Update in Acute Respiratory Distress Syndrome and ... - ATS Journals

Pulmonary, Sleep, and Critical Care Updates Update in Acute Respiratory Distress Syndrome and Mechanical Ventilation 2012 Dean R. Hess1,2*, B. Taylor Thompson2,3*, and Arthur S. Slutsky4,5,6* 1

Respiratory Care and 3Pulmonary and Critical Care Medicine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; 2Harvard Medical School, Boston, Massachusetts; 4Keenan Research Center at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada; and 5Interdepartmental Division of Critical Care Medicine and 6Department of Medicine, University of Toronto, Toronto, Ontario, Canada

In this Update, we highlight studies published in 2012 in the Journal and selected manuscripts from other journals that advanced our understanding of the acute respiratory distress syndrome (ARDS) and mechanical ventilation.

ARDS DEFINITIONS It has been more that 45 years since Ashbaugh and colleagues described a syndrome of hypoxemic respiratory failure, bilateral radiographic opacities, and poor outcomes in 12 intensive care unit (ICU) patients, and 25 years later the American European Consensus Committee produced a landmark definition for ARDS (1, 2). In 2012 a task force developed a new ARDS definition, which was termed the Berlin definition (1); it specifies that “acute” should be 1 week or less, it requires a minimum positive end-expiratory pressure (PEEP), and it abandons the term acute lung injury (ALI) in favor of three mutually exclusive categories of increasingly severe ARDS, based on the Pa O 2 / F I O 2 ratio (Table 1). The Berlin definition (1) recognizes that high left atrial pressures and ARDS may coexist and drops both the pulmonary artery occlusion pressure criterion and the requirement for no clinical evidence for left atrial hypertension. The new definition excludes patients only with left atrial hypertension as the sole cause of pulmonary edema. Clinical vignettes were given to help clinicians make this determination. The chest radiographic criteria were clarified to any opacity not fully explained by lobar/ lung collapse, pleural effusions, or nodules. Thus, bilateral lobar consolidation from bacterial pneumonia is a qualifying opacity. Sample radiographs consistent, equivocal, or inconsistent with the diagnosis of ARDS were published in an electronic supplement. The Berlin task force considered including the following: the most severe subset (1) should have PEEP greater than or equal to 10 cm H2O, three- or four-quadrant involvement on chest radiography, and either low respiratory system compliance or high corrected minute ventilation, the latter as a surrogate for dead space. However, analysis of a dataset of more than 4,000 subjects from observational cohorts and clinical trials from North America, Europe, and Australia indicated that these additional criteria added little, and thus the committee opted not to include these in the definition of severe ARDS (1). The (Received in original form April 25, 2013; accepted in final form June 1, 2013) * Each of the authors contributed equally to this work. Correspondence and requests for reprints should be addressed to Dean R. Hess, Ph.D., R.R.T., Ellison 401, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. E-mail: [email protected] Am J Respir Crit Care Med Vol 188, Iss. 3, pp 285–292, Aug 1, 2013 Copyright ª 2013 by the American Thoracic Society DOI: 10.1164/rccm.201304-0786UP Internet address: www.atsjournals.org

categorization of severe ARDS based on PaO2/FIO2 builds on recent evidence indicating differential effects of interventions by ARDS severity (3–5) and will be more suitable for future research, patient management, and triage (6). In an accompanying editorial, Angus (6) lauded the empirical validation step in the development of the new definition and noted the rarity of such approaches when expert committees develop new definitions. He encouraged expansion of the scope of future validation exercises to include assessment of patients who would or would not have been classified as having ARDS using the new definition (examples might be hypoxemic patients with unilateral opacities or hypoxemic patients managed without mechanical ventilation in the developing world) and to include longer-term patient-centered outcomes in the assessment of predictive validity.

NONINVASIVE VENTILATION There continues to be much interest in noninvasive ventilation (NIV). Chandra and colleagues (7) used data from the Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample to assess the pattern and outcomes of NIV use for chronic obstructive pulmonary disease (COPD) exacerbations. An estimated 7,511,267 admissions for exacerbations occurred from 1998 to 2008. Over this time, there was an increase in NIV use from 1.0 to 4.5% of all admissions and a decline in invasive mechanical ventilation use from 6.0 to 3.5%. This was associated with 61% greater odds of death for the small cohort of patients who transitioned from NIV to invasive mechanical ventilation. This group also had greater odds of death than patients treated with NIV alone. When these patients were removed from the analysis, in-hospital outcomes were favorable and improved steadily each year. The study provides additional support for the use of NIV in patients with COPD exacerbation. Carrillo and colleagues (8) compared the efficacy of NIV in patients presenting with acute respiratory failure due to obesity hypoventilation syndrome (OHS) and COPD. The groups had similar baseline respiratory acidosis. Patients with OHS were older, more frequently female, had less late NIV failure, had lower hospital mortality, and had a higher 1-year survival (odds ratio [OR], 1.83). Survival adjusted for confounders, NIV failure, length of stay, and hospital readmission was similar in both groups. In patients with COPD, obesity was associated with less late NIV failure and hospital readmission. This study supports the use of NIV in patients with OHS who develop respiratory failure.

VT AND FIO2 In 13 ICUs at four hospitals in Baltimore, Needham and colleagues evaluated the association of lung-protective mechanical ventilation and 2-year survival in 485 consecutive patients with

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TABLE 1. THE BERLIN DEFINITION OF ACUTE RESPIRATORY DISTRESS SYNDROME Timing Within 1 wk of a known clinical insult or new/worsening respiratory symptoms Chest imaging* Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules Origin of edema Respiratory failure not fully explained by cardiac failure or fluid overload; need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present Mild Moderate Severe † 200 , PaO2/FIO2 < 300 with PEEP or CPAP > 5 cm H2O‡ 100 , PaO2/FIO2 < 200 with PEEP > 5 cm H2O PaO2/FIO2 < 100 with PEEP > 5 cm H2O Oxygenation Definition of abbreviations: CPAP ¼ continuous positive airway pressure; FIO2 ¼ fraction of inspired oxygen; PaO2 ¼ partial pressure of arterial oxygen; PEEP ¼ positive end-expiratory pressure. Modified by permission from Reference 1. * Chest X-ray or computed tomography scan. y If altitude higher than 1,000 m, correction factor should be made as follows: PaO2/FIO2 3 (barometric pressure/760) z This may be delivered noninvasively in the group with mild acute respiratory distress syndrome.

ARDS (9). A ventilator setting was defined as lung protective if the VT was less than or equal to 6.5 ml/kg ideal body weight (IBW) and plateau pressure (Pplat) was less than or equal to 30 cm H2O. After adjusting for relevant covariates, each additional ventilator setting adherent to lung-protective ventilation was associated with a 3% decrease in mortality risk over 2 years (hazard ratio, 0.97). Compared with no adherence, the estimated absolute risk reduction in 2-year mortality for a patient with 50% adherence to lung-protective ventilation was 4% and with 100% adherence was 8%. This translates to an 18% relative increase in mortality for each 1 ml/kg IBW weight increase in VT. Rice and colleagues (10) used near real-time assessments of damage control, transfusion, and ventilation protocols from a multicenter study to evaluate whether protocol compliance was associated with lower mortality and other improved clinical outcomes. Deviations from the lung-protective ventilator protocol represented the most common violation. VT and Pplat deviations were associated with significantly higher mortality and fewer ventilation-free days, both at 30 days and 90 days. The OR for 30-day mortality was 2.4 for VT violations and 2.7 for Pplat violations. Lellouche and colleagues examined prospectively recorded data from 3,434 consecutive adult cardiac surgery patients (11). Three groups of patients were defined based on the VT setting at ICU arrival: (1) low: less than 10 ml/kg IBW; (2) traditional: 10 to 12 ml/kg; and (3) high: greater than 12 ml/ kg. Low, traditional, and high VT were used in 21, 46, and 33% of patients, respectively. Independent risk factors for high VT were body mass index (BMI) greater than or equal to 30 (OR, 6.25) and female sex (OR, 4.33). From multivariate analysis, high and traditional VT were independent risk factors for multiple organ failure and prolonged ICU stay. Organ failures were associated with increased ICU stay, hospital mortality, and long-term mortality. Serpa Neto and colleagues (12) conducted a metaanalysis to determine whether use of lower VT is associated with improved outcomes of patients receiving mechanical ventilation who do not have ARDS. Their analysis, based on 22 articles with 2,822 participants, showed a decrease in development of ARDS (number needed to treat [NNT], 11) and mortality (NNT, 23) in patients receiving low VT ventilation. Patients receiving lung-protective ventilation had fewer pulmonary infections (NNT, 26), shorter hospital lengths of stay (7 vs. 9 d), higher PaCO2 (41 mm Hg vs. 38 mm Hg), but similar PaO2/FIO2 (304 vs. 313 mm Hg). From a database of patients with mild ARDS, Rachmale and colleagues (13) evaluated ventilator settings for those who underwent mechanical ventilation for more than 48 hours over 1 calendar year. They found that 74% of patients were exposed to excessive FIO2 (defined as .0.5 despite oxygen saturation as

measured by pulse oximetry . 92%) for a median duration of 17 hours. Prolonged exposure to excessive FIO2 correlated with worse oxygenation index at 48 hours in a dose–response manner. Both exposure to higher FIO2 and longer duration of exposure were associated with worsening oxygenation index at 48 hours, more ventilator days, longer ICU stay, and longer hospital stay. No mortality difference was noted. These studies provide additional evidence that the selection of ventilator settings affects patient outcomes. Volume and pressure limitation should be standard practice in all mechanically ventilated patients, not just those with established ARDS.

VENTILATOR MODES One of the purported advantages of airway pressure-release ventilation is that it promotes spontaneous breathing. However, several recent experimental studies (14, 15), case reports (16, 17), editorials (18, 19), and a randomized controlled trial (5) bring into question the safety of spontaneous breathing in patients with severe ALI. Another study reported an increased in ventilator days associated with airway pressure-release ventilation (20). A mode that is receiving interest is neurally adjusted ventilatory assist (NAVA). Patroniti and colleagues (21) found that excessive increases in VT variability at higher NAVA levels were associated with increased incidence of VT greater than 10 ml/kg and uncomfortable respiratory patterns. They suggested that to preserve respiratory variability and a low risk of excessive VT and patient discomfort, NAVA levels less than 2 to 2.5 cm H2O/mV should be used. In patients receiving NIV, Schmidt and colleagues (19) found that both NAVA and NIV mode on the ventilator improved patient–ventilator synchrony, and they suggested that this combination offers the best compromise for patient–ventilator synchrony and minimal air leaks. However, whether insertion of a special nasogastric tube to facilitate NIV will be acceptable to patients and clinicians remains to be determined. Using fluoroscopy tracking of radiopaque markers, Li Bassi and colleagues (22) evaluated the effects of duty cycle and PEEP on mucus clearance in pigs receiving mechanical ventilation. No effect of PEEP was found. However, as duty cycle was prolonged, there was reduced velocity of mucus moving toward the lungs and increased outward mucus velocity, suggesting that ventilator settings might affect airway clearance—a hypothesis that deserves study in humans.

VENTILATOR LIBERATION Difficulty liberating a patient from mechanical ventilation is often associated with fluid overload. To investigate whether fluid management guided by B-type natriuretic peptide (BNP) plasma

Pulmonary, Sleep, and Critical Care Updates

concentrations improves weaning outcomes, Mekontso Dessap and colleagues (23) randomized 304 patients with multiple diagnoses to a BNP-driven or physician-driven strategy of fluid management during weaning. The BNP-driven group had a more negative fluid balance during weaning and significantly shorter times to successful extubation (59 vs. 42 h). Although the BNP-driven strategy increased ventilator-free days, there was no difference in mortality. Whether or not fluid management is driven by BNP measurements, the results of this study draw attention to the role of fluid overload during the process of ventilator liberation, especially in patients with left ventricular systolic dysfunction. For those patients who fail a spontaneous breathing trial (SBT), it is important to identify possible causes, and the paper by Mekontso Dessap and colleagues (23) reminds us that fluid overload is an important cause of failure. Schädler and colleagues (24) found that automated weaning did not change overall ventilation time compared with weaning using a standardized written protocol, even though the time to the first SBT was shorter in the automated-weaning group. In both groups, pressure support was weaned to 12 cm H2O before the SBT. It is possible that there would not have been any difference in the time to SBT if the SBT had been performed at the outset rather than after the pressure support wean (25). NIV has been used to facilitate earlier extubation (26) but has not been well studied in patients with acute hypoxemic respiratory failure. Vaschetto and colleagues (27) compared conventional weaning with early extubation followed immediately by NIV in patients with resolving hypoxemic respiratory failure. The number of invasive-ventilation–free days at Day 28 was 20 in the treatment group and 10 in the control group. Extubation failure, ICU and hospital mortality, tracheotomies, septic complications, use of continuous sedation, and ICU length of stay were not significantly different between the groups.

LONG-TERM OUTCOMES With the increasing focus on long-term morbidity in patients surviving critical illness, several recent studies suggest important morbidities in survivors of critical illness. To determine the frequency of long-term cognitive and psychiatric morbidity, Mikkelsen and colleagues (28) assessed neuropsychological function at 2 and 12 months post hospital discharge. Memory, verbal fluency, and executive function were impaired in 13, 16, and 49% of longterm survivors. Long-term cognitive impairment was present in 55% of survivors. Depression, post-traumatic stress disorder, or anxiety was present in 36, 39, and 62% of long-term survivors. The degree of hypoxemia or enrollment in the conservative fluidmanagement strategy of the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial (FACTT) (29, 30) was associated with greater cognitive impairment. In 186 ARDS survivors evaluated over 2 years, Bienvenu and colleagues (31) found the incidence of depressive symptoms and impaired physical function were 40 and 66%, respectively. Risk factors for depressive symptoms were education less than or equal to 12 years, baseline disability or unemployment, higher baseline medical comorbidity, and lower ICU blood glucose. Risk factors for impaired physical function were longer ICU stay and prior depressive symptoms. Lone and Walsh evaluated the relationship between organ failures and mortality within the 5 years after critical illness (32). Twenty-eight–day mortality was 34%, and 5-year mortality was 58%. In adjusted analyses, cardiovascular failure (OR, 2.5), liver failure (OR, 2.3), and respiratory failure (OR, 2.1) were independently associated with 5-year mortality. Organ failure

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burden was strongly associated with mortality, with 81% of patients in the highest tertile dying during follow-up. Iwashyna and colleagues (33) evaluated whether severe sepsis was associated with increased risk of geriatric conditions in 623 patients identified from the Health and Retirement Study. Surviving severe sepsis was associated with increased rates of low BMI, injurious falls, incontinence, and vision loss. The association of low BMI and severe sepsis persisted when controlling for patients’ presepsis trajectories, but there was no association of severe sepsis with other geriatric conditions.

SEDATION An increasing body of evidence suggests that sedation-limiting strategies improve important clinical outcomes. In a 25-center, prospective, longitudinal cohort study of 251 ICU patients, Shehabi and colleagues (34) observed that early, deep sedation (i.e., Richmond Agitation Sedation Scale of 23 to 25) was independently associated with prolonged time to extubation, death while in the hospital, and 180-day mortality. Each additional deep sedation occurrence within the first 48 hours was associated with a 12.3-hour delay in extubation. Although unmeasured prognostic confounders are possible, and the conflation of encephalopathy with sedation is a weakness of the study, the findings are yet another call for clinical trials in this area (35). As for other trials of time-sensitive interventions, such as resuscitation for septic shock and antibiotics for severe infections, clinical trials of sedation will likely need to intervene early in the ICU course for maximum impact. Contrary to an earlier single-center trial of daily interruption of sedatives (36), Mehta and colleagues (37) observed no differences in the duration of mechanical ventilation or ICU stay when a daily interruption protocol was compared with a targeted sedation and analgesia protocol. This well-conducted pragmatic multicenter trial included a broad mix of ICU patients but could not be blinded, and adherence with the protocol was a modest 72%. Reluctance to interrupt sedation may reflect a well-founded clinical concern for patient safety or comfort or a practice style that inadvertently errs on the side of oversedation. The finding of greater opioid use and benzodiazepine doses and more bolus doses in the interruption group was unexpected. This study did not evaluate propofol and dexmedetomidine, which were evaluated in another trial by Jakob and colleagues (38). In ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. However, dexmedetomidine reduced the duration of mechanical ventilation in comparison with midazolam and improved the patient’s ability to communicate pain compared with both other agents. Taken together, these and other studies suggest optimal sedation practices are dependent on the agents used, support the use of short-acting sedatives, and suggest that daily sedation interruptions should be coupled with SBTs, and perhaps sessions of physical therapy, to improve outcomes (35, 39, 40).

TRANSFUSION Red blood cells (RBCs) develop biochemical, metabolic, and molecular changes over the allowed storage period of 42 days. Increasing evidence suggests that these defects may result in adverse clinical consequences. In the first of five ongoing randomized trials of the clinical consequences of RBC storage time and clinical outcomes, Kor and colleagues compared fresh leukodepleted RBCs (median storage time, 4.0 d) to standard issue leukodepleted cells (median storage time, 26.5 d) (41, 42). They found no difference in the primary outcome, PaO2/FIO2, or other

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pulmonary or immunologic outcomes over an approximately 2-hour post-transfusion period. Subsequent organ failures and mortality were also similar, although the relatively small sample size (50/group) and the low event rates preclude a firm equivalence conclusion. This study helps provide clinical equipoise for the remaining larger clinical trials of storage time and should not result in changes to the current RBC allocation practices. Toy and coworkers of the transfusion-related acute lung injury (TRALI) study group (43) conducted a prospective active surveillance case-controlled study to determine TRALI risk factors and to identify both recipient and blood product factors that determine the risk for TRALI. Recipient factors included high IL-8 levels, hepatic surgery (mostly transplantation), chronic alcohol use, shock, higher peak airway pressure, current smoking, and fluid balance. Blood product factors included blood products from female donors, volume of high-titer HLA class II antibody, and volume of anti–human neutrophil antigen. Interestingly, RBC storage time was not a risk factor. The incidence of TRALI decreased after a reduction of transfusion of plasma from female donors, reduced transfusion of strong cognate HLA class II antibodies and human neutrophil antigen antibodies to patients who are susceptible to ALI, and decreases in other patient risk factors. These findings support a combined strategy for TRALI prevention that includes both patient and blood product mitigation factors.

INFECTION Invasive pulmonary aspergillosis (IPA) is a life-threatening complication of immune suppression. The European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definition is the current gold standard, defining proven, possible, and probable IPA in immune-suppressed individuals. In a major, 30-center undertaking, the Aspergillus ICU (AspICU) investigators (44) revised a new clinical algorithm for diagnosing IPA in 524 immunosuppressed and immunocompetent mechanically ventilated patients with aspergillus growth from a lower airway sample, 115 of whom had a tissue diagnosis. The new approach expands the computed tomographic criteria to include nearly any type of opacity. It also allows the diagnosis of probable IPA in nonimmunosuppressed patients if they meet clinical and radiographic criteria and have positive semiquantitative cultures on bronchoalveolar lavage (BAL) with the presence of branching hyphae on BAL cytology. The algorithm resulted in 61% specificity, 92% sensitivity, and 92% negative predictive value. Interestingly, 22 of 79 patients with proven IPA (by tissue diagnosis) had no immunosuppression by EORTC/MSG criteria. As pointed out in the accompanying editorial (45), these observations highlight the possibility that immunoparalysis from late sepsis or ARDS per se may predispose to IPA, although this complication is uncommon. This complication remains quite unusual in the nonimmunosuppressed, as only approximately 2% of the general ICU population will grow aspergillus in lower airway specimens, and only 20% of those will have IPA (45). Prospective studies are now needed to validate these diagnostic criteria in both immunosuppressed and immunocompetent patients. The proportion of community-acquired pneumonia (CAP) without an identifiable pathogen is growing smaller with increasing use of reverse transcriptase–polymerase chain reaction. In an important single-center prospective medical ICU cohort study of the etiologic agents responsible for either severe CAP or severe health care–associated pneumonia (HCAP), Choi and coworkers (46) found a potential pathogen in the majority of CAP (75%) and HCAP (63%). Importantly, a viral agent alone

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or in combination with another virus was isolated in 72 patients. Rhinovirus (24%), parainfluenza virus (21%), and metapneumovirus (18%) were the most common viral pathogens. Coinfection with a bacterial pathogen occurred in 25% of patients, a likely underestimate, as one-fourth of the patients had received antibacterial antibiotics before cultures. Even with this limitation, this report clearly shows that viruses are frequently isolated in patients with severe CAP and HCAP and, when combined with a growing body of other evidence, suggests these viruses may actually be the causative organism (47).

INFECTION CONTROL AND VENTILATOR-ASSOCIATED PNEUMONIA SURVEILLANCE Chlorhexidine-impregnated and strongly adherent dressings may decrease catheter colonization and catheter-related infection (CRI) rates. In a multicenter single-blinded randomized controlled trial of 1,879 patients (4,163 catheters and 34,339 catheter-days), Timsit and colleagues (48) found that with chlorhexidine dressings, the major CRI rate was 67% lower and the catheter-related bloodstream infection was 60% lower than with nonchlorhexidine dressings. Highly adhesive dressings decreased the detachment rate to 64 versus 72% and the number of dressings per catheter to two versus three but increased skin colonization and catheter colonization without influencing CRI or catheter-related bloodstream infection rates. Ventilator-associated pneumonia (VAP), among the most common infections in patients requiring invasive mechanical ventilation (49), is associated with increased hospital costs, more ICU days, longer duration of mechanical ventilation, and higher mortality. Many interventions have been widely accepted to reduce VAP rates, but there is not robust evidence supporting that many of these interventions improve outcomes. Moreover, there is uncertainty about the approach to VAP surveillance, with poor agreement between clinical and administrative surveillance methods for VAP diagnosis. The administratively applied National Healthcare Safety Network (NHSN) criteria may significantly underestimate the scope of the clinical problem (50). This led to the introduction in early 2013 of new surveillance definitions from the NHSN (51) that focus first on ventilator-associated events (VAE) rather than VAP specifically. Klompas and colleagues (52) explored the feasibility of creating objective surveillance definitions for VAP. They evaluated 32 candidate definitions with different combinations of the following signs: three thresholds for respiratory deterioration defined by sustained increases in daily minimum PEEP or FIO2 after either 2 or 3 days of stable or decreasing ventilator settings, abnormal temperature, abnormal white blood cell count, purulent pulmonary secretions, and positive cultures for pathogenic organisms. All candidate definitions were significantly associated with increased ventilator days and hospital days, but only definitions requiring objective evidence of respiratory deterioration were significantly associated with increased hospital mortality. Requiring additional clinical signs beyond respiratory deterioration alone decreased event rates, had little impact on length of stay, and diminished the sensitivity and positive predictive value for hospital mortality. These data inform the new NHSN tiered approach of VAE (51), which is triggered by a ventilator-associated condition (VAC), defined as a sustained increase in FIO2 or PEEP after a period of stability, and can escalate to an infection-related ventilator-associated complication (IVAC) and VAP. The new focus on VAE by NHSN has important implications, because VAC and IVAC, rather than VAP, are now reportable events in the United States.


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MUSCLE DYSFUNCTION

ALI AND VENTILATOR-INDUCED LUNG INJURY

Critically ill patients are at increased risk of developing muscle weakness, and this is particularly the case for the respiratory muscles, if the patient is being mechanically ventilated. Doorduin and colleagues (53) argue that although muscle dysfunction is so important in the critically ill, diaphragmatic dysfunction is rarely monitored because of limited knowledge of this entity by clinicians, inadequate tools to monitor dysfunction, and the belief that such monitoring would not provide clinically relevant data. In their perspective they highlight the available tools, including: history, physical, measurements of pressure, flow, transdiaphragmatic pressure, diaphragmatic EMG, assessment of the degree of patient–ventilator synchrony, usefulness of phrenic nerve stimulation, imaging, and measurement of biomarkers. They argue that although there are currently few clinically applicable strategies to improve respiratory muscle function, there is an increasing understanding at the cellular and molecular levels of the mechanisms underlying muscle dysfunction as well as putative approaches that could be used in the future to treat muscle dysfunction. Picard and colleagues (54) performed one such basic study addressing the causes of ventilator-induced diaphragmatic dysfunction using human and animal models. They found that the diaphragms of brain-dead patients had markedly impaired mitochondrial function, and they posited that this may in part be due to substrate oversupply relative to demand. Their data suggested possible pharmacologic approaches, including stimulation of AMP-activated protein kinase (e.g., using metformin) or the use of sirtuin agonists (e.g., resveratrol), or antioxidant therapies targeting the mitochondria. As pointed out in an accompanying editorial, it will be interesting to ascertain whether the lipid/energy oversupply concept is linked to other mechanisms, such as autophagy, apoptosis, and enhanced protein catabolism, which have been demonstrated to be associated with ventilator-induced diaphragmatic dysfunction (55). In addition to the basic studies addressing mechanisms, there are ongoing studies examining therapies that may improve respiratory muscle function. Based on the hypothesis that the contractile proteins of diaphragmatic muscle fibers of patients with COPD have reduced sensitivity to calcium, Doorduin and colleagues (56) performed a randomized study in normal subjects examining the effect of levosimendan. They found that levosimendan was effective in restoring the loss of diaphragmatic contractility associated with loaded breathing. In addition to diaphragmatic dysfunction, patients with ARDS and other critical illnesses often develop skeletal muscle weakness, which is an independent risk factor associated with mortality and a major factor in long-term quality of life of survivors. Files and colleagues (57) developed a nonventilated, LPS-induced mouse model of ALI-associated skeletal muscle wasting. Mice given intratracheal LPS developed skeletal muscle wasting that was temporally linked to the ALI and persisted after ALI resolution, the latter mimicking the generalized muscle weakness that is present in many patients after recovery from ARDS. Their results suggested that the most likely pathways responsible for the muscle wasting are the ubiquitin-mediated proteasomal and the autophagy-lysosomal pathways. All of these studies are increasing our understanding of the pathophysiology of muscle dysfunction during critical illness. Of course, there is still a great deal of work to be done to determine if these findings have physiological relevance to our patients with muscle dysfunction and more importantly whether they can be translated into therapies that have an impact on important clinical outcomes.

To slightly paraphrase Winston Churchill: I cannot forecast to you the mechanisms of action of ARDS. It is a riddle, wrapped in a mystery, inside an enigma; but perhaps there is a key. Despite intense research over 45 years, we have not found the key, and no pharmacological approaches targeting the underlying biological mechanisms have proven to be effective. Over the past few years there have been a number of papers highlighting the potential of bone marrow–derived stromal cells (BMSCs) to protect the lung from injury. A number of mechanisms have been proposed, including direct incorporation of the cells into the lung or the impact of mediators released from these cells. Islam and colleagues (58) proposed a novel mechanism. They observed that BMSCs formed connexin 43 (Cx43)-containing gap junctional channels with the alveolar epithelia and released mitochondria-containing microvesicles that were then engulfed by epithelial cells, leading to increased alveolar ATP concentrations and mitigation of LPS-induced lung injury. This BMSC restitution of alveolar energetics via mitochondrial transfer is an exciting concept. Inflammasomes are multimolecular complexes that are involved in activating caspase-1, which then activates members of the IL-1 cytokine family, leading to propagation of the inflammatory response, and hence represent an interesting target in ARDS. To examine the role of inflammasomes in ALI, Dolinay and colleagues (59) ventilated wild-type mice or mice genetically deficient in IL-18 or caspase-1. Ventilation caused lung injury and was associated with increased IL-18 levels in lung, serum, and BAL; genetic deletion of IL-18 or of caspase-1 was associated with decreased lung injury. Plasma IL-18 from patients with ARDS was increased. As highlighted by dos Santos (60) in an accompanying editorial, this pathway may be of particular interest given the fact that caspase inhibitors have been used successfully in patients with other diseases (e.g., hepatitis). She also pointed out that ventilator-induced lung injury might be a particularly interesting target, since therapy can begin immediately after initiation, or indeed even before initiation of the insult. A number of other studies have investigated various inflammatory pathways in models of ALI and again highlighted the importance of neutrophil-mediated injury. Ichikawa and colleagues (61) found that CSCL10-CXCR3 signaling might be important in exacerbating ALI of viral and nonviral origin. Of particular interest, the increased levels of CXCL10 in the lungs of animals with pulmonary injury appeared to originate from neutrophils that infiltrated into the lung and expressed a unique CXCR3 receptor. Grommes and colleagues (62) used three models of ALI (aerosolized LPS, intratracheal HCl, or cecal ligation and puncture) and showed that the pulmonary neutrophilic infiltration and associated injury is largely mediated by platelet-derived CCL5 and CXCL4. They proposed that disruption of CCL5CXCL4 heteromers represents an interesting target in ALI that should have minimal side effects and hence is of potential clinical importance. Dhaliwal and colleagues (63) found that infiltrating peripheral blood monocytes are important in regulating ongoing neutrophil recruitment and subsequent vascular leak in LPSinduced ARDS. Because vascular leak is a hallmark of ARDS, depletion of the peripheral blood monocytes pool is an interesting target in established ARDS. However, as pointed out by the authors, the precise time point at which to intervene with such a strategy is a challenge. The accompanying editorial noted that the increase in vascular permeability was minimal, and the mechanism should be addressed in a more injurious model (64). A study by Su and colleagues (65) found that anb3 subunit

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knockout mice develop worse vascular leak and increased mortality after intratracheal LPS or cecal ligation and puncture as well as increased pulmonary vascular leak after intratracheal LPS. As pointed out by Ward (66) in an accompanying editorial, there may very well be a network of integrins that interact and hence mitigate endothelial permeability by an as-yet undefined interaction, given the large number of integrins on endothelial cells. In an elegant study, Samapati and colleagues (67) proposed a novel signaling cascade in which stimulation of acid sphingomyelinase by platelet-activating factor leads to recruitment of transient receptor potential classical 6 channels to caveolae allowing Ca21 influx. This then leads to increased endothelial permeability, which is amplified by platelet-activating factor–induced cessation of endothelial NO production. In an extensive, welldesigned translational study, Apostolou and colleagues (68) demonstrated that Activin-A, a member of the transforming growth factor-b superfamily, may be important in ARDS. This is based on the observation that overexpression of Activin-A in a murine model leads to pathology similar to human ARDS and demonstration that Activin-A BAL levels of patients with ARDS were similar to those in the animal model. Neutralization of Activin-A attenuated the pulmonary pathology after intratracheal instillation of LPS. As such, Activin-A represents a very interesting target for ARDS (69). Park and colleagues (70) demonstrated that the prone position mitigated regional injury due to an injurious ventilatory strategy and that this was regulated by a mitogen-activated protein kinase phosphatase-1 (MKP-1) and nuclear factor-kΒ2dependent pathways. This study is important, given that a recent randomized clinical trial demonstrated that ventilation in the prone position markedly decreases mortality, presumably by decreasing ventilator-induced lung injury (71). What struck us after reviewing the exciting papers that have been published over just the past year addressing the mechanisms of ALI was how complex this field is, with numerous mediators, multiple pathways, a multitude of interacting networks acting in a time-dependent fashion and modulated by host factors, and therapeutic interventions such as mechanical ventilation. Determining which one or more of these mechanisms ultimately will turn out to be the key to unlock the enigma is certainly not an easy task! Author disclosures are available with the text of this article at www.atsjournals.org.

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