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1.  Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis 
BMJ : British Medical Journal  2007;334(7597):779.
Objective To review the literature on the use of inhaled nitric oxide to treat acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and to summarise the effects of nitric oxide, compared with placebo or usual care without nitric oxide, in adults and children with ALI or ARDS.
Design Systematic review and meta-analysis.
Data sources Medline, CINAHL, Embase, and CENTRAL (to October 2006), proceedings from four conferences, and additional information from authors of 10 trials.
Review methods Two reviewers independently selected parallel group randomised controlled trials comparing nitric oxide with control and extracted data related to study methods, clinical and physiological outcomes, and adverse events.
Main outcome measures Mortality, duration of ventilation, oxygenation, pulmonary arterial pressure, adverse events.
Results 12 trials randomly assigning 1237 patients met inclusion criteria. Overall methodological quality was good. Using random effects models, we found no significant effect of nitric oxide on hospital mortality (risk ratio 1.10, 95% confidence interval 0.94 to 1.30), duration of ventilation, or ventilator-free days. On day one of treatment, nitric oxide increased the ratio of partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2 ratio) (13%, 4% to 23%) and decreased the oxygenation index (14%, 2% to 25%). Some evidence suggested that improvements in oxygenation persisted until day four. There was no effect on mean pulmonary arterial pressure. Patients receiving nitric oxide had an increased risk of developing renal dysfunction (1.50, 1.11 to 2.02).
Conclusions Nitric oxide is associated with limited improvement in oxygenation in patients with ALI or ARDS but confers no mortality benefit and may cause harm. We do not recommend its routine use in these severely ill patients.
doi:10.1136/bmj.39139.716794.55
PMCID: PMC1852043  PMID: 17383982
2.  Study protocol: The Improving Care of Acute Lung Injury Patients (ICAP) study 
Critical Care  2005;10(1):R9.
Introduction
The short-term mortality benefit of lower tidal volume ventilation (LTVV) for patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has been demonstrated in a large, multi-center randomized trial. However, the impact of LTVV and other critical care therapies on the longer-term outcomes of ALI/ARDS survivors remains uncertain. The Improving Care of ALI Patients (ICAP) study is a multi-site, prospective cohort study that aims to evaluate the longer-term outcomes of ALI/ARDS survivors with a particular focus on the effect of LTVV and other critical care therapies.
Methods
Consecutive mechanically ventilated ALI/ARDS patients from 11 intensive care units (ICUs) at four hospitals in the city of Baltimore, MD, USA, will be enrolled in a prospective cohort study. Exposures (patient-based, clinical management, and ICU organizational) will be comprehensively collected both at baseline and throughout patients' ICU stay. Outcomes, including mortality, organ impairment, functional status, and quality of life, will be assessed with the use of standardized surveys and testing at 3, 6, 12, and 24 months after ALI/ARDS diagnosis. A multi-faceted retention strategy will be used to minimize participant loss to follow-up.
Results
On the basis of the historical incidence of ALI/ARDS at the study sites, we expect to enroll 520 patients over two years. This projected sample size is more than double that of any published study of long-term outcomes in ALI/ARDS survivors, providing 86% power to detect a relative mortality hazard of 0.70 in patients receiving higher versus lower exposure to LTVV. The projected sample size also provides sufficient power to evaluate the association between a variety of other exposure and outcome variables, including quality of life.
Conclusion
The ICAP study is a novel, prospective cohort study that will build on previous critical care research to improve our understanding of the longer-term impact of ALI/ARDS, LTVV and other aspects of critical care management. Given the paucity of information about the impact of interventions on long-term outcomes for survivors of critical illness, this study can provide important information to inform clinical practice.
doi:10.1186/cc3948
PMCID: PMC1550857  PMID: 16420652
3.  Contemporary Ventilator Management in Patients With and at Risk of ALI/ARDS 
Respiratory care  2013;58(4):10.4187/respcare.01755.
BACKGROUND
Ventilator practices in patients at risk for acute lung injury (ALI) and ARDS are unclear. We examined factors associated with choice of set tidal volumes (VT), and whether VT < 8 mL/kg predicted body weight (PBW) relates to the development of ALI/ARDS.
METHODS
We performed a secondary analysis of a multicenter cohort of adult subjects at risk of lung injury with and without ALI/ARDS at onset of invasive ventilation. Descriptive statistics were used to describe ventilator practices in specific settings and ALI/ARDS risk groups. Logistic regression analysis was used to determine the factors associated with the use of VT < 8 mL/kg PBW and the relationship of VT to ALI/ARDS development and outcome.
RESULTS
Of 829 mechanically ventilated patients, 107 met the criteria for ALI/ARDS at time of intubation, and 161 developed ALI/ARDS after intubation (post-intubation ALI/ARDS). There was significant intercenter variability in initial ventilator settings, and in the incidence of ALI/ARDS and post-intubation ALI/ARDS. The median VT was 7.96 (IQR 7.14–8.94) mL/kg PBW in ALI/ARDS subjects, and 8.45 (IQR 7.50–9.55) mL/kg PBW in subjects without ALI/ARDS (P = .004). VT decreased from 8.40 (IQR 7.38–9.37) mL/kg PBW to 7.97 (IQR 6.90–9.23) mL/kg PBW (P < .001) in those developing post-intubation ALI/ARDS. Among subjects without ALI/ARDS, VT ≥ 8 mL/kg PBW was associated with shorter height and higher body mass index, while subjects with pneumonia were less likely to get ≥ 8 mL/kg PBW. Initial VT ≥ 8 mL/kg PBW was not associated with the post-intubation ALI/ARDS (adjusted odds ratio 1.30, 95% CI 0.74–2.29) or worse outcomes. Post-intubation ALI/ARDS subjects had mortality similar to subjects intubated with ALI/ARDS.
CONCLUSIONS
Clinicians seem to respond to ALI/ARDS with lower initial VT. Initial VT, however, was not associated with the development of post-intubation ALI/ARDS or other outcomes.
doi:10.4187/respcare.01755
PMCID: PMC3840036  PMID: 22906363
acute lung injury; ARDS; mechanical ventilation; mortality; tidal volume
4.  Bench-to-bedside review: High-frequency oscillatory ventilation in adults with acute respiratory distress syndrome 
Critical Care  2006;10(6):240.
Mechanical ventilation is the cornerstone of therapy for patients with acute respiratory distress syndrome (ARDS). Paradoxically, mechanical ventilation can exacerbate lung damage – a phenomenon known as ventilator-induced lung injury. While new ventilation strategies have reduced the mortality rate in patients with ARDS, this mortality rate still remains high. High-frequency oscillatory ventilation (HFOV) is an unconventional form of ventilation that may improve oxygenation in patients with ARDS, while limiting further lung injury associated with high ventilatory pressures and volumes delivered during conventional ventilation. HFOV has been used for almost two decades in the neonatal population, but there is more limited experience with HFOV in the adult population. In adults, the majority of the published literature is in the form of small observational studies in which HFOV was used as 'rescue' therapy for patients with very severe ARDS who were failing conventional ventilation. Two prospective randomized controlled trials, however, while showing no mortality benefit, have suggested that HFOV, compared with conventional ventilation, is a safe and effective ventilation strategy for adults with ARDS. Several studies suggest that HFOV may improve outcomes if used early in the course of ARDS, or if used in certain populations. This review will summarize the evidence supporting the use of HFOV in adults with ARDS.
doi:10.1186/cc5096
PMCID: PMC1794464  PMID: 17184554
5.  Extracorporeal Lung Support Technologies – Bridge to Recovery and Bridge to Lung Transplantation in Adult Patients 
Executive Summary
For cases of acute respiratory distress syndrome (ARDS) and progressive chronic respiratory failure, the first choice or treatment is mechanical ventilation. For decades, this method has been used to support critically ill patients in respiratory failure. Despite its life-saving potential, however, several experimental and clinical studies have suggested that ventilator-induced lung injury can adversely affect the lungs and patient outcomes. Current opinion is that by reducing the pressure and volume of gas delivered to the lungs during mechanical ventilation, the stress applied to the lungs is eased, enabling them to rest and recover. In addition, mechanical ventilation may fail to provide adequate gas exchange, thus patients may suffer from severe hypoxia and hypercapnea. For these reasons, extracorporeal lung support technologies may play an important role in the clinical management of patients with lung failure, allowing not only the transfer of oxygen and carbon dioxide (CO2) but also buying the lungs the time needed to rest and heal.
Objective
The objective of this analysis was to assess the effectiveness, safety, and cost-effectiveness of extracorporeal lung support technologies in the improvement of pulmonary gas exchange and the survival of adult patients with acute pulmonary failure and those with end-stage chronic progressive lung disease as a bridge to lung transplantation (LTx). The application of these technologies in primary graft dysfunction (PGD) after LTx is beyond the scope of this review and is not discussed.
Clinical Applications of Extracorporeal Lung Support
Extracorporeal lung support technologies [i.e., Interventional Lung Assist (ILA) and extracorporeal membrane oxygenation (ECMO)] have been advocated for use in the treatment of patients with respiratory failure. These techniques do not treat the underlying lung condition; rather, they improve gas exchange while enabling the implantation of a protective ventilation strategy to prevent further damage to the lung tissues imposed by the ventilator. As such, extracorporeal lung support technologies have been used in three major lung failure case types:
As a bridge to recovery in acute lung failure – for patients with injured or diseased lungs to give their lungs time to heal and regain normal physiologic function.
As a bridge to LTx – for patients with irreversible end stage lung disease requiring LTx.
As a bridge to recovery after LTx – used as lung support for patients with PGD or severe hypoxemia.
Ex-Vivo Lung Perfusion and Assessment
Recently, the evaluation and reconditioning of donor lungs ex-vivo has been introduced into clinical practice as a method of improving the rate of donor lung utilization. Generally, about 15% to 20% of donor lungs are suitable for LTx, but these figures may increase with the use of ex-vivo lung perfusion. The ex-vivo evaluation and reconditioning of donor lungs is currently performed at the Toronto General Hospital (TGH) and preliminary results have been encouraging (Personal communication, clinical expert, December 17, 2009). If its effectiveness is confirmed, the use of the technique could lead to further expansion of donor organ pools and improvements in post-LTx outcomes.
Extracorporeal Lung support Technologies
ECMO
The ECMO system consists of a centrifugal pump, a membrane oxygenator, inlet and outlet cannulas, and tubing. The exchange of oxygen and CO2 then takes place in the oxygenator, which delivers the reoxygenated blood back into one of the patient’s veins or arteries. Additional ports may be added for haemodialysis or ultrafiltration.
Two different techniques may be used to introduce ECMO: venoarterial and venovenous. In the venoarterial technique, cannulation is through either the femoral artery and the femoral vein, or through the carotid artery and the internal jugular vein. In the venovenous technique cannulation is through both femoral veins or a femoral vein and internal jugular vein; one cannula acts as inflow or arterial line, and the other as an outflow or venous line. Venovenous ECMO will not provide adequate support if a patient has pulmonary hypertension or right heart failure. Problems associated with cannulation during the procedure include bleeding around the cannulation site and limb ischemia distal to the cannulation site.
ILA
Interventional Lung Assist (ILA) is used to remove excess CO2 from the blood of patients in respiratory failure. The system is characterized by a novel, low-resistance gas exchange device with a diffusion membrane composed of polymethylpentene (PMP) fibres. These fibres are woven into a complex configuration that maximizes the exchange of oxygen and CO2 by simple diffusion. The system is also designed to operate without the help of an external pump, though one can be added if higher blood flow is required. The device is then applied across an arteriovenous shunt between the femoral artery and femoral vein. Depending on the size of the arterial cannula used and the mean systemic arterial pressure, a blood flow of up to 2.5 L/min can be achieved (up to 5.5 L/min with an external pump). The cannulation is performed after intravenous administration of heparin.
Recently, the first commercially available extracorporeal membrane ventilator (NovaLung GmbH, Hechingen, Germany) was approved for clinical use by Health Canada for patients in respiratory failure. The system has been used in more than 2,000 patients with various indications in Europe, and was used for the first time in North America at the Toronto General Hospital in 2006.
Evidence-Based Analysis
The research questions addressed in this report are:
Does ILA/ECMO facilitate gas exchange in the lungs of patients with severe respiratory failure?
Does ILA/ECMO improve the survival rate of patients with respiratory failure caused by a range of underlying conditions including patients awaiting LTx?
What are the possible serious adverse events associated with ILA/ECMO therapy?
To address these questions, a systematic literature search was performed on September 28, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 to September 28, 2008. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Studies in which ILA/ECMO was used as a bridge to recovery or bridge to LTx
Studies containing information relevant to the effectiveness and safety of the procedure
Studies including at least five patients
Exclusion Criteria
Studies reporting the use of ILA/ECMO for inter-hospital transfers of critically ill patients
Studies reporting the use of ILA/ECMO in patients during or after LTx
Animal or laboratory studies
Case reports
Outcomes of Interest
Reduction in partial pressure of CO2
Correction of respiratory acidosis
Improvement in partial pressure of oxygen
Improvement in patient survival
Frequency and severity of adverse events
The search yielded 107 citations in Medline and 107 citations in EMBASE. After reviewing the information provided in the titles and abstracts, eight citations were found to meet the study inclusion criteria. One study was then excluded because of an overlap in the study population with a previous study. Reference checking did not produce any additional studies for inclusion. Seven case series studies, all conducted in Germany, were thus included in this review (see Table 1).
Also included is the recently published CESAR trial, a multicentre RCT in the UK in which ECMO was compared with conventional intensive care management. The results of the CESAR trial were published when this review was initiated. In the absence of any other recent RCT on ECMO, the results of this trial were considered for this assessment and no further searches were conducted. A literature search was then conducted for application of ECMO as bridge to LTx patients (January, 1, 2005 to current). A total of 127 citations on this topic were identified and reviewed but none were found to have examined the use of ECMO as bridge to LTx.
Quality of Evidence
To grade the quality of evidence, the grading system formulated by the GRADE working group and adopted by MAS was applied. The GRADE system classifies the quality of a body of evidence as high, moderate, low, or very low according to four key elements: study design, study quality, consistency across studies, and directness.
Results
Trials on ILA
Of the seven studies identified, six involved patients with ARDS caused by a range of underlying conditions; the seventh included only patients awaiting LTx. All studies reported the rate of gas exchange and respiratory mechanics before ILA and for up to 7 days of ILA therapy. Four studies reported the means and standard deviations of blood gas transfer and arterial blood pH, which were used for meta-analysis.
Fischer et al. reported their first experience on the use of ILA as a bridge to LTx. In their study, 12 patients at high urgency status for LTx, who also had severe ventilation refractory hypercapnea and respiratory acidosis, were connected to ILA prior to LTx. Seven patients had a systemic infection or sepsis prior to ILA insertion. Six hours after initiation of ILA, the partial pressure of CO2 in arterial blood significantly decreased (P < .05) and arterial blood pH significantly improved (P < .05) and remained stable for one week (last time point reported). The partial pressure of oxygen in arterial blood improved from 71 mmHg to 83 mmHg 6 hours after insertion of ILA. The ratio of PaO2/FiO2 improved from 135 at baseline to 168 at 24 hours after insertion of ILA but returned to baseline values in the following week.
Trials on ECMO
The UK-based CESAR trial was conducted to assess the effectiveness and cost of ECMO therapy for severe, acute respiratory failure. The trial protocol were published in 2006 and details of the methods used for the economic evaluation were published in 2008. The study itself was a pragmatic trial (similar to a UK trial of neonatal ECMO), in which best standard practice was compared with an ECMO protocol. The trial involved 180 patients with acute but potentially reversible respiratory failure, with each also having a Murray score of ≥ 3.0 or uncompensated hypercapnea at a pH of < 7.2. Enrolled patients were randomized in a 1:1 ratio to receive either conventional ventilation treatment or ECMO while on ventilator. Conventional management included intermittent positive pressure ventilation, high frequency oscillatory ventilation, or both. As a pragmatic trial, a specific management protocol was not followed; rather the treatment centres were advised to follow a low volume low pressure ventilation strategy. A tidal volume of 4 to 8 mL/kg body weight and a plateau pressure of < 30 cm H2O were recommended.
Conclusions
ILA
Bridge to recovery
No RCTs or observational studies compared ILA to other treatment modalities.
Case series have shown that ILA therapy results in significant CO2 removal from arterial blood and correction of respiratory acidosis, as well as an improvement in oxygen transfer.
ILA therapy enabled a lowering of respiratory settings to protect the lungs without causing a negative impact on arterial blood CO2 and arterial blood pH.
The impact of ILA on patient long-term survival cannot be determined through the studies reviewed.
In-hospital mortality across studies ranged from 20% to 65%.
Ischemic complications were the most frequent adverse events following ILA therapy.
Leg amputation is a rare but possible outcome of ILA therapy, having occurred in about 0.9% of patients in these case series. New techniques involving the insertion of additional cannula into the femoral artery to perfuse the leg may lower this rate.
Bridge to LTx
The results of one case series (n=12) showed that ILA effectively removes CO2 from arterial blood and corrects respiratory acidosis in patients with ventilation refractory hypercapnea awaiting a LTx
Eight of the 12 patients (67%) awaiting a LTx were successfully transplanted and one-year survival for those transplanted was 80%
Since all studies are case series, the grade of the evidence for these observations is classified as “LOW”.
ECMO
Bridge to recovery
Based on the results of a pragmatic trial and an intention to treat analysis, referral of patient to an ECMO based centre significantly improves patient survival without disability compared to conventional ventilation. The results of CESAR trial showed that:
For patients with information about disability, survival without severe disability was significantly higher in ECMO arm
Assuming that the three patients in the conventional ventilation arm who did not have information about severe disability were all disabled, the results were also significant.
Assuming that none of these patients were disabled, the results were at borderline significance
A greater, though not statistically significant, proportion of patients in ECMO arm survived.
The rate of serious adverse events was higher among patients in ECMO group
The grade of evidence for the above observations is classified as “HIGH”.
Bridge to LTx
No studies fitting the inclusion criteria were identified.
There is no accurate data on the use of ECMO in patients awaiting LTx.
Economic Analysis
The objective of the economic analysis was to determine the costs associated with extracorporeal lung support technologies for bridge to LTx in adults. A literature search was conducted for which the target population was adults eligible for extracorporeal lung support. The primary analytic perspective was that of the Ministry of Health and Long-Term Care (MOHLTC). Articles published in English and fitting the following inclusion criteria were reviewed:
Full economic evaluations including cost-effectiveness analyses (CEA), cost-utility analyses (CUA), cost-benefit analyses (CBA);
Economic evaluations reporting incremental cost-effectiveness ratios (ICER) i.e. cost per quality adjusted life year (QALY), life years gained (LYG), or cost per event avoided; and
Studies in patients eligible for lung support technologies for to lung transplantation.
The search yielded no articles reporting comparative economic analyses.
Resource Use and Costs
Costs associated with both ILA and ECMO (outlined in Table ES-1) were obtained from the University Health Network (UHN) case costing initiative (personal communication, UHN, January 2010). Consultation with a clinical expert in the field was also conducted to verify resource utilization. The consultant was situated at the UHN in Toronto. The UHN has one ECMO machine, which cost approximately $100,000. The system is 18 years old and is used an average of 3 to 4 times a year with 35 procedures being performed over the last 9 years. The disposable cost per patient associated with ECMO is, on average, $2,200. There is a maintenance cost associated with the machine (not reported by the UHN), which is currently absorbed by the hospital’s biomedical engineering department.
The average capital cost of an ILA device is $7,100 per device, per patient, while the average cost of the reusable pump $65,000. The UHN has performed 16 of these procedures over the last 2.5 years. Similarly, there is a maintenance cost not that was reported by UHN but is absorbed by the hospital’s biomedical engineering department.
Resources Associated with Extracorporeal Lung Support Technologies
Hospital costs associated with ILA were based on the average cost incurred by the hospital for 11 cases performed in the FY 07/08 (personal communication, UHN, January 2010). The resources incurred with this hospital procedure included:
Device and disposables
OR transplant
Surgical ICU
Laboratory work
Medical imaging
Pharmacy
Clinical nutrition
Physiotherapy
Occupational therapy
Speech and language pathology
Social work
The average length of stay in hospital was 61 days for ILA (range: 5 to 164 days) and the average direct cost was $186,000 per case (range: $19,000 to $552,000). This procedure has a high staffing requirement to monitor patients in hospital, driving up the average cost per case.
PMCID: PMC3415698  PMID: 23074408
6.  Lower tidal volume at initiation of mechanical ventilation may reduce progression to acute respiratory distress syndrome: a systematic review 
Critical Care  2013;17(1):R11.
Introduction
The most appropriate tidal volume in patients without acute respiratory distress syndrome (ARDS) is controversial and has not been rigorously examined. Our objective was to determine whether a mechanical ventilation strategy using lower tidal volume is associated with a decreased incidence of progression to ARDS when compared with a higher tidal volume strategy.
Methods
A systematic search of MEDLINE, EMBASE, CINAHL, the Cochrane Library, conference proceedings, and clinical trial registration was performed with a comprehensive strategy. Studies providing information on mechanically ventilated patients without ARDS at the time of initiation of mechanical ventilation, and in which tidal volume was independently studied as a predictor variable for outcome, were included. The primary outcome was progression to ARDS.
Results
The search yielded 1,704 studies, of which 13 were included in the final analysis. One randomized controlled trial was found; the remaining 12 studies were observational. The patient cohorts were significantly heterogeneous in composition and baseline risk for developing ARDS; therefore, a meta-analysis of the data was not performed. The majority of the studies (n = 8) showed a decrease in progression to ARDS with a lower tidal volume strategy. ARDS developed early in the course of illness (5 hours to 3.7 days). The development of ARDS was associated with increased mortality, lengths of stay, mechanical ventilation duration, and nonpulmonary organ failure.
Conclusions
In mechanically ventilated patients without ARDS at the time of endotracheal intubation, the majority of data favors lower tidal volume to reduce progression to ARDS. However, due to significant heterogeneity in the data, no definitive recommendations can be made. Further randomized controlled trials examining the role of lower tidal volumes in patients without ARDS, controlling for ARDS risk, are needed.
2013 Fuller et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
doi:10.1186/cc11936
PMCID: PMC3983656  PMID: 23331507
7.  Tidal Volume Reduction in Patients with Acute Lung Injury When Plateau Pressures Are Not High 
Use of a volume- and pressure-limited mechanical ventilation strategy improves clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS). However, the extent to which tidal volumes and inspiratory airway pressures should be reduced to optimize clinical outcomes is a controversial topic. This article addresses the question, “Is there a safe upper limit to inspiratory plateau pressure in patients with ALI/ARDS?” We reviewed data from animal models with and without preexisting lung injury, studies of normal human respiratory system mechanics, and the results of five clinical trials of lung-protective mechanical ventilation strategies. We also present an original analysis of data from the largest of the five clinical trials. The available data from each of these assessments do not support the commonly held view that inspiratory plateau pressures of 30 to 35 cm H2O are safe. We could not identify a safe upper limit for plateau pressures in patients with ALI/ARDS.
doi:10.1164/rccm.200501-048CP
PMCID: PMC2718413  PMID: 16081547
acute respiratory distress syndrome; acute lung injury; plateau; mechanical ventilation
8.  Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial 
Trials  2012;13:153.
Background
Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART).
Methods/Design
ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH2O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure ≤30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle.
Discussion
If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.
Trial registration
ClinicalTrials.gov Identifier: NCT01374022
doi:10.1186/1745-6215-13-153
PMCID: PMC3543273  PMID: 22929542
Acute respiratory distress syndrome; Alveolar recruitment; PEEP; Mechanical ventilation; Clinical trials; Randomized
9.  Neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials 
Background
Acute respiratory distress syndrome (ARDS) is a potentially fatal disease with high mortality. Our aim was to summarize the current evidence for use of neuromuscular blocking agents (NMBA) in the early phase of ARDS.
Methods
Systematic review and meta-analysis of publications between 1966 and 2012. The Medline and CENTRAL databases were searched for studies on NMBA in patients with ARDS. The meta-analysis was limited to: 1) randomized controlled trials; 02) adult human patients with ARDS or acute lung injury; and 03) use of any NMBA in one arm of the study compared with another arm without NMBA. The outcomes assessed were: overall mortality, ventilator-free days, time of mechanical ventilation, adverse events, changes in gas exchange, in ventilator settings, and in respiratory mechanics.
Results
Three randomized controlled trials covering 431 participants were included. Patients treated with NMBA showed less mortality (Risk ratio, 0.71 [95 % CI, 0.55 – 0.90]; number needed to treat, 1 – 7), more ventilator free days at day 28 (p = 0.020), higher PaO2 to FiO2 ratios (p = 0.004), and less barotraumas (p = 0.030). The incidence of critical illness neuromyopathy was similar (p = 0.540).
Conclusions
The use of NMBA in the early phase of ARDS improves outcome.
doi:10.1186/2110-5820-2-33
PMCID: PMC3475105  PMID: 22835162
ARDS; Neuromuscular blocking agents; Meta-analysis; Review
10.  Acute respiratory distress syndrome 
Clinical Evidence  2010;2010:1511.
Introduction
Acute respiratory distress syndrome (ARDS) is characterised by a profound deterioration in systemic oxygenation or ventilation, or both, despite supportive respiratory therapy. ARDS is an acute and progressive respiratory disease of a non-cardiac cause that is associated with progressively diffuse bilateral pulmonary infiltrates, reduced pulmonary compliance, and hypoxaemia. The main causes of ARDS include direct lung injury (e.g., pneumonia, gastric acid aspiration) or indirect lung injury (e.g., sepsis, pancreatitis, massive blood transfusion, non-thoracic trauma). Sepsis and pneumonia account for about 60% of cases. Between one third and one half of people with ARDS die from the disease, but mortality depends on the underlying cause. Some survivors have long-term respiratory or cognitive problems.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions in adults with acute respiratory distress syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 20 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: corticosteroids, low tidal-volume mechanical ventilation, nitric oxide, prone position, and protective ventilation.
Key Points
Acute respiratory distress syndrome (ARDS) is a syndrome of inflammation and increased permeability that is associated with clinical, radiological, and physiological abnormalities, which usually develops over 4 to 48 hours and persists for days or weeks. Pathologically, ARDS is associated with complex changes in the lungs, manifested by an early exudative phase and followed by proliferative and fibrotic phases. The main causes of ARDS are infections, aspiration of gastric contents, and trauma.Between one third and one half of people with ARDS die, but mortality depends on the underlying cause. Some survivors have long-term respiratory or cognitive problems.The treatment of ARDS is supportive care, including optimised mechanical ventilation, nutritional support, manipulation of fluid balance, source control and treatment of sepsis, and prevention of intervening medical complications.
Low tidal-volume ventilation, at 6 mL/kg of predicted body weight, reduces mortality compared with high tidal-volume ventilation, but can lead to respiratory acidosis. Positive end expiratory pressure (PEEP) that maintains PaO2 above 60 mmHg is considered effective in people with ARDS, but no difference in mortality has been found for high PEEP compared with lower PEEP strategies.
People with ARDS may remain hypoxic despite mechanical ventilation. Nursing in the prone position may improve oxygenation but it has not been shown to reduce mortality, and it can increase adverse effects such as pressure ulcers. The prone position is contraindicated in people with spinal instability and should be used with caution in people with haemodynamic and cardiac instability, or in people who have had recent thoracic or abdominal surgery.
We found insufficient evidence to draw reliable conclusions on the effects of corticosteroids on mortality or reversal of ARDS.
Nitric oxide has not been shown to improve survival or duration of ventilation, or hospital stay, compared with placebo. It may modestly improve oxygenation in the short term but the improvement is not sustained.
PMCID: PMC3217743  PMID: 21406126
11.  Lost in translation? The pursuit of lung-protective ventilation 
Critical Care  2008;12(2):122.
Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) remain important causes of morbidity and mortality in the critically ill patient, with far-reaching short-term and long-term implications for individual patients and for healthcare providers. It is well accepted that mechanical ventilation can worsen lung injury, potentially worsening systemic organ function, and can thus impact on mortality in acute lung injury (ALI)/ARDS. Unfortunately, although the concept of minimizing such damage via lung-protective ventilatory strategies is widely acknowledged, effective integration of such an approach into clinical practice remains more elusive. The study by the Irish Critical Care Trials Group published in the previous edition of Critical Care describes a 10-week real-life survey of all intensive care unit admissions across Ireland, detailing for the first time the epidemiology of ALI/ARDS in this population and clinician's attempts to deliver lung-protective ventilation. The authors also report hypothesis-generating data on the implications of statin use in this population. The present commentary reviews aspects of this work, with particular attention to the implementation of low-tidal-volume/lung-protective ventilatory strategies in ALI/ARDS.
doi:10.1186/cc6828
PMCID: PMC2447565  PMID: 18423069
12.  Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial 
Critical Care  2010;14(1):R1.
Introduction
Recent cohort studies have identified the use of large tidal volumes as a major risk factor for development of lung injury in mechanically ventilated patients without acute lung injury (ALI). We compared the effect of conventional with lower tidal volumes on pulmonary inflammation and development of lung injury in critically ill patients without ALI at the onset of mechanical ventilation.
Methods
We performed a randomized controlled nonblinded preventive trial comparing mechanical ventilation with tidal volumes of 10 ml versus 6 ml per kilogram of predicted body weight in critically ill patients without ALI at the onset of mechanical ventilation. The primary end point was cytokine levels in bronchoalveolar lavage fluid and plasma during mechanical ventilation. The secondary end point was the development of lung injury, as determined by consensus criteria for ALI, duration of mechanical ventilation, and mortality.
Results
One hundred fifty patients (74 conventional versus 76 lower tidal volume) were enrolled and analyzed. No differences were observed in lavage fluid cytokine levels at baseline between the randomization groups. Plasma interleukin-6 (IL-6) levels decreased significantly more strongly in the lower-tidal-volume group ((from 51 (20 to 182) ng/ml to 11 (5 to 20) ng/ml versus 50 (21 to 122) ng/ml to 21 (20 to 77) ng/ml; P = 0.01)). The trial was stopped prematurely for safety reasons because the development of lung injury was higher in the conventional tidal-volume group as compared with the lower tidal-volume group (13.5% versus 2.6%; P = 0.01). Univariate analysis showed statistical relations between baseline lung-injury score, randomization group, level of positive end-expiratory pressure (PEEP), the number of transfused blood products, the presence of a risk factor for ALI, and baseline IL-6 lavage fluid levels and the development of lung injury. Multivariate analysis revealed the randomization group and the level of PEEP as independent predictors of the development of lung injury.
Conclusions
Mechanical ventilation with conventional tidal volumes is associated with sustained cytokine production, as measured in plasma. Our data suggest that mechanical ventilation with conventional tidal volumes contributes to the development of lung injury in patients without ALI at the onset of mechanical ventilation.
Trial registration
ISRCTN82533884
doi:10.1186/cc8230
PMCID: PMC2875503  PMID: 20055989
13.  Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this health technology assessment was to determine the effectiveness and cost-effectiveness of noninvasive ventilation for stable chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Noninvasive ventilation is used for COPD patients with chronic respiratory failure. Chronic respiratory failure in COPD patients may be due to the inability of the pulmonary system to coordinate ventilation, leading to adverse arterial levels of oxygen and carbon dioxide. Noninvasive ventilation in stable COPD patients has the potential to improve quality of life, prolong survival, and improve gas exchange and sleep quality in patients who are symptomatic after optimal therapy, have hypercapnia or nocturnal hypoventilation and mild hypercapnia, and are frequently hospitalized.
Technology
Noninvasive positive pressure ventilation (NPPV) is any form of positive ventilatory support without the use of an endotracheal tube. For stable COPD, the standard of care when using noninvasive ventilation is bilevel positive airway pressure (BiPAP). Bilevel positive airway pressure involves both inspiratory and expiratory pressure, high during inspiration and lower during expiration. It acts as a pressure support to accentuate a patient’s inspiratory efforts. The gradient between pressures maintains alveolar ventilation and helps to reduce carbon dioxide levels. Outpatients typically use BiPAP at night. Additional advantages of using BiPAP include resting of respiratory muscles, decreased work of breathing, and control of obstructive hypopnea.
Research Question
What is the effectiveness and cost-effectiveness of noninvasive ventilation, compared with no ventilation while receiving usual care, for stable COPD patients?
Research Methods
Literature Search
Search Strategy
A literature search was performed on December 3, 2010, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database for studies published from January 1, 2004 to December 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. When the reviewer was unsure of the eligibility of articles, a second clinical epidemiologist and then a group of epidemiologists reviewed these until consensus was reached.
Inclusion Criteria
full-text English language articles,
studies published between January 1, 2004 and December 3, 2010,
journal articles that report on the effectiveness or cost-effectiveness of noninvasive ventilation,
clearly described study design and methods, and
health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs).
Exclusion Criteria
non-English papers
animal or in vitro studies
case reports, case series, or case-case studies
cross-over RCTs
studies on noninvasive negative pressure ventilation (e.g., iron lung)
studies that combine ventilation therapy with other regimens (e.g., daytime NPPV plus exercise or pulmonary rehabilitation)
studies on heliox with NPPV
studies on pulmonary rehabilitation with NPPV
Outcomes of Interest
mortality/survival
hospitalizations/readmissions
length of stay in hospital
forced expiratory volume
arterial partial pressure of oxygen
arterial partial pressure of carbon dioxide
dyspnea
exercise tolerance
health-related quality of life
Note: arterial pressure of oxygen and carbon dioxide are surrogate outcomes.
Statistical Methods
A meta-analysis and an analysis of individual studies were performed using Review Manager Version 5. For continuous data, a mean difference was calculated, and for dichotomous data, a relative risk ratio was calculated for RCTs. For continuous variables with mean baseline and mean follow-up data, a change value was calculated as the difference between the 2 mean values.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Conclusions
The following conclusions refer to stable, severe COPD patients receiving usual care.
Short-Term Studies
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation on oxygen gas exchange, carbon dioxide gas exchange, and exercise tolerance measured using the 6 Minute Walking Test.
Based on very low quality of evidence, there is no effect of NPPV therapy on lung function measured as forced expiratory volume in 1 second (Type II error not excluded).
Long-Term Studies
Based on moderate quality of evidence, there is no effect of NPPV therapy for the outcomes of mortality, lung function measured as forced expiratory volume in 1 second, and exercise tolerance measured using the 6 Minute Walking Test.
Based on low quality of evidence, there is no effect of NPPV therapy for the outcomes of oxygen gas exchange and carbon dioxide gas exchange (Type II error not excluded).
Qualitative Assessment
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation for dyspnea based on reduced Borg score or Medical Research Council dyspnea score.
Based on moderate quality of evidence, there is no effect of NPPV therapy for hospitalizations.
Health-related quality of life could not be evaluated.
PMCID: PMC3384378  PMID: 23074437
14.  Acute lung injury and the acute respiratory distress syndrome in Ireland: a prospective audit of epidemiology and management 
Critical Care  2008;12(1):R30.
Introduction
The aim of this study was to describe the epidemiology and management of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in Ireland.
Methods
As part of a 10-week prospective national audit of patient demographics and organ failure incidence in intensive care in Ireland, all patients with ALI/ARDS in 14 participating centres were prospectively identified using American European Consensus Conference definitions.
Results
There were 1,029 admissions during the study period; of these, 728 patients were invasively ventilated. A total of 196 (19%) patients had ALI/ARDS, and 141 of these (72%) had ALI/ARDS on admission and a further 55 (28%) developed ALI/ARDS after admission. For the patients with ALI/ARDS, the mean (± standard deviation) age was 58 ± 17 years and 62% were male. The most common predisposing risk factors were pneumonia (50%) and nonpulmonary sepsis (26%). Mean (± standard deviation) tidal volume/kg was 7.0 ± 1.7 ml/kg. Median (interquartile range) duration of ventilation was 6.8 (2.0 to 12.8) days. Median (interquartile range) length of stay in the intensive care unit was 10.0 (5.0 to 18.5) days. The overall intensive care unit mortality for ALI/ARDS was 32.3%. Lower baseline arterial oxygen tension/fraction of inspired oxygen ratio and higher Sequential Organ Failure Assessment scores were associated with increased mortality. Although not significant, patients receiving treatment with a statin during admission had a 73% lower odds of death (odds ratio 0.27, 95% confidence interval 0.06 to 1.21; P = 0.09).
Conclusion
The incidence of ALI/ARDS is high and is associated with significant mortality. Protective lung ventilation is used commonly throughout participating centres. With low tidal volume ventilation, the degree of hypoxaemia is associated with outcome. These data will inform future multicentre clinical trials in ALI/ARDS in Ireland.
doi:10.1186/cc6808
PMCID: PMC2374618  PMID: 18312626
15.  Prevention of LPS-Induced Acute Lung Injury in Mice by Mesenchymal Stem Cells Overexpressing Angiopoietin 1 
PLoS Medicine  2007;4(9):e269.
Background
The acute respiratory distress syndrome (ARDS), a clinical complication of severe acute lung injury (ALI) in humans, is a leading cause of morbidity and mortality in critically ill patients. ALI is characterized by disruption of the lung alveolar–capillary membrane barrier and resultant pulmonary edema associated with a proteinaceous alveolar exudate. Current specific treatment strategies for ALI/ARDS are lacking. We hypothesized that mesenchymal stem cells (MSCs), with or without transfection with the vasculoprotective gene angiopoietin 1 (ANGPT1) would have beneficial effects in experimental ALI in mice.
Methods and Findings
Syngeneic MSCs with or without transfection with plasmid containing the human ANGPT1 gene (pANGPT1) were delivered through the right jugular vein of mice 30 min after intratracheal instillation of lipopolysaccharide (LPS) to induce lung injury. Administration of MSCs significantly reduced LPS-induced pulmonary inflammation, as reflected by reductions in total cell and neutrophil counts in bronchoalveolar lavage (BAL) fluid (53%, 95% confidence interval [CI] 7%–101%; and 60%, CI 4%–116%, respectively) as well as reducing levels of proinflammatory cytokines in both BAL fluid and lung parenchymal homogenates. Furthermore, administration of MSCs transfected with pANGPT1 resulted in nearly complete reversal of LPS-induced increases in lung permeability as assessed by reductions in IgM and albumin levels in BAL (96%, CI 6%–185%; and 74%, CI 23%–126%, respectively). Fluorescently tagged MSCs were detected in the lung tissues by confocal microscopy and flow cytometry in both naïve and LPS-injured animals up to 3 d.
Conclusions
Treatment with MSCs alone significantly reduced LPS-induced acute pulmonary inflammation in mice, while administration of pANGPT1-transfected MSCs resulted in a further improvement in both alveolar inflammation and permeability. These results suggest a potential role for cell-based ANGPT1 gene therapy to treat clinical ALI/ARDS.
Using a mouse model of acute respiratory distress syndrome, Duncan Stewart and colleagues report that rescue with mesenchymal stem cells expressing human angiopoietin 1 can avert lung injury from lipopolysaccharide.
Editors' Summary
Background.
Critically ill people who have had an injury to their lungs, for example through pneumonia, trauma, or an immune response to infection, may end up developing a serious complication in the lung termed acute respiratory distress syndrome (ARDS). In ARDS, inflammation develops in the lung, and fluid builds up in the alveoli (the air sacs resembling “bunches of grapes” at the ends of the network of tubes in the lung). This buildup of fluid prevents oxygen from being carried efficiently from air into the blood; the individual consequently experiences problems breathing and can develop further serious complications, which contribute significantly to the burden of illness among people in intensive care units. The death rate among individuals who do develop ARDS is very high, upward of 30%. Normally, individuals with ARDS are given extra oxygen, and may need a machine to help them breathe; treatments also focus on addressing the underlying causes in each particular patient. However, currently there are very few specific treatments that address ARDS itself.
Why Was This Study Done?
The researchers here wanted to work toward new treatment options for individuals with ARDS. One possible approach involves cells known as mesenchymal stem cells (MSCs). These cells are typically found in the bone marrow and have a property shared by very few other cell types in the body; they are able to carry on dividing and renewing themselves, and can eventually develop into many other types of cell. The researchers already knew that MSCs could become incorporated into injured lungs in mice and develop there into the tissue layers lining the lung. Some interesting work had also been done on a protein called angiopoeitin 1 (ANGPT1), which seemed to play a role in protecting against inflammation in blood vessels. Therefore, there was a strong rationale for carrying out experiments in mice to see if MSCs engineered to produce the ANGPT1 protein might “rescue” lung injury in mice. These experiments would be an initial step toward developing possible new treatments for humans with ARDS.
What Did the Researchers Do and Find?
The researchers used a mouse model to mimic the human ARDS condition. This involved injecting the windpipe of experimental mice with lipopolysaccharide (a substance normally found on the outer surface of bacteria that brings about an immune reaction in the lung). After 30 minutes, the mice were then injected with either salt solution (as a control), the MSCs, or MSCs producing the ANGPT1 protein. The researchers then looked at markers of lung inflammation, the appearance of the lungs under a microscope, and whether the injected MSCs had become incorporated into the lung tissue.
The lipopolysaccharide brought about a large increase in the number of inflammatory cells in the lung fluid, which was reduced in the mice given MSCs. Furthermore, in mice given the MSCs producing ANGPT1 protein, the number of inflammatory cells was reduced to a level similar to that of mice that had not been given lipopolysaccharide. When the researchers looked at the appearance under the microscope of lungs from mice that had been given lipopolysaccharide, they saw signs of inflammation and fluid coming out into the lung air spaces. These signs were reduced among both mice treated with MSCs and those treated with MSCs producing ANGPT1. The researchers also measured the “leakiness” of the lung tissues in lipopolysaccharide-treated mice; MSCs seemed to reduce the leakiness to some extent, and the lungs of mice treated with MSCs producing ANGPT1 were no more leaky than those of mice that had never been injected with lipopolysaccharide. Finally, the MSCs were seen to be incorporated into lung tissue by three days after injection, but after that were lost from the lung.
What Do These Findings Mean?
Previous research done by the same group had shown that fibroblasts producing ANGPT1 could prevent lung injury in rats later given lipopolysaccharide. The experiments reported here go a step further than this, and suggest that MSCs producing ANGPT1 can “rescue” the condition of mouse lungs that had already been given lipopolysaccharide. In addition, treatment with MSCs alone also produced beneficial effects. This opens up a possible new treatment strategy for ARDS in humans. However, it should be emphasized that the animal model used here is not a precise parallel of ARDS in humans, and that more research remains to be done before human studies of this sort could be considered.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040269.
Medline Plus entry on acute respiratory distress syndrome, providing basic information about what ARDS is, its effects, and how it is currently managed
ARDS Network from the US National Heart, Lung, and Blood Institute of the National Institutes of Health; the site provides frequently asked questions about ARDS as well as a list of clinical trials conducted by the network
Information about stem cells from the US National Institutes of Health, including information about the potential uses of stem cells
Wikipedia page about mesenchymal stem cells (note: Wikipedia is an internet encyclopedia anyone can edit)
doi:10.1371/journal.pmed.0040269
PMCID: PMC1961632  PMID: 17803352
16.  Recent Trends in Acute Lung Injury Mortality: 1996-2005 
Critical care medicine  2009;37(5):1574-1579.
Background:
Studies from single centers have suggested that mortality from acute lung injury (ALI) has declined over time. However, recent trends in ALI mortality from centers across the U.S. are unknown. Whether recent advances in the treatment of ALI or related critical illnesses have resulted in decreased mortality from ALI is not clear.
Methods:
In a study of 2451 mechanically ventilated patients with ALI enrolled in the Acute Respiratory Distress Syndrome (ARDS) Network randomized controlled trials between 1996-2005, we evaluated whether there was a temporal improvement in 60-day mortality. We also investigated whether there were temporal improvements in mortality specific to individual causes of lung injury (pneumonia, sepsis, trauma, aspiration, transfusion).
Results:
Crude mortality was 35% in 1996-1997 and declined during each subsequent time period to a low of 26% in 2004-2005 (test for trend p<0.0005). After adjusting for demographic and clinical covariates, including receipt of lower tidal volume ventilation and severity of illness, the temporal trend persisted (test for trend p=0.002). When analyzed by individual causes of lung injury, there were not any statistically significant temporal trends in 60-day mortality for the most common causes of lung injury (pneumonia, sepsis, aspiration, trauma).
Conclusions:
Over the past decade, there appears to be a clear temporal improvement in survival among patients with ALI treated at ARDS Network centers. Our findings strongly suggest that other advancements in critical care, aside from lower tidal volume ventilation, accounted for this improvement in mortality.
doi:10.1097/CCM.0b013e31819fefdf
PMCID: PMC2696257  PMID: 19325464
acute respiratory distress syndrome; acute lung injury; mortality; temporal trend; epidemiology
17.  Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome 
Current medicinal chemistry  2008;15(19):1911-1924.
Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article.
PMCID: PMC2636692  PMID: 18691048
ARDS; ALI; inflammatory lung injury; lung injury therapy; anti-inflammatory therapy; surfactant therapy; INO therapy; anti-oxidants; pharmacotherapy
18.  Plasma G-CSF Levels Correlate With Clinical Outcomes in Patients with Acute Lung Injury 
Critical care medicine  2009;37(4):1322-1328.
Objectives
To evaluate the association between plasma granulocyte colony-stimulating factor (G-CSF) levels and clinical outcomes including mortality in patients with acute lung injury (ALI) and to determine whether lower tidal volume ventilation was associated with a more rapid decrease in plasma G-CSF over time in patients with ALI.
Design
Retrospective measurement of G-CSF levels in plasma samples that were collected prospectively as part of a large multicenter clinical trial.
Setting
Intensive care units in ten university centers.
Patients
The study included 645 patients enrolled in the NHBLI ARDS Clinical Network trial of lower tidal volumes compared with traditional tidal volumes for ALI.
Measurements and Main Results
Baseline plasma levels of G-CSF were associated with an increased risk of death and a decrease in ventilator-free and organ failure-free days (VFD and OFD) in multivariate analyses controlling for ventilation strategy, age, and sex (OR death 1.2/log10 increment G-CSF, 95% CI 1.01 to 1.4). Stratification of G-CSF levels into quartiles revealed a strong association between the highest levels of G-CSF and increased risk of death and decreased VFD and OFD in multivariate analyses controlling for ventilation strategy, APACHE III score, PF ratio, creatinine, and platelet count (p<0.05). Subgroup multivariate analysis of patients with sepsis as their risk factor for ALI revealed a U-shaped association between mortality and G-CSF levels such that risk increased linearly from the second through fourth (highest) quartiles, yet also increased in the first (lowest) quartile. G-CSF levels decreased over time in both tidal volume groups and there was no statistical difference in the extent of decrease between ventilator strategies.
Conclusions
In patients with ALI, plasma G-CSF levels are associated with morbidity and mortality, yet these levels are not influenced by tidal volume strategy. In patients with sepsis-related ALI we find a bimodal association between baseline plasma G-CSF levels and subsequent morbidity and mortality from this disease.
doi:10.1097/CCM.0b013e31819c14fa
PMCID: PMC2827851  PMID: 19242319
ALI; ARDS; G-CSF; low tidal volume ventilation; sepsis
19.  An updated study-level meta-analysis of randomised controlled trials on proning in ARDS and acute lung injury 
Critical Care  2011;15(1):R6.
Introduction
In patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS), recent randomised controlled trials (RCTs) showed a consistent trend of mortality reduction with prone ventilation. We updated a meta-analysis on this topic.
Methods
RCTs that compared ventilation of adult patients with ALI/ARDS in prone versus supine position were included in this study-level meta-analysis. Analysis was made by a random-effects model. The effect size on intensive care unit (ICU) mortality was computed in the overall included studies and in two subgroups of studies: those that included all ALI or hypoxemic patients, and those that restricted inclusion to only ARDS patients. A relationship between studies' effect size and daily prone duration was sought with meta-regression. We also computed the effects of prone positioning on major adverse airway complications.
Results
Seven RCTs (including 1,675 adult patients, of whom 862 were ventilated in the prone position) were included. The four most recent trials included only ARDS patients, and also applied the longest proning durations and used lung-protective ventilation. The effects of prone positioning differed according to the type of study. Overall, prone ventilation did not reduce ICU mortality (odds ratio = 0.91, 95% confidence interval = 0.75 to 1.2; P = 0.39), but it significantly reduced the ICU mortality in the four recent studies that enrolled only patients with ARDS (odds ratio = 0.71; 95% confidence interval = 0.5 to 0.99; P = 0.048; number needed to treat = 11). Meta-regression on all studies disclosed only a trend to explain effect variation by prone duration (P = 0.06). Prone positioning was not associated with a statistical increase in major airway complications.
Conclusions
Long duration of ventilation in prone position significantly reduces ICU mortality when only ARDS patients are considered.
doi:10.1186/cc9403
PMCID: PMC3222033  PMID: 21211010
20.  Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based analysis was to examine the effectiveness, safety, and cost-effectiveness of noninvasive positive pressure ventilation (NPPV) in the following patient populations: patients with acute respiratory failure (ARF) due to acute exacerbations of chronic obstructive pulmonary disease (COPD); weaning of COPD patients from invasive mechanical ventilation (IMV); and prevention of or treatment of recurrent respiratory failure in COPD patients after extubation from IMV.
Clinical Need and Target Population
Acute Hypercapnic Respiratory Failure
Respiratory failure occurs when the respiratory system cannot oxygenate the blood and/or remove carbon dioxide from the blood. It can be either acute or chronic and is classified as either hypoxemic (type I) or hypercapnic (type II) respiratory failure. Acute hypercapnic respiratory failure frequently occurs in COPD patients experiencing acute exacerbations of COPD, so this is the focus of this evidence-based analysis. Hypercapnic respiratory failure occurs due to a decrease in the drive to breathe, typically due to increased work to breathe in COPD patients.
Technology
There are several treatment options for ARF. Usual medical care (UMC) attempts to facilitate adequate oxygenation and treat the cause of the exacerbation, and typically consists of supplemental oxygen, and a variety of medications such as bronchodilators, corticosteroids, and antibiotics. The failure rate of UMC is high and has been estimated to occur in 10% to 50% of cases.
The alternative is mechanical ventilation, either invasive or noninvasive. Invasive mechanical ventilation involves sedating the patient, creating an artificial airway through endotracheal intubation, and attaching the patient to a ventilator. While this provides airway protection and direct access to drain sputum, it can lead to substantial morbidity, including tracheal injuries and ventilator-associated pneumonia (VAP).
While both positive and negative pressure noninvasive ventilation exists, noninvasive negative pressure ventilation such as the iron lung is no longer in use in Ontario. Noninvasive positive pressure ventilation provides ventilatory support through a facial or nasal mask and reduces inspiratory work. Noninvasive positive pressure ventilation can often be used intermittently for short periods of time to treat respiratory failure, which allows patients to continue to eat, drink, talk, and participate in their own treatment decisions. In addition, patients do not require sedation, airway defence mechanisms and swallowing functions are maintained, trauma to the trachea and larynx are avoided, and the risk for VAP is reduced. Common complications are damage to facial and nasal skin, higher incidence of gastric distension with aspiration risk, sleeping disorders, and conjunctivitis. In addition, NPPV does not allow direct access to the airway to drain secretions and requires patients to cooperate, and due to potential discomfort, compliance and tolerance may be low.
In addition to treating ARF, NPPV can be used to wean patients from IMV through the gradual removal of ventilation support until the patient can breathe spontaneously. Five to 30% of patients have difficultly weaning. Tapering levels of ventilatory support to wean patients from IMV can be achieved using IMV or NPPV. The use of NPPV helps to reduce the risk of VAP by shortening the time the patient is intubated.
Following extubation from IMV, ARF may recur, leading to extubation failure and the need for reintubation, which has been associated with increased risk of nosocomial pneumonia and mortality. To avoid these complications, NPPV has been proposed to help prevent ARF recurrence and/or to treat respiratory failure when it recurs, thereby preventing the need for reintubation.
Research Questions
What is the effectiveness, cost-effectiveness, and safety of NPPV for the treatment of acute hypercapnic respiratory failure due to acute exacerbations of COPD compared with
usual medical care, and
invasive mechanical ventilation?
What is the effectiveness, cost-effectiveness, and safety of NPPV compared with IMV in COPD patients after IMV for the following purposes:
weaning COPD patients from IMV,
preventing ARF in COPD patients after extubation from IMV, and
treating ARF in COPD patients after extubation from IMV?
Research Methods
Literature Search
A literature search was performed on December 3, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), Wiley Cochrane, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until December 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Since there were numerous studies that examined the effectiveness of NPPV for the treatment of ARF due to exacerbations of COPD published before 2004, pre-2004 trials which met the inclusion/exclusion criteria for this evidence-based review were identified by hand-searching reference lists of included studies and systematic reviews.
Inclusion Criteria
English language full-reports;
health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials (RCTs);
studies performed exclusively in patients with a diagnosis of COPD or studies performed with patients with a mix of conditions if results are reported for COPD patients separately;
patient population: (Question 1) patients with acute hypercapnic respiratory failure due to an exacerbation of COPD; (Question 2a) COPD patients being weaned from IMV; (Questions 2b and 2c) COPD patients who have been extubated from IMV.
Exclusion Criteria
< 18 years of age
animal studies
duplicate publications
grey literature
studies examining noninvasive negative pressure ventilation
studies comparing modes of ventilation
studies comparing patient-ventilation interfaces
studies examining outcomes not listed below, such as physiologic effects including heart rate, arterial blood gases, and blood pressure
Outcomes of Interest
mortality
intubation rates
length of stay (intensive care unit [ICU] and hospital)
health-related quality of life
breathlessness
duration of mechanical ventilation
weaning failure
complications
NPPV tolerance and compliance
Statistical Methods
When possible, results were pooled using Review Manager 5 Version 5.1, otherwise, the results were summarized descriptively. Dichotomous data were pooled into relative risks using random effects models and continuous data were pooled using weighted mean differences with a random effects model. Analyses using data from RCTs were done using intention-to-treat protocols; P values < 0.05 were considered significant. A priori subgroup analyses were planned for severity of respiratory failure, location of treatment (ICU or hospital ward), and mode of ventilation with additional subgroups as needed based on the literature. Post hoc sample size calculations were performed using STATA 10.1.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
NPPV for the Treatment of ARF due to Acute Exacerbations of COPD
NPPV Plus Usual Medical Care Versus Usual Medical Care Alone for First Line Treatment
A total of 1,000 participants were included in 11 RCTs1; the sample size ranged from 23 to 342. The mean age of the participants ranged from approximately 60 to 72 years of age. Based on either the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD stage criteria or the mean percent predicted forced expiratory volume in 1 second (FEV1), 4 of the studies included people with severe COPD, and there was inadequate information to classify the remaining 7 studies by COPD severity. The severity of the respiratory failure was classified into 4 categories using the study population mean pH level as follows: mild (pH ≥ 7.35), moderate (7.30 ≤ pH < 7.35), severe (7.25 ≤ pH < 7.30), and very severe (pH < 7.25). Based on these categories, 3 studies included patients with a mild respiratory failure, 3 with moderate respiratory failure, 4 with severe respiratory failure, and 1 with very severe respiratory failure.
The studies were conducted either in the ICU (3 of 11 studies) or general or respiratory wards (8 of 11 studies) in hospitals, with patients in the NPPV group receiving bilevel positive airway pressure (BiPAP) ventilatory support, except in 2 studies, which used pressure support ventilation and volume cycled ventilation, respectively. Patients received ventilation through nasal, facial, or oronasal masks. All studies specified a protocol or schedule for NPPV delivery, but this varied substantially across the studies. For example, some studies restricted the amount of ventilation per day (e.g., 6 hours per day) and the number of days it was offered (e.g., maximum of 3 days); whereas, other studies provided patients with ventilation for as long as they could tolerate it and recommended it for much longer periods of time (e.g., 7 to 10 days). These differences are an important source of clinical heterogeneity between the studies. In addition to NPPV, all patients in the NPPV group also received UMC. Usual medical care varied between the studies, but common medications included supplemental oxygen, bronchodilators, corticosteroids, antibiotics, diuretics, and respiratory stimulators.
The individual quality of the studies ranged. Common methodological issues included lack of blinding and allocation concealment, and small sample sizes.
Need for Endotracheal Intubation
Eleven studies reported the need for endotracheal intubation as an outcome. The pooled results showed a significant reduction in the need for endotracheal intubation in the NPPV plus UMC group compared with the UMC alone group (relative risk [RR], 0.38; 95% confidence interval [CI], 0.28−0.50). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Inhospital Mortality
Nine studies reported inhospital mortality as an outcome. The pooled results showed a significant reduction in inhospital mortality in the NPPV plus UMC group compared with the UMC group (RR, 0.53; 95% CI, 0.35−0.81). When subgrouped by severity of respiratory failure, the results remained significant for the moderate and severe respiratory failure groups.
GRADE: moderate
Hospital Length of Stay
Eleven studies reported hospital length of stay (LOS) as an outcome. The pooled results showed a significant decrease in the mean length of stay for the NPPV plus UMC group compared with the UMC alone group (weighted mean difference [WMD], −2.68 days; 95% CI, −4.41 to −0.94 days). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Complications
Five studies reported complications. Common complications in the NPPV plus UMC group included pneumonia, gastrointestinal disorders or bleeds, skin abrasions, eye irritation, gastric insufflation, and sepsis. Similar complications were observed in the UMC group including pneumonia, sepsis, gastrointestinal disorders or bleeds, pneumothorax, and complicated endotracheal intubations. Many of the more serious complications in both groups occurred in those patients who required endotracheal intubation. Three of the studies compared complications in the NPPV plus UMC and UMC groups. While the data could not be pooled, overall, the NPPV plus UMC group experienced fewer complications than the UMC group.
GRADE: low
Tolerance/Compliance
Eight studies reported patient tolerance or compliance with NPPV as an outcome. NPPV intolerance ranged from 5% to 29%. NPPV tolerance was generally higher for patients with more severe respiratory failure. Compliance with the NPPV protocol was reported by 2 studies, which showed compliance decreases over time, even over short periods such as 3 days.
NPPV Versus IMV for the Treatment of Patients Who Failed Usual Medical Care
A total of 205 participants were included in 2 studies; the sample sizes of these studies were 49 and 156. The mean age of the patients was 71 to 73 years of age in 1 study, and the median age was 54 to 58 years of age in the second study. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, patients in 1 study had very severe COPD. The COPD severity could not be classified in the second study. Both studies had study populations with a mean pH less than 7.23, which was classified as very severe respiratory failure in this analysis. One study enrolled patients with ARF due to acute exacerbations of COPD who had failed medical therapy. The patient population was not clearly defined in the second study, and it was not clear whether they had to have failed medical therapy before entry into the study.
Both studies were conducted in the ICU. Patients in the NPPV group received BiPAP ventilatory support through nasal or full facial masks. Patients in the IMV group received pressure support ventilation.
Common methodological issues included small sample size, lack of blinding, and unclear methods of randomization and allocation concealment. Due to the uncertainty about whether both studies included the same patient population and substantial differences in the direction and significance of the results, the results of the studies were not pooled.
Mortality
Both studies reported ICU mortality. Neither study showed a significant difference in ICU mortality between the NPPV and IMV groups, but 1 study showed a higher mortality rate in the NPPV group (21.7% vs. 11.5%) while the other study showed a lower mortality rate in the NPPV group (5.1% vs. 6.4%). One study reported 1-year mortality and showed a nonsignificant reduction in mortality in the NPPV group compared with the IMV group (26.1% vs. 46.1%).
GRADE: low to very low
Intensive Care Unit Length of Stay
Both studies reported LOS in the ICU. The results were inconsistent. One study showed a statistically significant shorter LOS in the NPPV group compared with the IMV group (5 ± 1.35 days vs. 9.29 ± 3 days; P < 0.001); whereas, the other study showed a nonsignificantly longer LOS in the NPPV group compared with the IMV group (22 ± 19 days vs. 21 ± 20 days; P = 0.86).
GRADE: very low
Duration of Mechanical Ventilation
Both studies reported the duration of mechanical ventilation (including both invasive and noninvasive ventilation). The results were inconsistent. One study showed a statistically significant shorter duration of mechanical ventilation in the NPPV group compared with the IMV group (3.92 ± 1.08 days vs. 7.17 ± 2.22 days; P < 0.001); whereas, the other study showed a nonsignificantly longer duration of mechanical ventilation in the NPPV group compared with the IMV group (16 ± 19 days vs. 15 ± 21 days; P = 0.86). GRADE: very low
Complications
Both studies reported ventilator-associated pneumonia and tracheotomies. Both showed a reduction in ventilator-associated pneumonia in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 34.6%, P = 0.07; and 6.4% vs. 37.2%, P < 0.001, respectively). Similarly, both studies showed a reduction in tracheotomies in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 23.1%, P = 0.29; and 6.4% vs. 34.6%; P < 0.001).
GRADE: very low
Other Outcomes
One of the studies followed patients for 12 months. At the end of follow-up, patients in the NPPV group had a significantly lower rate of needing de novo oxygen supplementation at home. In addition, the IMV group experienced significant increases in functional limitations due to COPD, while no increase was seen in the NPPV group. Finally, no significant differences were observed for hospital readmissions, ICU readmissions, and patients with an open tracheotomy, between the NPPV and IMV groups.
NPPV for Weaning COPD Patients From IMV
A total of 80 participants were included in the 2 RCTs; the sample sizes of the studies were 30 and 50 patients. The mean age of the participants ranged from 58 to 69 years of age. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, both studies included patients with very severe COPD. Both studies also included patients with very severe respiratory failure (mean pH of the study populations was less than 7.23). Chronic obstructive pulmonary disease patients receiving IMV were enrolled in the study if they failed a T-piece weaning trial (spontaneous breathing test), so they could not be directly extubated from IMV.
Both studies were conducted in the ICU. Patients in the NPPV group received weaning using either BiPAP or pressure support ventilation NPPV through a face mask, and patients in the IMV weaning group received pressure support ventilation. In both cases, weaning was achieved by tapering the ventilation level.
The individual quality of the studies ranged. Common methodological problems included unclear randomization methods and allocation concealment, lack of blinding, and small sample size.
Mortality
Both studies reported mortality as an outcome. The pooled results showed a significant reduction in ICU mortality in the NPPV group compared with the IMV group (RR, 0.47; 95% CI, 0.23−0.97; P = 0.04).
GRADE: moderate
Intensive Care Unit Length of Stay
Both studies reported ICU LOS as an outcome. The pooled results showed a nonsignificant reduction in ICU LOS in the NPPV group compared with the IMV group (WMD, −5.21 days; 95% CI, −11.60 to 1.18 days).
GRADE: low
Duration of Mechanical Ventilation
Both studies reported duration of mechanical ventilation (including both invasive and noninvasive ventilation) as an outcome. The pooled results showed a nonsignificant reduction in duration of mechanical ventilation (WMD, −3.55 days; 95% CI, −8.55 to 1.44 days).
GRADE: low
Nosocomial Pneumonia
Both studies reported nosocominal pneumonia as an outcome. The pooled results showed a significant reduction in nosocomial pneumonia in the NPPV group compared with the IMV group (RR, 0.14; 95% CI, 0.03−0.71; P = 0.02).
GRADE: moderate
Weaning Failure
One study reported a significant reduction in weaning failure in the NPPV group compared with the IMV group, but the results were not reported in the publication. In this study, 1 of 25 patients in the NPPV group and 2 of 25 patients in the IMV group could not be weaned after 60 days in the ICU.
NPPV After Extubation of COPD Patients From IMV
The literature was reviewed to identify studies examining the effectiveness of NPPV compared with UMC in preventing recurrence of ARF after extubation from IMV or treating acute ARF which has recurred after extubation from IMV. No studies that included only COPD patients or reported results for COPD patients separately were identified for the prevention of ARF postextubation.
One study was identified for the treatment of ARF in COPD patients that recurred within 48 hours of extubation from IMV. This study included 221 patients, of whom 23 had COPD. A post hoc subgroup analysis was conducted examining the rate of reintubation in the COPD patients only. A nonsignificant reduction in the rate of reintubation was observed in the NPPV group compared with the UMC group (7 of 14 patients vs. 6 of 9 patients, P = 0.67). GRADE: low
Conclusions
NPPV Plus UMC Versus UMC Alone for First Line Treatment of ARF due to Acute Exacerbations of COPD
Moderate quality of evidence showed that compared with UMC, NPPV plus UMC significantly reduced the need for endotracheal intubation, inhospital mortality, and the mean length of hospital stay.
Low quality of evidence showed a lower rate of complications in the NPPV plus UMC group compared with the UMC group.
NPPV Versus IMV for the Treatment of ARF in Patients Who Have Failed UMC
Due to inconsistent and low to very low quality of evidence, there was insufficient evidence to draw conclusions on the comparison of NPPV versus IMV for patients who failed UMC.
NPPV for Weaning COPD Patients From IMV
Moderate quality of evidence showed that weaning COPD patients from IMV using NPPV results in significant reductions in mortality, nosocomial pneumonia, and weaning failure compared with weaning with IMV.
Low quality of evidence showed a nonsignificant reduction in the mean LOS and mean duration of mechanical ventilation in the NPPV group compared with the IMV group.
NPPV for the Treatment of ARF in COPD Patients After Extubation From IMV
Low quality of evidence showed a nonsignificant reduction in the rate of reintubation in the NPPV group compared with the UMC group; however, there was inadequate evidence to draw conclusions on the effectiveness of NPPV for the treatment of ARF in COPD patients after extubation from IMV
PMCID: PMC3384377  PMID: 23074436
21.  Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients 
Background
Preventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation.
Methods
Plasma levels of surfactant protein D (SP-D), Clara Cell protein (CC16), KL-6 and soluble receptor for advanced glycation end-products (sRAGE) were measured in plasma samples obtained from 36 patients - 16 patients who were intubated and mechanically ventilated because of ALI/ARDS and 20 patients without lung injury at the onset of mechanical ventilation and during conduct of the study. Patients were ventilated with either a lung-protective strategy using lower tidal volumes or a potentially injurious strategy using conventional tidal volumes. Levels of biological markers were measured retrospectively at baseline and after 2 days of mechanical ventilation.
Results
Plasma levels of CC16 and KL-6 were higher in ALI/ARDS patients at baseline as compared to patients without lung injury. SP-D and sRAGE levels were not significantly different between these patients. In ALI/ARDS patients, SP-D and KL-6 levels increased over time, which was attenuated by lung-protective mechanical ventilation using lower tidal volumes (P = 0.02 for both biological markers). In these patients, with either ventilation strategy no changes over time were observed for plasma levels of CC16 and sRAGE. In patients without lung injury, no changes of plasma levels of any of the measured biological markers were observed.
Conclusion
Plasma levels of SP-D and KL-6 rise with potentially injurious ventilator settings, and thus may serve as biological markers of VALI in patients with ALI/ARDS.
doi:10.1186/1471-2466-10-6
PMCID: PMC2841652  PMID: 20158912
22.  Cardiac index and oxygen delivery during low and high tidal volume ventilation strategies in patients with acute respiratory distress syndrome: a crossover randomized clinical trial 
Critical Care  2013;17(4):R146.
Introduction
The beneficial effect of low tidal volume (TV) ventilation strategy on mortality in patients with acute respiratory distress syndrome (ARDS) has been attributed to the protective effect on ventilator-induced lung injury, and yet its effect on cardiovascular function might also play an important role. The aim of this study was to assess whether low TV ventilation improves cardiac output and oxygen delivery compared with high TV ventilation strategy in patients with ARDS.
Methods
In this crossover randomized clinical trial 16 ARDS patients were recruited in an intensive care unit at a university-affiliated hospital. Each patient was ventilated for 30 min with low (6 mL/kg) and 30 min with high (12 mL/kg) TV. The two experimental periods, applied in random order and with allocation concealment, were separated by 30 min of basal ventilation. Minute ventilation was constantly maintained by appropriate respiratory rate changes.
Results
Compared with high TV ventilation, low TV ventilation showed decreased pH (7.37 vs. 7.41, P = 0.001) and increased PaCO2 (49 vs. 43 mmHg; P = 0.002). Cardiac index and oxygen delivery index were increased with low compared with high TV ventilation (3.9 vs. 3.5 L.min-1.m-2, P = 0.012, and 521 vs. 463 mL.min-1.m-2, P = 0.002, respectively), while oxygen extraction ratio decreased (0.36 vs. 0.44, P = 0.027). In four patients oxygen extraction ratio was >0.5 during high TV but not during low TV strategy. The magnitude of the change in cardiac index was positively associated with PaCO2 variation (P = 0.004), while it was unrelated to the magnitude of changes in TV and airway pressure. The decrease of cardiac index was predicted by PaCO2 reduction, with and area under ROC curve of 0.72.
Conclusions
Our findings suggest that a low TV ventilation strategy increases cardiac index and oxygen delivery, thus supporting the hypothesis that the beneficial effect of low TV ventilation in patients with ARDS could be partially explained by hemodynamic improvement. In other words, low tidal volume ventilation could be protective also for the cardiovascular system and not only for the lung. The slight increase of PaCO2 during low TV ventilation seems to predict the increase of cardiac index.
Trial registration
ClinicalTrials.gov: NCT00713713
doi:10.1186/cc12825
PMCID: PMC4057210  PMID: 23880084
Cardiac Output; Tidal Volume; Respiratory Distress Syndrome; Adult; Hemodynamics
23.  A ventilator strategy combining low tidal volume ventilation, recruitment maneuvers, and high positive end-expiratory pressure does not increase sedative, opioid, or neuromuscular blocker use in adults with acute respiratory distress syndrome and may improve patient comfort 
Background
The Lung Open Ventilation Study (LOV Study) compared a low tidal volume strategy with an experimental strategy combining low tidal volume, lung recruitment maneuvers, and higher plateau and positive end-expiratory pressures (PEEP) in adults with acute respiratory distress syndrome (ARDS). Herein, we compared sedative, opioid, and neuromuscular blocker (NMB) use among patients managed with the intervention and control strategies and clinicians' assessment of comfort in both groups.
Methods
This was an observational substudy of the LOV Study, a randomized trial conducted in 30 intensive care units in Canada, Australia, and Saudi Arabia. In 16 centers, we recorded daily doses of sedatives, opioids, and NMBs and surveyed bedside clinicians about their own comfort with the assigned ventilator strategy and their perceptions of patient comfort. We compared characteristics and outcomes of patients who did and did not receive NMBs.
Results
Study groups received similar sedative, opioid, and NMB dosing on days 1, 3, and 7. Patient comfort as assessed by clinicians was not different in the two groups: 93% perceived patients had no/minimal discomfort. In addition, 92% of clinicians were comfortable with the assigned ventilation strategy without significant differences between the two groups. When clinicians expressed discomfort, more expressed discomfort about PEEP levels in the intervention vs control group (2.9% vs 0.7%, P <0.0001), and more perceived patient discomfort among controls (6.0% vs 4.3%, P = 0.049). On multivariable analysis, the strongest associations with NMB use were higher plateau pressure (hazard ratio (HR) 1.15; 95% confidence interval (CI) 1.07 to 1.23; P = 0.0002) and higher daily sedative dose (HR 1.03; 95% CI 1.02 to 1.05; P <0.0001). Patients receiving NMBs had more barotrauma, longer durations of mechanical ventilation and hospital stay, and higher mortality.
Conclusions
In the LOV Study, high PEEP, low tidal volume ventilation did not increase sedative, opioid, or NMB doses in adults with ARDS, compared with a lower PEEP strategy, and appeared at least as comfortable for patients. NMB use may reflect worse lung injury, as these patients had more barotrauma, longer durations of ventilation, and higher mortality.
Trial registration
ClinicalTrials.gov Identifier NCT00182195
doi:10.1186/s13613-014-0033-9
PMCID: PMC4273695  PMID: 25593749
ARDS; Neuromuscular blocker; Sedation; Opioid; Mechanical ventilation; Clinician comfort
24.  Positive end-expiratory pressure optimization with forced oscillation technique reduces ventilator induced lung injury: a controlled experimental study in pigs with saline lavage lung injury 
Critical Care  2011;15(3):R126.
Introduction
Protocols using high levels of positive end-expiratory pressure (PEEP) in combination with low tidal volumes have been shown to reduce mortality in patients with severe acute respiratory distress syndrome (ARDS). However, the optimal method for setting PEEP is yet to be defined. It has been shown that respiratory system reactance (Xrs), measured by the forced oscillation technique (FOT) at 5 Hz, may be used to identify the minimal PEEP level required to maintain lung recruitment. The aim of the present study was to evaluate if using Xrs for setting PEEP would improve lung mechanics and reduce lung injury compared to an oxygenation-based approach.
Methods
17 pigs, in which acute lung injury (ALI) was induced by saline lavage, were studied. Animals were randomized into two groups: in the first PEEP was titrated according to Xrs (FOT group), in the control group PEEP was set according to the ARDSNet protocol (ARDSNet group). The duration of the trial was 12 hours. In both groups recruitment maneuvers (RM) were performed every 2 hours, increasing PEEP to 20 cmH2O. In the FOT group PEEP was titrated by monitoring Xrs while PEEP was reduced from 20 cmH2O in steps of 2 cmH2O. PEEP was considered optimal at the step before which Xrs started to decrease. Ventilatory parameters, lung mechanics, blood gases and hemodynamic parameters were recorded hourly. Lung injury was evaluated by histopathological analysis.
Results
The PEEP levels set in the FOT group were significantly higher compared to those set in the ARDSNet group during the whole trial. These higher values of PEEP resulted in improved lung mechanics, reduced driving pressure, improved oxygenation, with a trend for higher PaCO2 and lower systemic and pulmonary pressure. After 12 hours of ventilation, histopathological analysis showed a significantly lower score of lung injury in the FOT group compared to the ARDSNet group.
Conclusions
In a lavage model of lung injury a PEEP optimization strategy based on maximizing Xrs attenuated the signs of ventilator induced lung injury. The respiratory system reactance measured by FOT could thus be an important component in a strategy for delivering protective ventilation to patients with ARDS/acute lung injury.
doi:10.1186/cc10236
PMCID: PMC3218989  PMID: 21575220
25.  The Value of PEEP and FiO2 Criteria in the Definition the Acute Respiratory Distress Syndrome 
Critical care medicine  2011;39(9):2025-2030.
OBJECTIVES:
The criteria that define acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) include PaO2/FiO2 but not positive end-expiratory pressure (PEEP) or FiO2. PaO2/FiO2s of some patients increase substantially after mechanical ventilation with PEEP of 5-10 cm H2O, and the mortality of these patients may be lower than those whose PaO2/FiO2s remain < 200. Also, PaO2/FiO2 may increase when FiO2 is raised from moderate to high levels, suggesting that patients with similar PaO2/FiO2s but different FiO2s have different risks of mortality. The primary purpose of this study was to assess the value of adding baseline PEEP and FiO2 to PaO2/FiO2 for predicting mortality of ALI/ARDS patients enrolled in ARDS Network clinical trials. We also assessed effects of two study interventions on clinical outcomes in subsets of patients with mild and severe hypoxemia as defined by PaO2/FiO2.
DESIGN:
Analysis of baseline physiologic data and outcomes of patients previously enrolled in clinical trials conducted by the National Institutes of Health ARDS Network.
SETTING:
Intensive care units of 40 hospitals in North America.
PATIENTS:
2312 patients with ALI/ARDS.
INTERVENTIONS:
None.
MEASUREMENTS AND MAIN RESULTS:
Only 1.3% of patients enrolled in ARDS Network trials had baseline PEEP < 5 cm H2O, and 50% had baseline PEEP ≥ 10 cm H2O. Baseline PaO2/FiO2 predicted mortality, but after controlling for PaO2/FiO2, baseline PEEP did not predict mortality. In contrast, after controlling for baseline PaO2/FiO2, baseline FiO2 did predict mortality. Effects of two study interventions (lower tidal volumes and fluid-conservative hemodynamic management) were similar in mild and severe hypoxemia subsets as defined by PaO2/FiO2 ratios.
CONCLUSION:
At ARDS Network hospitals, the addition of baseline PEEP would not have increased the value of PaO2/FiO2 for predicting mortality of ALI/ARDS patients. In contrast, the addition of baseline FiO2 to PaO2/FiO2 could be used to identify subsets of patients with low or high mortality.
doi:10.1097/CCM.0b013e31821cb774
PMCID: PMC3157575  PMID: 21532473
Acute lung injury; Clinical trials, randomized; Ventilation, mechanical; Positive end-expiratory pressure

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