Conceived and designed the experiments: KEAB NKA ASS GG JV HZ DC TS MOM. Performed the experiments: KEAB NKA MOM. Analyzed the data: KEAB ASS GG JV HZ QZ DC TS MOM. Contributed reagents/materials/analysis tools: QZ. Wrote the paper: KEAB NKA ASS GG JV HZ QZ DC TS MOM. Designed the review protocol, conducted the literature searches, screened abstracts and related articles, selected studies meeting inclusion criteria, extracted data, assessed study quality, prepared initial and subsequent drafts of the manuscript and integrated comments from other authors into revised and final versions of the manuscript: KEAB. Conducted the literature searches, screened abstracts, participated in protocol design, selected studies meeting inclusion criteria, extracted data, assessed study quality, revised and approved the final version the manuscript: NKJA. Provided guidance in drafting the manuscript, aided in interpreting the pooled results, and revised and approved the final version of the manuscript: ASS DC TS. Provided methodologic guidance in designing the protocol, drafting the manuscript, facilitated correspondence with authors to clarify study methodology, aided in interpreting the pooled results, and revised and approved the final version of the manuscript: GG. Aided in interpreting the pooled results, assisted in preparing the manuscript, and revised and approved the final version of the manuscript: JV. Facilitated translation of foreign language publications and correspondence with authors to clarify study methodology, and revised and approved the final version of the manuscript: HZ. Provided statistical guidance for the meta-analysis, conducted the analyses aided in interpreting the pooled results, and revised and approved the final version of the manuscript: QZ. Designed the review protocol, screened abstracts and related articles, adjudicated disagreements regarding study selection and methodologic quality, provided methodologic guidance in drafting the manuscript, prepared the evidence table, integrated comments from other authors into revised versions of the manuscript, and revised and approved the final version of the manuscript: MOM.
Drs. Burns, Adhikari, Zhang and Zhou have no known or perceived conflicts of interest to declare, including specific financial interests or relationships or affiliations relevant to the subject of the manuscript. Drs. Slutsky, Meade, Guyatt, Stewart and Cook coauthored one of the trials included in this review. Dr. Villar was the first author of a separate randomized trial included in this review. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life threatening clinical conditions seen in critically ill patients with diverse underlying illnesses. Lung injury may be perpetuated by ventilation strategies that do not limit lung volumes and airway pressures. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing pressure and volume-limited (PVL) ventilation strategies with more traditional mechanical ventilation in adults with ALI and ARDS.
We searched Medline, EMBASE, HEALTHSTAR and CENTRAL, related articles on PubMed™, conference proceedings and bibliographies of identified articles for randomized trials comparing PVL ventilation with traditional approaches to ventilation in critically ill adults with ALI and ARDS. Two reviewers independently selected trials, assessed trial quality, and abstracted data. We identified ten trials (n = 1,749) meeting study inclusion criteria. Tidal volumes achieved in control groups were at the lower end of the traditional range of 10–15 mL/kg. We found a clinically important but borderline statistically significant reduction in hospital mortality with PVL [relative risk (RR) 0.84; 95% CI 0.70, 1.00; p = 0.05]. This reduction in risk was attenuated (RR 0.90; 95% CI 0.74, 1.09, p = 0.27) in a sensitivity analysis which excluded 2 trials that combined PVL with open-lung strategies and stopped early for benefit. We found no effect of PVL on barotrauma; however, use of paralytic agents increased significantly with PVL (RR 1.37; 95% CI, 1.04, 1.82; p = 0.03).
This systematic review suggests that PVL strategies for mechanical ventilation in ALI and ARDS reduce mortality and are associated with increased use of paralytic agents.
Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), are common life-threatening complications of critical illness. While support with mechanical ventilation is crucial for survival, use of ventilators without regard for lung volumes and airway pressures may perpetuate lung injury and contribute to the associated high mortality of these clinical conditions. Despite recent randomized controlled trials (RCTs), the benefit of current ventilation strategies designed to limit iatrogenic lung injury remains controversial.
In 1964, Greenfield et al proposed that mechanical ventilation can induce lung injury.
These observations challenged the conventional primary goal of mechanical ventilation, which was to achieve normal arterial blood gas values. Accordingly, clinicians used tidal volumes in the range of 10–15 mL/kg with no particular restrictions of airway pressures.
Several RCTs and meta-analyses
We conducted this review according to current standards for systematic review and meta-analysis,
We electronically searched Medline (1966-July 2010), EMBASE (1980-July 2010), HEALTHSTAR (1975-July 2010), and CENTRAL (to July 2010) without language restrictions, and hand-searched abstracts published in the
Reviewers (KB, NA, MM) independently screened all titles and abstracts in duplicate (except conference proceedings) and then the full articles of all potentially relevant citations. We selected RCTs including critically ill patients, of which at least 80% were adults, at least 80% were mechanically ventilated, and at least 80% had ALI (using author's definitions). We resolved disagreements by consensus.
Conceptually, we were interested in trials comparing ventilation strategies that differed with respect to tidal volumes, airway pressures, or both. Therefore, in addition to trials comparing ventilation strategies with explicit constraints on tidal volumes or airway pressures, we also considered trials that observed an incidental gradient in tidal volume (at least 3 mL/kg) or plateau pressure (at least 5 cm H2O) during the first 7 days of study. We included trials that reported on mortality, barotrauma, duration of mechanical ventilation, use of sedation or paralytic agents, need for acute dialysis, or non-pulmonary organ dysfunction. We excluded quasi-randomized trials, such as those assigning patients by alternate allocation or hospital file number, and trials evaluating high frequency ventilation or oscillation, extracorporeal circulation, or implantable devices to augment gas exchange.
Two reviewers (KB, MM) independently abstracted data and methodological features, resolving disagreements in consultation with a third reviewer. We contacted trial investigators for relevant unpublished data and to obtain trial databases. Two reviewers (KB, MM) worked together to collate data with the assistance of a data analyst.
We assessed: allocation concealment, baseline similarity of groups (with regard to age, severity of illness, severity of lung injury, airway pressures, non-pulmonary organ dysfunction, and duration of hospitalization); relevant cointerventions (management of acidosis, application of positive end-expiratory pressure [PEEP], prone positioning, inhaled nitric oxide, systemic corticosteroids, sedation and weaning protocols), and early stopping.
To assess effects of PVL on hospital mortality, we used the most protracted follow up in each trial up to hospital discharge. We explored as potential effect modifiers: i) incorporation of ‘open lung’ techniques (using authors' definitions) into experimental PVL strategies; ii) varied thresholds for correcting respiratory acidosis; iii) between-group gradients in tidal volumes, and airway pressures; and iv) case mix effects. We reasoned that each of these might influence the effect of PVL on mortality. To explore a modifying influence of ‘open lung’ strategies, we compared pooled effects among studies with and without ‘open lung’ strategies.
To assess tolerance for respiratory acidosis we planned 4 separate analyses and resolved to report positive findings only if results were consistent. Two subgroup analyses assessed the effect of different approaches to acidosis management. Trials were classified by their pH thresholds for sodium bicarbonate administration as either above or below (i) a clinically reasonable pH threshold (7.25), and (ii) the mean pH threshold across trials. In addition, we conducted 2 univariate meta-regressions
To assess the influence of between-group gradients in tidal volume, we conducted meta-regressions of the gradients in assigned tidal volumes, and meta-regressions of the gradients in tidal volumes achieved on day 1. We used the same approach to assess the influence of variable airway pressure gradients and the impact of having mean airway pressures in the 2 groups spanning a threshold of 30 cm H2O. We hypothesized that treatment effects would be greater in trials in which mean day 1 airway pressures (ideally plateau airway pressures, if available) in the 2 groups were on either side of 30 cm H2O.
To explore the influence of case mix, we evaluated 2 baseline variables in separate meta-regressions: mean age and mean baseline arterial partial pressure of oxygen/fractional concentration of inspired oxygen ratio (PaO2/FiO2). Baseline data on plateau airway pressure were insufficiently reported to evaluate this variable as an effect modifier. Data on the Lung Injury Score (LIS)
To assess the effect of PVL on barotrauma we pooled trial estimates of the relative risk of barotrauma, using authors' definitions. We also explored the influence of ‘open lung’ ventilation, gradients in assigned and achieved (day1) tidal volume, and airway pressure gradients. To assess the influence of PVL on acute dialysis, we pooled study estimates of the relative risk of instituting dialysis.
We planned to evaluate the effects of PVL on duration of mechanical ventilation and ICU and hospital length of stay. Recognizing that early deaths systematically underestimate the duration of these outcomes among survivors, we pooled data for these outcomes separately among survivors and non-survivors. We also planned sensitivity analyses to explore the influence of weaning and sedation protocols on these outcomes.
We used random effects models
After evaluation of 14,484 citations, 20 references were evaluated in detail, and 10 were excluded.
Study[year] | Reason for Exclusion |
Lee |
Included a small number of patients with ALI (14.6%). |
Rappaport |
Neither compared the desired alternative approaches to ventilation nor achieved a gradient in tidal volume or airway pressure during follow-up |
Carvalho |
Physiologic substudy of an included trial. |
Ranieri |
Randomized trial implemented over a 40 hour study period. |
Esteban |
Neither compared the desired alternative approaches to ventilation or achieved a gradient in tidal volume or airway pressure during follow-up. |
Niu |
Neither compared the desired alternative approaches to ventilation or achieved a gradient in tidal volume or airway pressure during follow-up. |
Long |
Neither compared the desired alternative approaches to ventilation or achieved a gradient in tidal volume or airway pressure during follow-up |
McKinley |
Single centre substudy of an included larger, multicentre trial |
Amato |
Preliminary data from an included trial |
Wang |
Did not achieve difference between treatment groups in plateau airway pressure or tidal volumes. |
StudyYear[Sample Size] | InclusionCriteria | VentilatorModes | PVL Strategy | Control Strategy | PEEP |
pH Thresholds |
||
Tidal Volume | Airway Pressure | Tidal Volume | Airway Pressure | |||||
Wu |
PaO2/FiO2 <300,PaO2 <60 mm Hg, Infiltrates,Risk factor for ARDS | AC and SIMV/PS | 7–10 cc/kgDry BW |
10–15 cc/kgDry BW |
Suggested guidelines Titrated to PaO2Range: 3–12 cm H2O | |||
Brochard |
LIS >2.5 for <72 h Bilateral infiltratesSingle organ failure | AC | 6–10 cc/kgActual BW |
PPLAT ≤25 cm H2Oor ≤30 cm H2O if FiO2≥0.90, reduced chest wall compliance or pH <7.05 | 10–15 cc/kgActual BW |
PIP ≤60 cm H2O | Explicit protocolPre study PEEP trialNo titration during studyRange: 0–15 cm H2O | pH <7.05- violate VT,- NaHCO3,−- dialysis |
Amato |
LIS ≥2.5Risk factor for ARDS | PS, PCIRV or volume ensured PS (PVL)PCIRV if FiO2≥0.50 (PVL) AC or controlled ventilation (Control) | <6 cc/kgActual BW | PIP <40 cm H2ODriving pressure (Pplat – PEEP) <20 cm H2O | 12 cc/kgActual BW | Explicit protocolsPVL: 2 cm H2O aboveLIP (recruitment maneuvres) Control: Titrated to Fi02 | pH <7.20- NaHCO3− | |
Stewart |
PaO2/FiO2 <250 at PEEP 5 cm H2ORisk factor for ARDS | ACPC if PIP consistently at threshold | ≤8 cc/kgIdeal BW |
PIP ≤30 cm H2O | 10–15 cc/kgIdeal BW |
PIP ≤50 cm H2O | Suggested guidelines Titrated to FiO2 and PaO2 Range: 5–20+ |
pH <7.0- NaHCO3−- violate PIP,- if refractoryprotocol violations at MD discretion |
Brower |
PaO2/FiO2 ≤200 Bilateral infiltrates | AC and SIMV/PS(≤5 cm H2O) | 5–8 cc/kg Predicted BW |
PPLAT <30 cm H2O | 10–12 cc/kg Predicted BW |
PPLAT <45–55 cm H2O | Explicit protocolTitrated to FiO2 and PaO2 Range: 5–20+ |
pH <7.20- Adjust RR (max 30 b/min)- pH <7.30 NaHCO3−permitted andrequired if pH <7.20 |
PaO2/FiO2≤200 Bilateral infiltrates Risk factor for ARDS Static compliance≤50 ml/cm H2O | AC (PVL) | 6 cc/kg(6–10 cc/kg)Ideal BW Computerized protocol | Airway pressure not controlled | Clinician discretion | NA | PVL: Explicit protocol Titrated to FiO2 and PaO2 Range: 5–25 cm H20 Control: Clinician discretion | Target pH = 7.30(range: 7.25 –7.35)- VT (PVL) range- 6–10 cc/kg- RR (PVL) max 35 b/min | |
ARDS Network |
PaO2/FiO2≤300Bilateral infiltrates | AC | 6 cc/kg(4–8 cc/kg) Predicted BW |
PPLAT≤30 cm H2O | 12 cc/kgPredicted BW |
PPLAT≤50 cm H2O | Explicit protocolTitrated to FiO2 and PaO2 Range: 5–24 cm H2O | If 7.15≤ pH ≤7.30RR to max 35 or pH>7.30 or PaCO2 <25If RR = 35 or PaCO2 <25 may give NaHCO3−If pH <7.15RR to max 35, If RR = 35 or PaCO2 <25 NaHCO3−, violate VT by 1cc/kg and exceed PPlat |
McKinley |
PaO2/FiO2≤200 Bilateral infiltrates Risk factor for ARDSStatic compliance<50 ml/cm H2O | AC (PVL) | 6 cc/kg(6–10 cc/kg) Ideal BW Computerized protocol | Airway pressure not controlled | Clinician discretion | PIP <50 cm H2O: procedure manual | PVL: explicit protocol Titrated to FiO2 and PaO2 Range: 5–25 cm H2O Control: Suggested guideline and clinician discretion | Target pH = 7.30(range: 7.25 –7.35)- VT (PVL) range- 6–10 cc/kg- RR (PVL) max 35 b/min |
Orme |
PaO2/FiO2≤150 Infiltrates in at least 3 of 4 quadrantsRisk factor for ARDS | AC | 4–8 cc/kgPredicted BW |
PPLAT <40 cm H2O | 10–15 cc/kgPredicted BW |
PPLAT <70 cm H2O | Computerized protocols or rules (both groups) Titrated to PaO2>55 mm Hg adjusting FiO2 and PEEP | If pH <7.35 (HTV) orpH <7.20 (LTV)- Adjust RR,- dialysis,- NaHCO3− |
Villar |
PaO2/FiO2≤200 on PEEP 5, VT 5 cc/kg ×24 hrsBilateral infiltrates Criteria persist ×24 h | ACP-AC if barotrauma | 5–8 cc/kgPredicted BW |
PIP <35–40 cm H2O | 9–11 cc/kgPredicted BW |
PIP <35–40 cm H2O | PVL: 2 cm H2O above LIP or 13 cm H2OControl: PEEP ≥5 cm H2O | pH: clinician discretion PaCO2 between 35–50 mm Hg |
Sun |
PaO2/FiO2≤300 Bilateral infiltrates PAWP ≤18 mm Hg | V-AC (PVL)P-AC or SIMV+PS or PS (Control) | 4–6 cc/kgPredicted BW | PPLAT≤30 cm H2O | Target: ∼12 cc/kg PBW | PIP ≤35 cm H2O (P-AC) or PPLAT ≤30 cm (PS) | Explicit protocol |
If pH <7.20 receivedNaHCO3− until pH >7.30 |
*Details obtained from a separate publication of a subgroup with trauma-induced ARDS by McKinley et al (n = 67)
PVL = pressure and volume-limitation, LIS = lung injury score
Dry BW: Actual body weight minus the estimated weight gain due to salt and water retention.
Predicted body weight (PBW): male PBW = 50+2.3 [height (inches) –60]; female PBW = 45.5+2.3 [height (inches) – 60]. Alternatively, male PBW = 50+0.91 (centimeters of height –152.4); female PBW = 45.5+0.91 (centimeters of height –152.4).
PBW based on actuarial data.
IBW (kg) = height (meters)2×25.
Actual Body Weight minus the estimated weight gain due to water and salt retention.
PEEP: Line 1: We assessed for the presence of an explicit protocol, suggested guideline or titration of PEEP at physician discretion; Line 2: description of initial settings or titration to specific parameters; Line 3: details the range of PEEP permitted.
PEEP >20 cm H2O permitted if profoundly hypoxemic.
pH Thresholds: We assessed for a threshold pH value (or pH range) and strategies utilized to increase pH.
Study[Year] | Allocation Concealment | Baseline Similarity |
Experimental Cointerventions |
Sedation |
Weaning |
Early Stopping |
Sealed envelopes | Not specified | None | Clinician discretion | Clinician discretion | Yes,Futility | |
Sealed envelopes | Age: similarPulmonary injury: similar(PaO2/FiO2, LIS)Illness severity: similar (APACHE II |
Nitric oxideFrequent but similar | Clinician discretion | Clinician discretion | Yes,Futility, |
|
Sealed, opaque, sequentially numbered envelopes | Age: similarPulmonary injury: modestly favors controls(PaO2/FiO2, LIS |
Recruitment maneuvresPVL group onlyNo others | Suggested guideline (sedation type; not amount) | Suggested guideline | Yes,Benefit, |
|
Sealed, opaque sequentially numbered envelopes | Age: similarPulmonary injury: modest favors controls (PaO2/FiO2, oxygen index)Illness severity: similar (APACHE II |
No nitric oxideNo prone positioning | Clinician discretion | Clinician discretion | No | |
Independent randomization centre | Age: similarPulmonary injury: modestly favors controls (PaO2/FiO2, LIS |
No nitric oxideProne position: NA | Clinician discretion | Clinician discretion | Yes,Futility, |
|
Independent randomization centre | NA | None | Clinician discretion | PVL: explicit protocol Control: clinician discretion | No | |
Independent randomization centre | Age: similarPulmonary injury: similar (PaO2/FiO2, ARDS)Illness severity: similar (APACHE III |
Prone positionRare but similarOthers: <1% | Clinician discretion | Explicit protocol | Yes,Benefit,a priori rules | |
Independent randomization centre | Age: similarIllness severity: similar (ISS |
None (PVL) group | Suggested guideline and clinician discretion | PVL: explicit protocol Control: clinician discretion | No | |
Sealed, opaque, sequentially numbered envelopes | NA | Unknown | Suggested guideline | Explicit protocol | No | |
Sealed, opaque, envelopes | Age: similarPulmonary injury: similar (LIS |
NA | Clinician discretion | Clinician discretion | Yes,Benefita priori rules | |
Assigned numbers, Random number table | Age: similarPulmonary injury: similar proportion with PaO2/FiO2<200 mm HgIllness severity: similar(APACHE II |
No steroids or, inhaled Nitric oxide (both groups) Prone position occasionally at MD discretionRecruitment maneuvers (both groups) | Suggested guideline (type, amount, route) Protocolized daily awakening | Explicit Protocol (both groups) | No |
Details obtained from a separate publication of a subgroup with trauma-induced ARDS by McKinley et al (n = 67)
PVL = pressure and volume-limitation; LIS = lung injury score
StudyYear[N] | PopulationAge,PaO2/FiO2LIS |
PEEPTimePEEP Gradient Achieved (cm H2O)PEEP Achieved - Control Group (cm H2O)PEEP Achieved - PVL Group (cm H2O) | Tidal VolumeTimeTidal Volume Gradient Achieved (cc/kg or cc)Tidal Volume - Control Group (cc/kg or cc)Tidal Volume - PVL Group (cc/kg or cc) | Airway PressureTimeAirway Pressure Gradient Achieved (cm H2O)Airway Pressure - Control Group (cm H2O)Airway Pressure - PVL Group (cm H2O) | |||||||||
Wu |
40.3 ± 12.7——— | Unspecified time 9.9 cm H2O |
|||||||||||
Brochard |
56.8 ± 15.3149.5 ± 64.63.0 ± 0.317.5 ± 7.5 | Day 1010.710.7 | Day 20.210.810.6 | Day 7−1.18.59.6 | Day 140.58.37.8 | Day 13.2 cc/kg |
Day 23.43 cc/kg |
Day 73.33 cc/kg |
Day 142.3 cc/kg |
Day 16.0 cm H2O |
Day 25.9 cm H2O |
Day 76.0 cm H2O |
Day 149.1 cm H2O |
Amato |
34.4 ± 13.5122.0 ± 58.83.3 ± 0.427.5 ± 6.6 | 36 hours−7.7 |
Days 2-7−3.9 |
36 hours420 cc |
Days 2 – 7351 cc |
36 hours6.7 cm H2O |
Days 2 – 713.9 cm H2O |
||||||
Stewart |
58.5 ± 18.0134.0 ± 60.8—22.0 ± 8.5 | Day 1−1.4 |
Day 3−0.38.48.7 | Day 7−1.68.09.6 | Day 13.7 cc/kg |
Day 33.6 cc/kg |
Day 73.3 cc/kg |
Day 14.5 cm H2O |
Day 36.3 cm H2O |
Day 78.6 cm H2O |
|||
Brower |
48.4 ± 15.8139.5 ± 60.72.8 ± 0.587.6 |
Days 1 - 52.9 cc/kg |
Days 1 - 55.7 cm H2O |
||||||||||
ARDS Network |
51.5 ± 17.5136.0 ± 61.1—82.5 |
Day 1−0.8 |
Day 3−0.6 |
Day 71.0 |
Day 15.6 cc/kg |
Day 35.6 cc/kg |
Day 74.9 cc/kg |
Day 18.0 cm H2O |
Day 38.0 cm H2O |
Day 711.0 cm H2O |
|||
39.0 ± 2.5——— | Day 1−1.010.011.0 | Day 3010.010.0 | Day 5010.010.0 | Day 12.011.09.0 | Day 34.012.08.0 | Day 53.011.08.0 | Day 11.038.037.0 | Day 3 4.0 39.0 35.0 | Day 55.040.035.0 | ||||
Villar |
49.9—2.9±0.4518.0 ± 6.5 | Day 1−5.1 |
Day 3−2.5 |
Day 60.18.38.2 | Day 12.9 |
Day 32.9 |
Day 62.8 |
Day 12.032.630.6 | Day 34.1 |
Day 66.7 |
|||
Sun |
50.5 ± 13.2——83.5 ± 28.0 | 1st week3.79.86.1 | 1st week1.025.726.7 |
Details obtained from a separate publication of East et al
PVL = pressure and volume-limitation,
Subgroup of a multicentre RCT comparing protocol directed, pressure and volume-limited ventilation to non-protocol directed ventilation by East et al (n = 200)
Gradients reflect the difference between the control and treatment groups (i.e. Control – Treatment).
Characteristics of the study populations are presented as pooled mean and standard deviation.
idal volume in cc.
APACHE III.
p≤0.001;
0.001<p<0.01;
0.01≤p≤0.05.
One trial measured “death before discharge home and breathing without assistance” and reported a statistically significant difference favoring a PVL approach (RR 0.78; 95%CI 0.65, 0.93).
The various analyses that we conducted to assess tolerance for acidosis with PVL strategies as an effect modifier generated inconsistent results and were, therefore, inconclusive (data not shown). Meta-regression analyses did not identify the magnitude of within-study gradients in assigned (or achieved) tidal volumes or airway pressures between treatment groups as important effect modifiers (data not shown). We did not find a linear relationship between study mean age or mean baseline PaO2/FiO2 and mortality. However, these analyses were underpowered and limited by the small number of included studies (range 3 to 9).
Rates of barotrauma varied across trials from 3.8%
Quality |
Relative Risk (95% CI)p-value | Illustrative risks | ||||||||
Outcome | No. of patients (studies) | Risk of Bias | Inconsistency |
Indirectness |
Imprecision | Publication Bias | Example control rate | Associated risk with PVL | ||
Hospital mortality | 1,749 (10) | Inability to blind.2 trials stopped early with few events and large effects; were also confounded by ‘open lung’ strategies. | p = 0.07I2 = 45.6%Varied populations, interventions.Not robust in sensitivity analyses | Direct | Precise | Undetected | Moderate due to (inconsistency) | 0.84(0.70 – 1.00) p = 0.05 | 40% | 33.6%(28.0 – 40.0) |
Barotrauma | 1,497 (7) | Inability to blind. | p = 0.24I2 = 25.3%Varied populations, interventions | Direct | Imprecise | Undetected | Moderate due to (imprecision) | 0.90(0.66 – 1.24) p = 0.53 | NS | NS |
Paralysis | 1,202 (5) | Inability to blind. | p = 0.004I2 = 59%Varied populations, interventions, measurements | Direct | Precise | Not assessed | Moderate due to (inconsistency) | 1.37(1.04 – 1.82) p = 0.03 | 30% | 41.1%(31.2 – 54.6) |
Dialysis | 173 (2) | Inability to blind. | p = 0.26I2 = 22.8%Varied populations, interventions | Direct | Imprecise | Not assessed | Moderate due to (imprecision) | 1.76(0.79 – 3.90) p = 0.16 | NS | NS |
This Summary of Evidence Table corresponds to the GRADE method of summarizing clinical research evidence.
Inconsistency is described by the p-value corresponding to the Cochrane Q test for heterogeneity, the I2 statistic, and differences among study methods.
Indirectness relates to proximity to the question of survival benefit.
The quality of randomized trial evidence can be downgraded for risk of bias, inconsistency, indirectness, imprecision, or publication bias.
Five trials
Two trials
We provide descriptive data related to the evolution of pulmonary and non-pulmonary organ dysfunction. While the evolution of gas exchange was measured variably, between-group differences were modest and inconsistent. Measurements of oxygenation over the first week included PaO2 in 4 trials
Three trials
Data on duration of ventilation, ventilator-free days, length of ICU and hospital stay were infrequently reported or reported non-uniformly, which precluded meta-analysis.
This systematic review of 10 RCTs comparing PVL strategies to ventilation strategies designed to approach more traditional ventilatory goals in ALI and ARDS suggests that PVL reduces mortality. However, this finding was not robust in sensitivity analyses and the confidence intervals include unity, so some uncertainty remains. We did not detect dose-response interactions between treatment effect and the magnitude the differences in tidal volumes or airway pressures. However, control group ventilation strategies did not achieve the full range of traditional tidal volumes; mean tidal volumes were consistently at the lower end of the traditional range. We found no effects of PVL ventilation on barotrauma, which was an anticipated benefit. We observed more acidosis with PVL strategies and a significant increase in the use of paralytic agents.
The analysis in which we pooled survival data from trials involving 1,749 patients may represent an overestimate of treatment effect. The summary estimate suggests a 16.0% reduction in the relative risk of mortality with PVL, and the confidence intervals suggest that the relative risk of mortality might be reduced as much as 30.0%, or not at all. While the ARDS Network trial
Whether or not open lung strategies improve survival is a subject of ongoing controversy. A recent meta-analysis of 6 RCTs involving 2,484 patients and comparing 2 different levels of PEEP (with or without other interventions) suggested that the use of high levels of PEEP may have an independent beneficial effect on mortality with an absolute risk reduction of approximately 5%.
Historically, investigators using high tidal volumes reported high rates of barotrauma in clinical practice.
A notable physiological effect of PVL strategies is respiratory acidosis. Among 6 trials reporting on the evolution of arterial carbon dioxide levels there were significantly higher arterial partial pressures of carbon dioxide and lower pH levels over the first week of study. Analyses exploring a possible interaction between tolerance for acidosis and survival effects of PVL were inconclusive.
The higher rate of paralysis with PVL strategies may be related to higher rates of respiratory acidosis and ventilator dysynchrony. While early observational studies suggested that neuromuscular blockade may increase rates of ICU polyneuropathy, a recent RCT suggested that neuromuscular blockade, itself, may improve gas exchange and biological markers of lung injury.
Pooling results in a systematic review with meta-analysis implicitly assumes that the trials are sufficiently similar with respect to populations, study interventions, measurement of outcomes and methodologic quality that one could reasonably expect a similar underlying treatment effect. While this was our assumption in pooling data across trials, we launched this review with the explicit goal of testing hypotheses to explain the differences among study results. The most prominent of the 10 trials is the ARDS Network trial
This review was strengthened by following a predetermined protocol for review methods and statistical analysis. Our extensive search strategy allowed us to identify an additional 341 patients from 3 trials
This systematic review suggests that PVL strategies for mechanical ventilation in ALI and ARDS may reduce mortality and, therefore, supports the current practice to ventilate these patients with low tidal volumes. However, we did not find a dose-response effect and this borderline significant finding was not robust in sensitivity analyses. Therefore, some uncertainty regarding the effect of PVL ventilation remains.
The authors wish to express their gratitude to Drs. Roy Brower, Marcello Amato and Laurent Brochard for providing their study databases. Additionally, we wish to thank Dr Roy Brower for reviewing the manuscript prior to submission.