or titrated to best PaO2:FiO2.


OutcomesPrimary: mortality at day 28, in-hospital mortality.
Secondary: development of MOF, barotrauma.


NotesBicarbonate if pH < 7.20. Use of PV curve to set Vt and PEEP. PCV. NNT=4.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate

Allocation concealment (selection bias)Low riskAdequate

Blinding (performance bias and detection bias)
All outcomes
High riskUnblinding stated

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskData not provided to judge

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskData not provided to judge

Incomplete outcome data (attrition bias)
All outcomes
Low risk

ARDS Network 2000

MethodsProspective, multi-centre, controlled, RCT.
Concealment of treatment allocation: yes.
Generation of allocation sequences: centralized interactive voice system. Each research coordinator had a unique PIN.
Intent to treat: yes.
Double blind: not stated.


Participants861 adults > 18 years old (10 centres).
Included: AECCC, PaO2:FiO2 < 300 mmHg, Pwedge < 18 mmHg.
Exclusion: Pregnancy, high intracranial pressure, sickle cell disease, COPD, weight > 1 kg/cm height, neuromuscular disease, burns over more than 30% BSA, bone marrow or lung transplantation, chronic liver disease.
Time period of study: March 1996 - March 1999.


InterventionsTidal volume 6 mml/kg or 12 ml/kg of IBW.
Plateau pressure ≤ 30 mmHg or ≤ 50 mmHg.
PEEP titrated to SaO2 88-95%.


OutcomesPrimary: mortality before hospital discharge or at day 180.
Secondary: development of MOF, duration of mechanical ventilation, ventilator-free days, barotrauma.


NotesPowered for 1000 patients. Stopped early because of statistically significant benefit in the experimental arm (fourth interim analysis).
Increased ventilation if pH < 7.15. NNT=12.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk

Allocation concealment (selection bias)Low riskAdequate

Blinding (performance bias and detection bias)
All outcomes
Unclear riskData not provided to judge

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskData not provided to judge

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskData not provided to judge

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Brochard 1998

MethodsProspective, multi-centre, controlled, RCT.
Concealment of treatment allocation: yes.
Generation of allocation sequences: sealed envelopes.
Intent to treat: yes.
Double blind: not stated.


Participants116 patients ≤ 76 years old (25 centres).
Inclusion: LISS ≥ 2.5, PaO2:FiO2 < 200 mmHg, Pwedge < 18.
Exclusion: History of left heart failure, cardiogenic oedema, organ failure other than the lung, need for epinephrine > 1mg/hr or norepinephrine > 2 mg/hr, COPD or liver failure or renal failure, moribund state, intracranial hypertension, head injury, chest wall abnormalities.
Time period of study: January 1994 - September 1997.


InterventionsTidal volume 7 ml/kg or 10 ml/kg.
Plateau pressure between 25-30 mmHg or peak pressure ≤ 60 mmHg.
PEEP titrated to PaO2:FiO2 > 200 mmHg.


OutcomesPrimary: mortality at day 60.
Secondary: development of MOF, duration of mechanical ventilation, barotrauma.


NotesUse of nitric oxide allowed. Bicarbonate if pH < 7.05. NNH=12.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk

Allocation concealment (selection bias)Low riskAdequate

Blinding (performance bias and detection bias)
All outcomes
Unclear riskData not provided to judge

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskData not provided to judge

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskData not provided to judge

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Brower 1999

MethodsProspective, multi-centre, controlled, RCT.
Concealment of treatment allocation: yes.
Generation of allocation sequences: yes, block design, method not stated.
Intent to treat: yes.
Double blind: not stated.


Participants52 patients ≥ 18 years old.
Included: AECCC, PaO2:FiO2 < 200 mmHg, Pwedge < 18 mmHg.
Exclusion: Pregnancy, Acute neurologic disease, life expectancy < 3 months, COPD, sickle cell disease, lobectomy or pneumonectomia.
Time period of study: not stated.


InterventionsTidal volume 8 ml/kg or (10-12) mm/kg of IBW.
Plateau pressure ≤ 30 mmHg or ≤ (45-55) mmHg.
PEEP titrated to SaO2 86-94%.


OutcomesPrimary: in-hospital mortality.
Secondary: duration of mechanical ventilation, reversal of respiratory failure, barotrauma.


NotesBicarbonate if pH < 7.30. NNH=26.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not stated

Allocation concealment (selection bias)Low riskAdequate

Blinding (performance bias and detection bias)
All outcomes
Unclear riskData not provided to judge

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskData not provided to judge

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskData not provided to judge

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Stewart 1998

MethodsProspective, multi-centre, controlled, RCT.
Concealment of treatment allocation: yes.
Generation of allocation sequences: block design, computer-generated random numbers tables.
Intent to treat: yes.
Double blind: not stated.


Participants120 patients ≥ 18 years old (8 centres).
Included: High risk for ARDS, PaO2/FiO2 < 250 mmHg.
Exclusion: MV expected to be required for > 48 hrs, PIP > 30 cmH2O for 2 hrs or more before randomization; moribund state; cardiogenic pulmonary oedema myocardial ischaemia; pregnancy; known intracranial abnormalities.
Time period of study: not stated.


InterventionsTidal volume 8 ml/kg or (10-15) ml/kg of IBW.
Peak pressure 30 mmHg or 50 mmHg.
PEEP titrated to 89-93%.


OutcomesPrimary: in-hospital mortality.
Secondary: development of MOF, duration of mechanical ventilation, total duration of stay in intensive care, total duration of stay in hospital, barotrauma.


NotesBicarbonate if pH < 7.00, or increased ventilation if refractory acidosis. NNH=30.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk

Allocation concealment (selection bias)Low riskAdequate

Blinding (performance bias and detection bias)
All outcomes
Unclear riskData not provided to judge

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskData not provided to judge

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskData not provided to judge

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Villar 2006

MethodsProspective, multi-centre, controlled, RCT. Concealment of allocation: yes.
Generation of allocation sequences: sealed envelopes.
Intent to treat: yes.
Double blind: not stated.


Participants103 patients > 15 years old (8 centres). Included: AECCC, Included: AECCC, PaO2:FiO2 < 200 mmHg, Pwedge < 18 mmHg.
Exclusion: Pregnancy, severe neurologic damage, cancer patients in terminal stage, high risk of mortality within 3 months.
Time period of study: March 1999 - March 2001.


InterventionsTidal volume (5-8) ml/kg (n=53) or tidal volume (9-11) ml/kg (n=50).
PEEP 2 cmH2O above LIP or > 5 cmH2O, titrated to SaO2 > 90%.


OutcomesPrimary: ICU mortality. Secondary: in-hospital mortality, ventilator-free days, non-pulmonary organ dysfunction, barotrauma.


NotesUse of PV curve to set PEEP.
Stopped early because of statistically significant benefit in the experimental arm.
NNT=5.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk

Allocation concealment (selection bias)Low riskAdequate

Blinding (performance bias and detection bias)
All outcomes
Unclear riskData not provided to judge

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskData not provided to judge

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskData not provided to judge

Incomplete outcome data (attrition bias)
All outcomes
Low risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Brower 2004This trial used low tidal volumes in both the study groups. Thus, it is not eligible for inclusion because it did not compare different tidal volumes but only different levels of PEEP.

Esteban 2000This RCT has not been designed to test MV with lower tidal volume in ARDS. Tidal volume and plateau pressure in the experimental arm overlap tidal volume and plateau pressure in the control group.

Meade 2008This RCT has not been designed to test MV with lower tidal volume, as both groups used lower tidal volume. The groups differed by the levels of PEEP and recruitment manoeuvres.

Mercat 2008This RCT has not been designed to test MV with lower tidal volume, as both groups used lower tidal volume. The groups differed only by the levels of PEEP.

Ranieri 1999This RCT tested the hypothesis that protective ventilation minimizes pulmonary and systemic cytokine response and was not specifically designed to assess the benefit on mortality of lower tidal volume ventilation. Although the context of interventions in both groups met the inclusion criteria for this review, the protocol was designed to be a 36-hour study, and 28-day mortality was reported as a post hoc analysis. In addition, analysis was not conducted on an intention-to-treat basis. Loss to follow up was 14%.

Rappaport 1994Prospective, non-blinded RCT. Analysis was not conducted on intention-to-treat basis (attrition bias). Tidal volumes overlap in both groups.

 
Comparison 1. Protective versus conventional

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality at the end of the follow up period for each trial61297Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.72, 0.95]

 2 Mortality at day 2831030Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.61, 0.88]

 3 Hospital mortality51181Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.69, 0.92]

 4 Duration of mechanical ventilation3288Mean Difference (IV, Fixed, 95% CI)-0.83 [-1.92, 0.27]

 5 Mortality at different plateau pressure in control groups6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 low-pressure control (< or = 31 cm H2O)
3288Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.88, 1.45]

    5.2 high-pressure control (> 31 cm H2O)
31009Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.63, 0.87]

 6 Mortality at the end of the follow-up period for each trial - best case61297Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.69, 0.90]

 7 Mortality at the end of the follow-up period for each trial - worst case61297Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.78, 1.02]

 
Table 1. Secondary publications

Publications

Eisner MD, Thomson T, Hudson LD, Luce JM, HaydenD, Schoenfeld D, et al Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 2001;164:231-6.

Ely EW, Wheeler AP, Thompson T, Ancukiewicz M, Steinberg KP, Bernard GR. Recovery rate and prognosis in older persons who developed acute lung injury and the acute respiratory distress syndrome. Annals of Internal Medicine 2002;136:25-36.

Eisner MD, Thompson BT, Schoenfeld D, Anzueto A, Matthay MA; Acute Respiratory Distress Syndrome Network. Airway pressures and early barotrauma in patients with acute lung injury and acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 2002;165:978-82.

Cheng IW, Eisner MD, Thomson BT, Ware LB, Matthay MA; Acute Respiratory Distress Syndrome Network. Acute effects of tidal volume strategy on hemodynamics, fluid balance, and sedation in acute lung injury. Critical Care Medicine 2005;33:239-40.

Parsons PE, Eisner MD, Thomson BT, Matthay MA, Ancukiewicz M, Bernard GR, et al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Critical Care Medicine 2005;33:1-6.

 
Table 2. Results of individual studies

StudyEffect NameTreatedControlTotalEffectLower 95%CIUpper 95%CI

Amato 1998Hospital mortality13/2917/24530.630.391.02

Amato 1998Mortality at day 2811/2917/24530.540.310.91

ARDS Network 2000Mortality at day 180133/432170/4298610.780.650.93

Brochard 1998Mortality at day 6027/5822/581161.230.801.89

Brower 1999Hospital mortality13/2612/26521.080.621.91

Stewart 1998Hospital mortality30/6028/601201.070.741.55

Villar 2006Hospital mortality17/5025/45950.610.380.98

 
Table 3. Secondary outcomes considered for this review

OutcomesAmato 1998ARDS network 2000Brochard 1998Brower 1999Stewart 1998Villar 2006

Development of MOFN/A15±11 versus 12±11 (days without organ failure)24/58 versus 24/58 (no of patients)N/A2 versus 2 (no of organs/patients)0.3 versus 1.2 (no of organ failure post-pre randomization)

Duration of mechanical ventilationN/A8-10 both groups (median)23±20 versus 21±1611±2.2 versus 12±1.916.6±39 versus 9.7±10N/A

Total duration of mechanical supportN/AN/AN/AN/AN/AN/A

Total duration of stay in intensive careN/AN/AN/AN/A20±39 versus 14±16N/A

Total duration of stay in hospitalN/AN/AN/AN/A33±48 versus 27±26N/A

Long-term mortalityN/AN/AN/AN/AN/AN/A

Long-term health-related quality of lifeN/AN/AN/AN/AN/AN/A

Long-term cognitive outcomesN/AN/AN/AN/AN/AN/A

CostsN/AN/AN/AN/AN/AN/A