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.
acute respiratory distress syndrome; acute lung injury; plateau; mechanical ventilation
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
The use of NMBA in the early phase of ARDS improves outcome.
ARDS; Neuromuscular blocking agents; Meta-analysis; Review
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.
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.
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.
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.
Ventilator-induced lung injury is a major outcome determinant of the acute respiratory distress syndrome (ARDS). Ventilatory strategies that limit ventilator-induced lung injury should improve outcome from ARDS. The ARDSnet trial showed improved survival in subjects ventilated with a lower tidal volume. Although this trial developed and tested a rigorous clinical protocol, it did not define the limits to which tidal volume reduction would benefit outcome. It is also not at all clear if it is the reduction in tidal volume or the reduction in plateau airway pressure that confers this benefit. Finally, ventilator-induced lung injury occurs more commonly from repetitive collapse and re-expansion of injured lung units rather than from the overdistention of persistently aerated lung units. This was not addressed in the trial design. Thus, further study using targeted open-lung strategies are also needed.
ARDS; outcome; ventilation; ventilator-induced lung injury
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.
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.
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.
Long duration of ventilation in prone position significantly reduces ICU mortality when only ARDS patients are considered.
Despite recent advances in critical care and ventilator management, acute lung injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS) continue to cause significant morbidity and mortality. Granulocyte-macrophage colony stimulating factor (GM-CSF) may be beneficial for patients with ARDS.
To determine whether intravenous infusion of GM-CSF would improve clinical outcomes for patients with ALI/ARDS.
A randomized, double-blind, placebo-controlled clinical trial of human recombinant GM-CSF vs. placebo. The primary outcome was days alive and breathing without mechanical ventilatory support within the first 28 days after randomization. Secondary outcomes included mortality and organ failure free days.
Medical and Surgical Intensive Care Units at three academic medical centers.
One hundred-thirty individuals with ALI of at least three days duration were enrolled, out of a planned cohort of 200 subjects.
Patients were randomized to receive human recombinant GM-CSF (64 subjects, 250 μg/M2) or placebo (66 subjects) by intravenous infusion daily for 14 days. Patients received mechanical ventilation using a lung protective protocol.
Measurements and Main Results
There was no difference in ventilator-free days between groups (10.7 ± 10.3 days placebo vs. 10.8 ± 10.5 days GM-CSF, p=0.82). Differences in 28-day mortality (23% in placebo vs. 17% in patients receiving GM-CSF (p=0.31)) and organ failure free days (12.8 ± 11.3 days placebo vs. 15.7 ± 11.9 days GM-CSF, p=0.16) were not statistically significant. There were similar numbers of serious adverse events in each group.
In a randomized phase II trial, GM-CSF treatment did not increase the number of ventilator free days in patients with ALI/ARDS. A larger trial would be required to determine whether treatment with GM-CSF might alter important clinical outcomes such as mortality or multiorgan failure. (ClinicalTrials.gov number, NCT00201409 [ClinicalTrials.gov])
Acute Respiratory Distress Syndrome; growth factors; sepsis; innate immunity
In this month's issue of Critical Care, Determann and colleagues report the results of a randomized controlled trial comparing the effects of mechanical ventilation (MV) with two tidal volumes (6 versus 10 ml/kg predicted body weight) on cytokine levels in lung lavage fluid and plasma as a surrogate for early identification of acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). The study was stopped early after an interim analysis - when 150 patients were enrolled - showing that the incidence of ALI/ARDS according to the current definition was 10.9% higher in the 10 ml/kg group, although duration of MV and mortality was similar in both groups. We examine these interesting results after providing a brief historical perspective and discuss the limitations and implications of the study.
Acute lung injury (ALI) remains a major cause of morbidity and mortality in critically ill patients. Despite improved understanding of the pathogenesis of ALI, supportive care with a lung protective strategy of mechanical ventilation remains the only treatment with a proven survival advantage. Most clinical trials in ALI have targeted mechanically ventilated patients. Past trials of pharmacologic agents may have failed to demonstrate efficacy in part due to the resultant delay in initiation of therapy until several days after the onset of lung injury. Improved early identification of at-risk patients provides new opportunities for risk factor modification to prevent the development of ALI and novel patient groups to target for early treatment of ALI before progression to the need for mechanical ventilation. This review will discuss current strategies that target prevention of ALI and some of the most promising pharmacologic agents for early treatment of ALI prior to the onset of respiratory failure that requires mechanical ventilation.
Acute lung injury (ALI), and its more severe form, acute respiratory distress syndrome (ARDS), are syndromes of acute hypoxemic respiratory failure resulting from a variety of direct and indirect injuries to the gas exchange parenchyma of the lungs. Current treatment of ALI/ARDS is primarily supportive, with lung protective ventilation and fluid conserving strategies. Despite improvement in these strategies, recent data indicate that the mortality of ALI/ARDS is still as high as 30 to 50%. Thus, there is a need for innovative therapies to further improve clinical outcomes of ALI/ARDS. Recent studies involving the administration of mesenchymal stem cells (MSCs) for the treatment of experimental ALI/ARDS have shown promising results. This review focuses on existing studies that have tested the use of MSCs in models of ALI/ARDS, and the potential mechanisms underlying their therapeutic effects.
Enrolling critically ill patients in clinical trials is challenging. We observed that eligible patients at San Francisco General Hospital (SFGH), a public hospital that cares largely for indigent patients, were less likely to be enrolled in a clinical trial of acute lung injury (ALI) than eligible patients at the University of California, San Francisco (UCSF), a university referral center. We examined the reasons for nonenrollment and the impact of the availability of a surrogate decision maker on critical care clinical trials enrollment.
Data collected from the ARDS Network trial of lower vs traditional tidal volume ventilation for patients with ALI was analyzed. Patient demographics and reasons for nonenrollment were analyzed among 531 consecutively screened patients at the two hospitals: UCSF and SFGH.
At UCSF, 1% of screened patients were not enrolled because they lacked surrogates, whereas 18% of screened patients were not enrolled at SFGH because they lacked surrogates. Lack of surrogate was the most common reason for nonenrollment among eligible patients at SFGH.
Critically ill patients with ALI at a public hospital were less likely to be enrolled in a clinical trial than patients at a university hospital primarily because they lacked surrogates. Lack of a surrogate also was a major factor in nonenrollment in other ARDS Network hospitals. In order to provide all affected patients an opportunity to participate in research, innovative strategies for increasing enrollment in critical care research without compromising protection from research risks are needed.
acute lung injury; ARDS; clinical trials; critical care; informed consent; surrogate consent
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.
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).
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).
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.
acute respiratory distress syndrome; acute lung injury; mortality; temporal trend; epidemiology
Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are a frequent cause of intensive care unit admission, affecting over 200,000 patients in the United States each year. Mechanical ventilation is a life-saving intervention in the setting of ARDS and ALI, but clinical trials have demonstrated that mechanical ventilation with excessive tidal volumes plays a role in promoting and perpetuating lung injury and leads to excess mortality. This process has been labeled ventilator-induced lung injury (VILI), but the molecular mechanisms driving this process and its interactions with predisposing risk factors such as sepsis and chemical injury remain incompletely understood. Genome-wide measurements of gene expression using microarray technology represent a powerful tool to examine the pathophysiology of VILI. Several recent studies have used this approach to study VILI in isolation and associated with endotoxin instillation or saline lavage. These studies and others examining gene expression profiles in epithelial cells subjected to cyclic stretch have provided novel insights on the molecular mechanisms underlying VILI. This review will summarize these findings and discuss implications for future studies.
microarray analysis; lung injury; mechanical ventilation; gene expression; genomics
Acute lung injury (ALI) remains a significant source of morbidity and mortality in the critically ill patient population. Defined by a constellation of clinical criteria (acute onset of bilateral pulmonary infiltrates with hypoxemia without evidence of hydrostatic pulmonary edema), ALI has a high incidence (200,000 per year in the US) and overall mortality remains high. Pathogenesis of ALI is explained by injury to both the vascular endothelium and alveolar epithelium. Recent advances in the understanding of pathophysiology have identified several biologic markers that are associated with worse clinical outcomes. Phase III clinical trials by the NHLBI ARDS Network have resulted in improvement in survival and a reduction in the duration of mechanical ventilation with a lung-protective ventilation strategy and fluid conservative protocol. Potential areas of future treatments include nutritional strategies, statin therapy, and mesenchymal stem cells.
acute respiratory distress syndrome (ARDS); pulmonary edema; acute respiratory failure
Acute Respiratory Distress Syndrome (ARDS) is a common entity in critical care. ARDS is associated with many diagnoses, including trauma and sepsis, can lead to multiple organ failure and has high mortality. The present article is a narrative review of the literature on ARDS, including ARDS pathophysiology and therapeutic options currently being evaluated or in use in clinical practice. The literature review covers relevant publications until January 2011. Recent developments in the therapeutic approach to ARDS include refinements of mechanical ventilatory support with emphasis on protective lung ventilation using low tidal volumes, increased PEEP with use of recruitment maneuvers to promote reopening of collapsed lung alveoli, prone position as rescue therapy for severe hypoxemia, and high frequency ventilation. Supportive measures in the management of ARDS include attention to fluid balance, restrictive transfusion strategies, and minimization of sedatives and neuromuscular blocking agents. Inhaled bronchodilators such as inhaled nitric oxide and prostaglandins confer short term improvement without proven effect on survival, but are currently used in many centers. Use of corticosteroids is also important, and appropriate timely use may reduce mortality. Finally, extra corporeal oxygenation methods are very useful as rescue therapy in patients with intractable hypoxemia, even though a survival benefit has not, to this date been demonstrated. Despite intense ongoing research on the pathophysiology and treatment of ARDS, mortality remains high. Many pharmacologic and supportive strategies have shown promising results, but data from large randomized clinical trials are needed to fully evaluate the true effectiveness of these therapies.
ARDS; Pathophysiology; Treatment
It has recently been shown that strategies aimed at preventing ventilator-induced lung injury, such as ventilating with low tidal volumes, can reduce mortality in patients with acute respiratory distress syndrome (ARDS). High-frequency oscillatory ventilation (HFOV) seems ideally suited as a lung-protective strategy for these patients. HFOV provides both active inspiration and expiration at frequencies generally between 3 and 10 Hz in adults. The amount of gas that enters and exits the lung with each oscillation is frequently below the anatomic dead space. Despite this, gas exchange occurs and potential adverse effects of conventional ventilation, such as overdistension and the repetitive opening and closing of collapsed lung units, are arguably mitigated. Although many investigators have studied the merits of HFOV in neonates and in pediatric populations, evidence for its use in adults with ARDS is limited. A recent multicenter, randomized, controlled trial has shown that HFOV, when used early in ARDS, is at least equivalent to conventional ventilation and may have beneficial effects on mortality. The present article reviews the principles and practical aspects of HFOV, and the current evidence for its application in adults with ARDS.
acute lung injury; acute respiratory distress syndrome; high-frequency oscillatory ventilation; mechanical ventilation; ventilator-induced lung injury
Mechanical ventilation, often required to maintain normal gas exchange in critically ill patients, may itself cause lung injury. Lung-protective ventilatory strategies with low tidal volume have been a major success in the management of acute respiratory distress syndrome (ARDS). Volutrauma causes mechanical injury and induces an acute inflammatory response. Our objective was to determine whether neutrophil elastase (NE), a potent proteolytic enzyme in neutrophils, would contribute to ventilator-induced lung injury. NE-deficient (NE−/−) and wild-type mice were mechanically ventilated at set tidal volumes (10, 20, and 30 ml/kg) with 0 cm H2O of positive end-expiratory pressure for 3 hours. Lung physiology and markers of lung injury were measured. Neutrophils from wild-type and NE−/− mice were also used for in vitro studies of neutrophil migration, intercellular adhesion molecule (ICAM)-1 cleavage, and endothelial cell injury. Surprisingly, in the absence of NE, mice were not protected, but developed worse ventilator-induced lung injury despite having lower numbers of neutrophils in alveolar spaces. The possible explanation for this finding is that NE cleaves ICAM-1, allowing neutrophils to egress from the endothelium. In the absence of NE, impaired neutrophil egression and prolonged contact between neutrophils and endothelial cells leads to tissue injury and increased permeability. NE is required for neutrophil egression from the vasculature into the alveolar space, and interfering with this process leads to neutrophil-related endothelial cell injury.
neutrophil elastase; ventilator-induced lung injury; endothelial injury; emigration
In the present issue of Critical Care, Frank and Matthay review the physiologic mechanisms that lead to ventilator-induced lung injury. Our greater understanding of basic physiologic principles has already had a major impact on the treatment of critically ill patients. Novel strategies to limit ventilator-induced lung injury have now been shown to improve survival. However, there has been debate in the literature regarding the safety and efficacy of the Acute Respiratory Distress Syndrome (ARDS) Network study protocol in reducing ventilator-induced lung injury. The issues surrounding the ARDS Network protocol and a recent meta-analysis criticizing its use are presented. As clinicians, we now have the responsibility to ensure that our patients benefit from these recent developments.
acute respiratory distress syndrome; ARDS Network; lung injury; lung protective strategy; mechanical ventilation
The 'open lung' approach has been proposed as a reasonable ventilation strategy to mitigate ventilator-induced lung injury (VILI) and possibly reduce acute respiratory distress syndrome (ARDS)-related mortality. However, several randomized clinical trials have failed to show any significant clinical benefit of a ventilation strategy applying higher positive end-expiratory pressure (PEEP) and low tidal volume.
Dispute regarding the optimal levels of PEEP in ARDS patients represents the substrate for a translational research effort from the bedside to the bench, driving animal studies aimed at elucidating which ventilation strategies reduce biotrauma, considered one of the most important driving forces of VILI and ARDS-related multi-organ failure and mortality. Inappropriate values for end-inspiratory or end-expiratory pressure have clear potential to damage a lung predisposed to VILI. In the heterogeneous environment of the ARDS 'baby lung', lung recruitment and the avoidance of tidal overstretch with high-frequency oscillation ventilation or conventional mechanical ventilation, guided by respiratory mechanics, appears to reduce VILI.
This study sought to assess whether the use of thoraco-pelvic supports during prone positioning in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) improves, deteriorates or leaves unmodified gas exchange, hemodynamics and respiratory mechanics.
We studied 11 patients with ALI/ARDS, sedated and paralyzed, mechanically ventilated in volume control ventilation. Prone positioning with or without thoraco-pelvic supports was applied in a random sequence and maintained for a 1-hour period without changing the ventilation setting. In four healthy subjects the pressures between the body and the contact surface were measured with and without thoraco-pelvic supports. Oxygenation variables (arterial and central venous), physiologic dead space, end-expiratory lung volume (helium dilution technique) and respiratory mechanics (partitioned between lung and chest wall) were measured after 60 minutes in each condition.
With thoraco-pelvic supports, the contact pressures almost doubled in comparison with those measured without supports (19.1 ± 15.2 versus 10.8 ± 7.0 cmH2O, p ≤ 0.05; means ± SD). The oxygenation-related variables were not different in the prone position, with or without thoraco-pelvic supports; neither were the CO2-related variables. The lung volumes were similar in the prone position with and without thoraco-pelvic supports. The use of thoraco-pelvic supports, however, did lead to a significant decrease in chest wall compliance from 158.1 ± 77.8 to 102.5 ± 38.0 ml/cmH2O and a significantly increased pleural pressure from 4.3 ± 1.9 to 6.1 ± 1.8 cmH2O, in comparison with the prone position without supports. Moreover, when thoraco-pelvic supports were added, heart rate increased significantly from 82.1 ± 17.9 to 86.7 ± 16.7 beats/minute and stroke volume index decreased significantly from 37.8 ± 6.8 to 34.9 ± 5.4 ml/m2. The increase in pleural pressure change was associated with a significant increase in heart rate (p = 0.0003) and decrease in stroke volume index (p = 0.0241).
The application of thoraco-pelvic supports decreases chest wall compliance, increases pleural pressure and slightly deteriorates hemodynamics without any advantage in gas exchange. Consequently, we stopped their use in clinical practice.
Appropriate management of patients with acute respiratory distress syndrome (ARDS) represents a challenge for physicians working in the critical care environment. Significant advances have been made in understanding the pathophysiology of ARDS. There is also an increasing appreciation of the role of ventilator-induced lung injury (VILI). VILI is most likely related to several different aspects of ventilator management: barotrauma due to high peak airway pressures, lung overdistension or volutrauma due to high transpulmonary pressures, alveolar membrane damage due to insufficient positive end-expiratory pressure levels and oxygen-related cell toxicity. Various lung protective strategies have been suggested to minimize the damage caused by conventional modes of ventilation. These include the use of pressure- and volume-limited ventilation, the use of the prone position in the management of ARDS, and extracorporeal methods of oxygen delivery and carbon dioxide removal. Although the death rate resulting from ARDS has been declining over the past 10 years, there is no evidence that any specific treatment or change in approach to ventilation is the cause of this improved survival.
Limiting the energy transfer between ventilator and lung is crucial for ventilatory strategy in acute respiratory distress syndrome (ARDS). Part of the energy is transmitted to the viscoelastic tissue components where it is stored or dissipates. In mechanically ventilated patients, viscoelasticity can be investigated by analyzing pulmonary stress relaxation. While stress relaxation processes of the lung have been intensively investigated, non-linear interrelations have not been systematically analyzed, and such analyses have been limited to small volume or pressure ranges. In this study, stress relaxation of mechanically ventilated lungs was investigated, focusing on non-linear dependence on pressure. The range of inspiratory capacity was analyzed up to a plateau pressure of 45 cmH2O.
Twenty ARDS patients and eleven patients with normal lungs under mechanical ventilation were included. Rapid flow interruptions were repetitively applied using an automated super-syringe maneuver. Viscoelastic resistance, compliance and time constant were determined by multiple regression analysis using a lumped parameter model. This same viscoelastic model was used to investigate the frequency dependence of the respiratory system's impedance.
The viscoelastic time constant was independent of pressure, and it did not differ between normal and ARDS lungs. In contrast, viscoelastic resistance increased non-linearly with pressure (normal: 8.4 (7.4-11.9) [median (lower - upper quartile)] to 35.2 (25.6-39.5) cmH2O·sec/L; ARDS: 11.9 (9.2-22.1) to 73.5 (56.8-98.7)cmH2O·sec/L), and viscoelastic compliance decreased non-linearly with pressure (normal: 130.1(116.9-151.3) to 37.4(34.7-46.3) mL/cmH2O; ARDS: 125.8(80.0-211.0) to 17.1(13.8-24.7)mL/cmH2O). The pulmonary impedance increased with pressure and decreased with respiratory frequency.
Viscoelastic compliance and resistance are highly non-linear with respect to pressure and differ considerably between ARDS and normal lungs. None of these characteristics can be observed for the viscoelastic time constant. From our analysis of viscoelastic properties we cautiously conclude that the energy transfer from the respirator to the lung can be reduced by application of low inspiratory plateau pressures and high respiratory frequencies. This we consider to be potentially lung protective.