The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material.

“… Dr. Blum et al. have provided important new insights into the incidence and risk factors for postoperative ARDS among low-risk surgical populations.” During the 1960s, advances in positive pressure mechanical ventilation led to recognition of a distinct form of respiratory failure precipitated by widespread acute injury to both lungs. Today, clinicians recognize this as the acute respiratory distress syndrome (ARDS), a devastating complication seen after acute illness or injury. Notably, ARDS is also a common cause of postoperative respiratory failure.1It is a devastating postoperative complication, with an associated mortality rate of up to 45%.1Beyond mortality, ARDS imparts a substantial burden on healthcare resource utilization. Furthermore, survivors frequently experience long-term physical impairments as well.2As a remarkably underappreciated complication of surgery, it is not surprising that research that is specifically focused on ARDS in the surgical setting has been sparse. Moreover, the limited work performed in this regard has primarily focused on populations undergoing high-risk cardiothoracic and vascular surgery. In this issue of Anesthesiology, Dr. Blum et al. 3aim to enhance our understanding of this critical illness syndrome by focusing on an understudied cohort, namely those patients undergoing low-risk surgery.Despite promising preclinical data for a variety of treatments for ARDS, translation to clinical benefit has been frustratingly elusive. Presently, we are mostly left with the avoidance of additional lung injury via protective ventilator settings and a conservative approach to fluid management as supportive therapies.4,5In light of this fact, interest in ARDS prevention is gaining steam. Indeed, prevention of ARDS was recently identified as a key priority for the National Heart Lung and Blood Institute. This new emphasis is manifested in recent ARDS working group publications and in a change of emphasis in the current renewal of the ARDS network. Specifically, this network will now be known as the National Heart Lung and Blood Institute Clinical Trials Network for the Prevention and Treatment of Acute Lung Injury (PETAL Network - NHLBI-HR-14-03).6Importantly, however, prevention strategies for ARDS are similarly limited at present. With the exception of restrictive transfusion practices and the avoidance of injurious ventilator settings,7no effective ARDS prevention agents currently exist. Indeed, the first major ARDS prevention trial, evaluating the efficacy of aspirin, has just recently been initiated.8Historically, a critical barrier to progress in prevention of ARDS has been the lack of effective prediction models that can reliably identify populations with high risk for this serious complication. Without early and effective risk stratification, any potentially beneficial prevention strategies will be delivered either too late or to the wrong population. Furthermore, with an estimated incidence of 3% in high-risk surgical populations, testing prevention strategies in unselected surgical populations is inefficient, expensive, and potentially unsafe.1To this end, identification of important risk factors for ARDS is the necessary first step in making progress toward effective prevention. Although recent efforts have begun to address this important knowledge gap, to date, work has primarily focused on medical patients or on those undergoing surgical procedures that are already understood to place the patient at risk.9,10Examples include those undergoing cardiac, noncardiac thoracic, and vascular surgery. In contrast, the incidence, risk factors, and outcomes of patients with ARDS have been largely ignored in lower-risk surgical populations. The work of Dr. Blum et al. 3aims to address this important knowledge gap. Specifically, the objectives of this investigation included determination of: (1) the incidence and preoperative risk factors for ARDS in patients undergoing low-risk surgery and (2) the intraoperative variables associated with increased risk of this life-threatening respiratory complication.To identify the desired low-risk surgical population, the investigators evaluated all anesthetics administered at a single major academic medical center and cross-referenced this list with a second prospectively collected database containing all adult critical care patients receiving mechanical ventilation, who were screened for entry into ARDS-related studies. Patients undergoing high-risk procedures such as cardiac, thoracic, transplant, trauma, and vascular surgery were specifically excluded. Using this large database-driven retrospective cohort, the investigators were able to determine the incidence of ARDS in this population. From within this large cohort, a nested case-control study was then used to facilitate the targeted identification of intraoperative risk factors that may contribute to the development of postoperative ARDS. Confounding effects from baseline demographic and clinical predictors of ARDS were largely mitigated by matching each ARDS case to four control subjects, based upon their preoperative likelihood of developing ARDS (American Society of Anesthesiologists physical status 3 or higher, emergent procedure, asthma, renal failure, chronic obstructive pulmonary disease, male sex, and the number of anesthetics administered during the admission).A number of important findings from this investigation deserve mention. First and foremost is the remarkably low incidence rate for ARDS. Indeed, the incidence of 0.2% noted by Blum et al .10contrasts starkly with previously reported incidence rates ranging as high as 23% for specific high-risk vascular surgery populations. However, previous studies have repeatedly reinforced a key role of the specific surgical procedure in determining risk for postoperative ARDS. Indeed, multiple previous investigations have also identified widely disparate rates of ARDS, with the variability largely depending on the nature of the surgical procedure.1,9,10Therefore, it is not entirely surprising that such a low rate was encountered in this study, given the low-risk nature of the surgical population evaluated. In contrast, the impact of ARDS on patient-important outcomes remained substantial despite the low-risk nature of the surgical procedures included. As the investigators correctly point out, an ARDS-associated mortality rate of 27% is quite consistent with the available literature and is entirely unacceptable in a low-risk surgical population. Indeed, it seems the ARDS-related risk of death is largely independent of the population’s baseline surgery-related risk.Additional key findings of Dr. Blum’s work include the identified risk factors for postoperative ARDS. The associations between American Society of Anesthesiologists physical status, emergent surgery, chronic obstructive lung disease, increased intraoperative airway pressures, high fraction of inspired oxygen, and aggressive fluid and transfusion therapies with postoperative ARDS seem robust as they are consistent with multiple previous reports in high-risk surgical populations. Although the association between the number of anesthetics administered during an admission and rate of ARDS is less well described, there would seem to be biologic plausibility. Indeed, the need for multiple anesthetic encounters during the same admission would seem to suggest either the staging of a complex surgical procedure/patient or the presence of complications arising from the index surgical procedure. As multiple reports suggest that the occurrence of a postoperative complication begets additional complications, we might expect this to hold true for ARDS as well. In contrast, the causal links associating male sex and renal failure with postoperative ARDS are less well described and without further validation should be interpreted with caution.Of perhaps greatest interest to the readers of this journal are the potentially modifiable risk factors that have been identified from within the operating room environment. Indeed, the temporal proximity of these variables with the great preponderance of ARDS cases (consistent with prior reports, the majority of cases in the current investigation occurred within the first 24–48 h of the surgical procedure) suggests that intraoperative exposures and patient responses may indeed play key roles in ARDS pathogenesis. However, although the potential for mitigating risk for ARDS by altering anesthetic management is enticing, we must proceed with caution as important questions remain. In particular, this observational study (indeed all observational studies) cannot reliably differentiate cause–effect relationships from simple associations. For example, it is not clear whether the high ventilator driving pressures encountered during the operative course truly lead to increased risk for ARDS. These may simply indicate the presence of prevalent lung/chest-wall disease in these patients. The lack of an association between tidal volume and development of ARDS may suggest the latter. This dissonance suggests that lowering tidal volume, although important, is not always enough and that additional measures to reduce the ventilator driving pressure may be necessary in certain patients. Such measures could include raising the level of positive end-expiratory pressure to improve lung recruitment or ensuring adequate muscle relaxation.11,12Similarly, though prolonged exposure to high levels of oxygen may clearly result in lung injury, it is less certain whether relatively brief exposure to high FiO2s (as would be expected in this low-risk surgical cohort) might have a similar effect. Perhaps more likely, the presence of a high FiO2may again simply identify those with prevalent lung disease, or alternatively, the early development of lung injury. Regardless, in light of the well-documented potential for cause–effect relationships, particularly for transfusion therapies and injurious ventilator settings, it would clearly seem prudent to limit tidal volume/peak airway pressures and to avoid overly aggressive transfusion strategies whenever possible.Overall, the findings of this study are both novel and significant. However, though the clearly defined hypotheses, large sample size (more than 50,000 patients), and detailed statistical plan are clear strengths of the current investigation, several limitations should be noted. In addition to the inability to determine cause–effect relationships, it must be recognized that the study population arose from a single academic medical center. As a result, the external validity and generalizability of the findings remain unclear. In addition, as with any large database study, data integrity and validity were largely untested. Therefore, concerns relating to both false-positive (type I error) and false negative (type II error) associations remain. Perhaps the lack of an association between alcohol abuse (and perhaps smoking) with risk for ARDS, which has been described in multiple prior studies, is partially explained by this concern.10In addition, a database-driven design precludes an evaluation of potentially important variables that are simply not in the database. In the current case, missing variables that have previously been associated with postoperative ARDS included elements from both the preoperative domain (e.g. , gastroesophageal reflux disease, sepsis, aspiration, pancreatitis, immunosuppression) and the intraoperative course (e.g ., duration of the surgical procedure and hemodynamic status). The lack of such variables results in a less robust understanding of who is at risk for postoperative ARDS. In addition, these missing data also lead to potentially important unmeasured confounding. Finally, the definition for ARDS in this investigation required endotracheal intubation. Although consistent with the definition of ARDS used in multiple other investigations, less-severe cases could well have been missed. As a result, the true incidence of ARDS in patients undergoing low-risk surgery may be somewhat greater than reported in this investigation.Despite the abovementioned limitations, Dr. Blum et al. 3have provided important new insights into the incidence and risk factors for postoperative ARDS among low-risk surgical populations. Although the incidence seems low, the impact of ARDS on patient-important outcomes remains substantial. As we work to make progress on the prevention of postoperative ARDS, our ability to identify surgical populations who are at high risk is an essential first step. To this end, the current investigation has clearly advanced our knowledge. In addition to validating the associations identified in the current investigation, future studies must work to enhance our understanding of true nature of these associations. If causal relationships are confirmed, the potential for mitigating the onset and severity of postoperative ARDS by the way we deliver care in the operating room may well exist. If true, how important this would be. After all, an ounce of prevention is worth a pound of cure

1 in 10 were helped (life saved at 28 days from hospitalization) 1 in 12 were helped (life saved at time of hospital discharge) 10% absolute risk reduction in 28-day mortality with lung-protective ventilation 8% absolute risk reduction in 28-day mortality Acute respiratory distress syndrome (ARDS) is a type of acute, diffuse, and inflammatory lung injury. The Berlin definition (2012)1 includes the following ARDS criteria: 1) onset within 1 week of a known clinical insult, 2) bilateral opacities consistent with pulmonary edema, 3) respiratory failure not fully explained by cardiac failure or fluid overload, and 4) ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) of less than 300 mm Hg at a positive end expiratory pressure (PEEP) of 5 cm H2O. The new definition also categorizes ARDS as being mild for PaO2/FiO2 ratio of 200 to 300, moderate for PaO2/FiO2 ratio of 100 to 200, or severe for PaO2/FiO2 ratio of less than 100 on PEEP of 5 cm H2O. Sepsis is the most common etiology for ARDS.2 Studies done before the introduction of Sepsis-3 in 2016 (which made the use of the term severe sepsis obsolete) showed that two of three cases with severe sepsis enter the health care system through the emergency department (ED). Prevalence of ARDS among medical patients in the ED has been estimated to be about 9%.2, 3 ED-based studies suggest an ARDS progression rate after admission of 27.5% in patients with severe sepsis and septic shock.4 The early onset and rapid progression of ARDS after ED admission which results in worsened outcomes suggest that time spent and treatments provided in the ED could alter the course of ARDS. According to a prospective multicenter cohort study (LUNG SAFE trial 2016),5 which was conducted with the aim of assessing the burden of acute hypoxemic respiratory failure requiring ventilatory support with a specific focus on ARDS, reported a prevalence of 10.4% for ARDS among intensive care admissions and 23.4% among ventilated patients. In this trial, the rates of hospital mortality were 35, 40, and 46% for patients with mild, moderate, and severe ARDS, respectively. There is considerable evidence that progressive lung parenchymal injury is induced by excessive alveolar distension by large tidal volumes.5 Lung-protective strategy has been developed to reduce further damage to already injured lungs. Lung-protective strategy is often divided into three strategies that include: 1) low tidal volume (6 mL/kg), 2) plateau pressure (Pplat) < 31 cmH2O, and 3) appropriate PEEP. A Cochrane systematic review published in 2013 by Petrucci and De Feo6 examined lung-protective strategies of mechanical ventilation for ARDS. This systematic review included six randomized controlled trials comprising 1,297 patients and compared mechanical ventilation with a lower tidal volume (VT) of ≤7 mL/kg (lung-protective ventilation) versus VT of 10 to 15 mL/kg (conventional ventilation). Lung-protective ventilation was associated with a significantly decreased 28-day mortality (relative risk [RR] = 0.74, 95% confidence interval [CI] = 0.61 to 0.88, absolute risk reduction [ARR] = 10%, number needed to treat [NNT] = 10). Hospital mortality was similarly reduced (RR = 0.80, 95% CI = 0.69 to 0.92, ARR = 8%, NNT = 12). Overall mortality at the end of the follow-up period for each trial did not reach statistical significance (RR = 0.86, 95% CI = 0.69 to 1.06). The follow-up period varied from hospital discharge to 180 days in the largest trial included in the study.6 Plateau pressure is defined as airway pressure during the end expiratory pause and roughly reflects the level of alveolar overdistension. The mortality benefit for lung-protective strategy was evident only when the control group received "higher" (>31 cm H2O) Pplat (RR = 0.74, 95% CI = 0.63 to 0.87). The mortality rate between the groups was not statistically different when control groups received a "lower" Pplat (31 cm H2O or less).6 The Cochrane analysis reported insufficient data to analyze secondary outcomes such as development of multiorgan failure, duration of mechanical ventilation and total duration of mechanical support, total duration of stay in intensive care unit and hospital, long-term mortality, long-term health-related quality of life, and long-term cognitive outcome. The only secondary outcome with sufficient data for analysis was duration of mechanical ventilation (three trials, 288 patients) which was not statistically different between the groups. A subsequent 2013 Cochrane review7 assessed the benefits and harms of high versus low PEEP in patients with ARDS. The use of higher levels of PEEP is part of the lung-protective strategy aimed at reducing ventilator-induced lung injury. PEEP is a mechanical maneuver that exerts a positive pressure in the lung and is used primarily to correct the hypoxemia caused by alveolar hypoventilation. The optimal level of PEEP in patients with ARDS is still controversial. The Cochrane review7 analyzed seven randomized controlled trials, and the authors found no difference in in-hospital mortality for those who received mechanical ventilation with high versus low PEEP, although there was a trend toward decreased mortality. There was no significant difference between the two groups for the number of ventilator-free days, with the latter referring to the number of days between successful weaning from mechanical ventilation and day 28 after study enrollment. Higher PEEP was associated with improved oxygenation on Days 1, 3, and 7, without an increase in barotrauma risk, defined as the presence of pneumothorax on chest radiograph or chest tube insertions for known or suspected spontaneous pneumothorax. A multilevel mediation analysis that analyzed individual data from 3,562 patients with ARDS enrolled in nine previously reported randomized trials of nine randomized controlled trials suggested that it is the driving pressure (ΔP = VT/CRS) that is most strongly associated with survival.8 Driving pressure looks at the change in pressure across the alveoli, focusing on the ratio of the patient's target tidal volume and the lung compliance, and targets functional lung rather than predicted lung size. Patient survival was linked to a lower driving pressure, with VT and PEEP being linked to survival only if they led to reductions in driving pressure.8 Despite the fact that lung-protective strategy is widely accepted as the only intervention that improves mortality in ARDS, its use in the ED has been found to be uncommon, and hence prolonged ED length of stay can result in iatrogenic lung injury from excessively high tidal volumes.2 Evidence demonstrates that potentially injurious ventilator practices are common in the ED,9-13 especially because ventilator-associated lung injury can occur shortly after the initiation of mechanical ventilation.9, 14, 15 Early lung-protective ventilation during vulnerable periods results in subsequent benefit even when delivered for short periods of time.9, 16, 17 A before–after study of mechanically ventilated patients in the ED conducted by Fuller et al.17 in 2017 showed that 1) lung-protective strategies can be effectively implemented in the ED; 2) the implementation of an ED-based lung-protective ventilator protocol resulted in early utilization of lung-protective strategies in the intensive care unit, which increased subsequent adherence to lung-protective ventilation in ARDS patients; and 3) the intervention was associated with a significant reduction in pulmonary complications, hospital mortality, and health care resource use.17 The 2013 Cochrane review6 of lung-protective strategies with low tidal volumes was heavily influenced by two studies, the ARDS Network 200018 and the study by Villar et al.,19 which are the only trials that showed a mortality benefit.6 Additionally, different lengths of follow-up and higher plateau pressure in control arms in two of the trials makes the interpretation of the combined results and long-term mortality difficult. Except for the one trial that reached the target sample size, all other five trials were terminated early. None of the trials reported a long-term outcome follow-up. Lowering the tidal volume might not be without harm. Low tidal volumes can result in severe hypercapnia and acidosis which can in turn lead to increased intracranial pressure, depressed myocardial contractility, pulmonary hypertension, and depressed renal blood flow.20 The issue of adverse effects of a lower tidal volume was not addressed in the trials included in the Cochrane review. Specifically, the impact of acidosis and hypercapnia on the development of organ failure was not clear.6 Although the test of heterogeneity in the Cochrane meta-analysis6 was not statistically significant, the authors of Cochrane report that certain "hidden" heterogeneity due to clinical differences between the trials should be factored in. They also warn the readers about the fact that most of the trials did not report protocols of concomitant treatments and associated diseases (that is ventilator-associated pneumonia).6 In conclusion, the existing evidence supports the use of lung-protective strategy with low tidal volumes (6 mL/kg) and low plateau pressure (<30 mm Hg) in patients with ARDS due to mortality benefits. Despite the possibility of underreported harms, the benefits are prominent enough to justify assigning a color recommendation of green (benefit > harm) to this strategy. Editor's Note: Brass Tacks are concise reviews of published evidence. This series is a result of collaboration between Academic Emergency Medicine and the evidence-based medicine website, www.TheNNT.com. For inquiries please contact the section editor, Shahriar Zehtabchi, MD ([email protected]).

The Kigali modification of the berlin definition: a new epidemiological tool for ARDS?

The fibroproliferative reaction to acute lung injury may limit restoration of normal lung function and increase mortality in patients with acute lung injury. A biologic marker of collagen synthesis in the lung may be useful for studying the pathogenesis of acute lung injury and for identifying patients with acute lung injury who are at high risk for death and might benefit from new therapeutic modalities. Using an immunoassay, type III procollagen NH2 terminal peptide was measured in the pulmonary edema fluid of 44 patients with either acute lung injury or hydrostatic pulmonary edema (control group) within the first 24 h after endotracheal intubation for acute respiratory failure. Patients with acute lung injury (n = 33) or hydrostatic edema (n = 11) had the same degree of lung dysfunction as measured by the severity of oxygenation defect, the level of positive end-expiratory pressure, the decrease in static lung compliance, and the extent of infiltrates on the chest radiograph. However, the median procollagen III level was 5-fold higher in the pulmonary edema fluid of patients with acute lung injury than in the patients with hydrostatic pulmonary edema (p = 0.0001). Of the 33 patients with acute lung injury, 21 patients died and 12 lived. Nonsurvivors had significantly higher procollagen III levels than did survivors (p = 0.05). The positive and negative predictive values for nonsurvival for a procollagen III level > or = 1.75 U/ml were 74 and 83%, respectively. The relative risk of dying in the presence of a procollagen III value > or = 1.75 U/ml was 4.5 (95% CI, 0.7 to 27). Collagen synthesis in the lung, as reflected by elevated levels of procollagen III in pulmonary edema fluid, begins within the first 24 h of acute lung injury concurrent with the acute phase of increased endothelial and epithelial permeability to protein. This evidence suggests that fibrosing alveolitis begins much earlier in the course of clinical acute lung injury than has previously been appreciated. In addition, the presence of an elevated level of procollagen III is an early predictor of poor outcome. Thus, elevation of procollagen III in pulmonary edema fluid may have both pathogenetic and prognostic significance in patients with acute lung injury.

ARDS: progress unlikely with non-biological definition

To investigate the incidence, outcomes, and risk factors of postoperative acute respiratory distress syndrome (ARDS) in patients undergoing surgical repair for acute type A aortic dissection.This retrospective study involved 270 patients who underwent surgical repair for acute type A aortic dissection between January 2009 and December 2015. Data on clinical characteristics and outcomes were collected. Patients who immediately died after surgery and with preoperative myocardial dysfunction were excluded. The included patients were divided into the ARDS (ARDS patients who met the Berlin definition) and non-ARDS groups. Primary outcome was postoperative ARDS, according to the 2012 Berlin definition for ARDS and was reviewed by 2 qualified physicians with expertise in critical care and cardiac surgery. Outcomes of interest were the incidence and severity of risk factors for ARDS in this population, and perioperative outcomes and survival rates were compared with patients with or without ARDS.A total of 233 adult patients were enrolled into this study; of these, 37 patients (15.9%) had ARDS. Three, 20, and 14 patients had mild, moderate, and severe ARDS, respectively, according to the Berlin definition, with no significant difference in age, sex, and underlying disease. The ARDS group had lower mean oxygenation index (OI) than the non-ARDS group in the first 3 days post-surgery and demonstrated an improvement in lung function after the fourth day. Postoperative complication risks were higher in the ARDS group than in the non-ARDS group. However, no significant difference was observed in in-hospital mortality between the 2 groups (10.8% vs 5.6%, P = .268). Additionally, there was also no significant difference in the 3-year mortality rate between the 2 groups (P of log-rank test = .274). Postoperative hemoglobin level (odds ratio [OR]: 0.78; 95% confidence interval [CI]: 0.62–0.99) and perioperative blood transfusion volume (OR: 1.07; 95% CI: 1.03–1.12) were associated with ARDS risk.Postoperative ARDS after type A aortic dissection repair surgery was associated with risks of postoperative complications but not with risk of in-hospital mortality or 3-year mortality. A higher perioperative blood transfusion volume and a lower postoperative hemoglobin level may be risk factors for ARDS.

To investigate the predictive value of the acute physiology and chronic health evaluation 2 (APACHE2) score and lung injury prediction score (LIPS) for acute respiratory distress syndrome (ARDS) when combined with biomarkers for this condition in patients with ARDS risk factors. In total, 158 Han Chinese patients with ARDS risk factors were recruited from the Respiratory and Emergency Intensive Care Units. The LIPS, APACHE2 score, primary diagnosis at admission, and ARDS risk factors were determined within 6 h of admission, and PaO2/FiO2 was determined on the day of admission. Blood was collected within 24 h of admission for the measurement of angiopoietin-2 (ANG-2), sE-selectin, interleukin-6 (IL-6), and interleukin-8 (IL-8) levels. ARDS was monitored for the next 7 days. Univariate and multivariate analyses and receiver operating characteristic (ROC) analyses were employed to construct a model for ARDS prediction. Forty-eight patients developed ARDS within 7 days of admission. Plasma ANG-2 level, sE-selectin level, LIPS, and APACHE2 score in ARDS patients were significantly higher than those in non-ARDS patients. ANG-2 level, LIPS, and APACHE2 score were correlated with ARDS (P < 0.001, P < 0.006, and P < 0.042, resp.). When the APACHE2 score was used in combination with the LIPS and ANG-2 level to predict ARDS, the area under the ROC curve (AUC) was not significantly increased. Compared to LIPS or ANG-2 alone, LIPS in combination with ANG-2 had significantly increased positive predictive value (PPV) and AUC for the prediction of ARDS. In conclusion, plasma ANG-2 level, LIPS, and APACHE2 score are correlated with ARDS. Combined LIPS and ANG-2 level displays favorable sensitivity, specificity, and AUC for the prediction of ARDS.

Estimates of the incidence of the acute respiratory distress syndrome (ARDS) in high- and middle-income countries vary from 10.1 to 86.2 per 100,000 person-years in the general population. The epidemiology of ARDS has not been reported for a low-income country at the level of the population, hospital, or intensive care unit (ICU). The Berlin definition may not allow identification of ARDS in resource-constrained settings. To estimate the incidence and outcomes of ARDS at a Rwandan referral hospital using the Kigali modification of the Berlin definition: without requirement for positive end-expiratory pressure, hypoxia cutoff of SpO2/FiO2 less than or equal to 315, and bilateral opacities on lung ultrasound or chest radiograph. We screened every adult patient for hypoxia at a public referral hospital in Rwanda for 6 weeks. For every patient with hypoxia, we collected data on demographics and ARDS risk factors, performed lung ultrasonography, and evaluated chest radiography when available. Forty-two (4.0%) of 1,046 hospital admissions met criteria for ARDS. Using various prespecified cutoffs for the SpO2/FiO2 ratio resulted in almost identical hospital incidence values. Median age for patients with ARDS was 37 years, and infection was the most common risk factor (44.1%). Only 30.9% of patients with ARDS were admitted to an ICU, and hospital mortality was 50.0%. Using traditional Berlin criteria, no patients would have met criteria for ARDS. ARDS seems to be a common and fatal syndrome in a hospital in Rwanda, with few patients admitted to an ICU. The Berlin definition is likely to underestimate the impact of ARDS in low-income countries, where resources to meet the definition requirements are lacking. Although the Kigali modification requires validation before widespread use, we hope this study stimulates further work in refining an ARDS definition that can be consistently used in all settings.

Acute respiratory distress syndrome (ARDS) is a common disorder associated with significant mortality and morbidity. The American-European Consensus Conference (AECC) definition of ARDS, established in 1994, has advanced the knowledge of ARDS by allowing the acquisition of clinical and epidemiological data, which in turn have led to improvements in care for patients with ARDS. However, after 18 years of applied research, a number of issues regarding various criteria of AECC definition have emerged. For these reason, and because all disease definitions should be reviewed periodically, the European Society of Intensive Care Medicine convened an international expert panel to revise the ARDS definition from September 30 to October 2, 2011, Berlin, Germany, with endorsement from American Thoracic Society and the Society of Critical Care Medicine. This consensus discussion, following empirical evaluation and consensus revision, addressed some of the limitations of the AECC definition by incorporating current data, physiologic concepts, and clinical trials to develop a new definition of ARDS (Berlin definition). The Berlin definition should facilitate case recognition and better match treatment options to severity in both the research trials and clinical practice.

Positive End-Expiratory Pressure Levels in Adult Patients With Acute Lung Injury and Acute Respiratory Distress Syndrome

Driving pressure has been proposed as a major determinant of outcome in patients with acute respiratory distress syndrome (ARDS), but there is little data examining the association between pulmonary mechanics, including driving pressure, and outcomes in mechanically ventilated patients without ARDS. Secondary analysis from 1,705 mechanically ventilated patients enrolled in a clinical study that examined outcomes associated with the use of early lung-protective mechanical ventilation. The primary outcome was mortality and the secondary outcome was the incidence of ARDS. Multivariable models were constructed to: define the association between pulmonary mechanics (driving pressure, plateau pressure, and compliance) and mortality; and evaluate if driving pressure contributed information beyond that provided by other pulmonary mechanics. The mortality rate for the entire cohort was 26.0%. Compared with survivors, non-survivors had significantly higher driving pressure [15.9 (5.4) vs. 14.9 (4.4), P = 0.005] and plateau pressure [21.4 (5.7) vs. 20.4 (4.6), P = 0.001]. Driving pressure was independently associated with mortality [adjusted OR, 1.04 (1.01-1.07)]. Models related to plateau pressure also revealed an independent association with mortality, with similar effect size and interval estimates as driving pressure. There were 152 patients who progressed to ARDS (8.9%). Along with driving pressure and plateau pressure, mechanical power [adjusted OR, 1.03 (1.00-1.06)] was also independently associated with ARDS development. In mechanically ventilated patients, driving pressure and plateau pressure are risk factors for mortality and ARDS, and provide similar information. Mechanical power is also a risk factor for ARDS.

Because the Berlin definition of acute respiratory distress syndrome (ARDS) has only moderate reliability, physicians disagree about the diagnosis of ARDS in some patients. Understanding the clinical differences between patients with agreement and disagreement about the diagnosis of ARDS may provide insight into the epidemiology and pathophysiology of this syndrome, and inform strategies to improve the reliability of ARDS diagnosis. To characterize patients with diagnostic disagreement about ARDS among critical-care-trained physicians and compare them with patients with a consensus that ARDS developed. Patients with acute hypoxemic respiratory failure (arterial oxygen tension/pressure [PaO2]/fraction of inspired oxygen [FiO2] < 300 during invasive mechanical ventilation) were independently reviewed for ARDS by multiple critical-care physicians and categorized as consensus-ARDS, disagreement about the diagnosis, or no ARDS. Among 738 patients reviewed, 110 (15%) had consensus-ARDS, 100 (14%) had disagreement, and 528 (72%) did not have ARDS. ARDS diagnosis rates ranged from 9% to 47% across clinicians. Patients with disagreement had baseline comorbidity rates similar to those of patients with consensus-ARDS, but lower rates of ARDS risk factors and less severe measures of lung injury. Mean days of severe hypoxemia (PaO2/FiO2 < 100) were 3.2 (95% confidence interval [CI], 2.6-3.9), 2.0 (95% CI, 1.5-2.4), and 0.8 (95% CI, 0.7-0.9) among patients with consensus-ARDS, disagreement, and no ARDS, respectively. Hospital mortality was 37% (95% CI, 28-46%), 35% (95% CI, 26-44%), and 19% (95% CI, 15-22%) across groups. Simple combinations of specific ARDS risk factors and lowest PaO2/FiO2 value could effectively discriminate patients (area under the receiver operating characteristic curve = 0.90; 95% CI, 0.88-0.92). For example, 63% of patients with pneumonia, shock, and PaO2/FiO2 < 110 had consensus-ARDS, whereas 100% of patients without pneumonia or shock and PaO2/FiO2 > 180 did not have ARDS. Disagreement about the diagnosis of ARDS is common and can be partly explained by the difficulty of dichotomizing patients along a continuous spectrum of ARDS manifestations. Considering both the presence of key ARDS risk factors and hypoxemia severity can help guide clinicians in identifying patients with diagnosis of ARDS agreed upon by a consensus of physicians.

In late 2019, a novel coronavirus later named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as a cause of pneumonia in Wuhan, China. The World Health Organization named the disease coronavirus disease 2019 (COVID-19) and, on 11 March 2020, characterized COVID-19 as a pandemic. As of late July 2020, over 15 million confirmed cases have been reported globally with a case fatality rate of 4%. In the United States, as of July 23, there are nearly 4 million confirmed cases with over 140 000 deaths.1 This commentary focuses on the respiratory management of adults with COVID-19-associated hypoxaemic respiratory failure and acute respiratory distress syndrome (ARDS). The pathophysiological mechanisms in COVID-19 include airflow obstruction, ARDS and 'cytokine storm'. Gattinoni et al. described two phenotypes of ARDS: type L (low elastance, high compliance and patchy ground-glass opacities on chest imaging) and type H (high elastance, low compliance, diffuse and bilateral infiltrates on chest imaging).2 Histological examination shows diffuse alveolar damage, hyaline membrane formation, type 2 pneumocyte hyperplasia, multinucleated giant cells and platelet-fibrin thrombi in small vessels and capillaries of the lung. The most common symptoms are fever, cough and shortness of breath. The disease course is variable with an incubation period of up to 14 days (median: 5 days).3 Diagnosis of COVID-19 is made by the detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing of a nasal or nasopharyngeal swab. Laboratory findings in the acute phase include lymphopenia, elevated C-reactive protein, ferritin, d-dimer, fibrinogen and lactate dehydrogenase, and normal or low procalcitonin. The hypoxaemic respiratory failure and ARDS observed in COVID-19 range from mild to severe. Basic management principles may be applied based on the type L or H phenotype. Type L patients respond to an increase in fraction of inspired oxygen (FiO2) with nasal cannula, high-flow nasal oxygen (HFNO) or non-invasive ventilation (NIV). Type H patients who require mechanical ventilation should be managed following the traditional ARDSnet ventilator protocol.4 Hospitalized patients with mild symptomatic respiratory insufficiency require supplemental oxygen via nasal canula (up to 6 L) to maintain arterial O2 saturation greater than 90%. Bronchodilators, if needed, should be administered via metred dose inhalers instead of nebulizers to prevent aerosolization of the virus. Patients with moderate hypoxaemic respiratory failure are those requiring HFNO, non-rebreather masks or NIV. Controversy exists regarding the safety of bilevel positive pressure ventilation (BiPAP), continuous positive airway pressure ventilation (CPAP) and HFNO, given the risk of aerosolization with these devices to healthcare providers. Professional societies recommend their use with airborne precautions and appropriate personal protective equipment (PPE), preferably in a negative pressure room.5 CPAP has a theoretical benefit of being able to provide the highest mean airway pressures, thus helping with alveolar recruitment. The National Health Service (United Kingdom) recommends the use of NIV with a non-vented mask, an exhalation port and a bacterial/viral filter between the mask and oxygen, over HFNO given the lower risk of aerosolization.6 Another strategy in patients with mild to moderate respiratory failure is awake proning. Proning facilitates oxygenation by improving ventilation/perfusion mismatch with increased perfusion to the healthier alveoli in the anterior lung, improved secretion management and alveolar recruitment in the posterior lung. Larger epidemiological studies have reported rates of invasive mechanical ventilation ranging from 2.3% to 33.1% of hospitalized COVID-19 patients and 29.1% to 89.9% among patients admitted to the intensive care unit (ICU).7 Risk factors of ARDS and need for ICU admission include age >60 years, male gender and comorbidities such as heart disease, diabetes mellitus, chronic lung disease, immunocompromised state and malignancy.3 Given that COVID-19 may cause hypoxia with minimal respiratory distress ('silent hypoxia'), the threshold for intubation should be lower particularly for those patients with persistent hypoxia despite escalation to HFNO and exhibiting shortness of breath. When needed, rapid sequence intubation technique without bagging should be used. Intubation should be performed by the most experienced clinician under strict airborne precautions. Other considerations include use of dry ventilator circuits, heat moisture exchangers and bacterial/viral filters at exhalation ports. The approach to mechanical ventilation in COVID-19 patients should adhere to evidence-based practices utilized in the general population with ARDS.2, 3, 8 Ventilatory strategies to implement are low tidal volume ventilation (tidal volume 6 mL/kg of predicted body weight) and targeting plateau pressures of <30 cm H2O. There are no studies of high versus low positive end-expiratory pressure (PEEP) in patients with COVID-19 ARDS; however, previous studies on non-COVID ARDS patients showed that high PEEP strategies reduced ICU and in-hospital mortality and need for rescue measures. Prone ventilation should be considered in mechanically ventilated patients with moderate to severe ARDS. Neuromuscular blocking agents may be necessary in proned patients along with deep sedation and in patients with severe ventilator dyssynchrony, severe hypoxaemia and persistently high plateau pressures. Extracorporeal membrane oxygenation (ECMO) may serve as life-saving rescue therapy for refractory ARDS. However, it is resource intensive and not widely available. To summarize, the timing of intubation, use of high versus low PEEP, high versus low tidal volume ventilation, prone positioning and ECMO are the most important factors to consider while keeping the patient's preferences at the forefront. Table 1 provides a summary of the oxygen therapies and ventilator strategies employed by ICU globally to treat patients with COVID-19 respiratory failure.7 Most recently, based on the results of the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, corticosteroids (i.e. dexamethasone 6 mg per day for up to 10 days) are recommended for patients who are mechanically ventilated, and in patients who require supplemental oxygen but who are not mechanically ventilated.17 The pandemic has posed unprecedented challenges to the healthcare system, given the number of patients, illness severity and limited number of ventilators. Disaster ventilator strategies such as use of one ventilator for multiple people (splitting ventilators), home BiPAP and anaesthesia ventilators have been proposed. The challenges of splitting ventilators include the patient's interaction with the ventilator and simultaneously affecting other patients connected to the ventilator, suboptimal ventilation given increase in the dead space, increased need for deep sedation and paralysis, and cross contamination. Professional societies recently issued a joint statement advising against the use of split ventilator strategy.18 Finally, patients and front-line clinicians should be optimally prepared for extubation in an airborne isolation room and with appropriate PPE as it is usually associated with coughing and could cause aerosolization of the virus. This manuscript was supported, in part, by the Core Grant (P30 CA008748) and the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Fluid Balance: Another Variable to Consider with Diaphragm Dysfunction?

The Berlin definition of acute respiratory distress syndrome has introduced three classes of severity according to PaO2/FIO2 thresholds. The level of positive end-expiratory pressure applied may greatly affect PaO2/FIO2, thereby masking acute respiratory distress syndrome severity, which should reflect the underlying lung injury (lung edema and recruitability). We hypothesized that the assessment of acute respiratory distress syndrome severity at standardized low positive end-expiratory pressure may improve the association between the underlying lung injury, as detected by CT, and PaO2/FIO2-derived severity. Retrospective analysis. Four university hospitals (Italy, Germany, and Chile). One hundred forty-eight patients with acute lung injury or acute respiratory distress syndrome according to the American-European Consensus Conference criteria. Patients underwent a three-step ventilator protocol (at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure). Whole-lung CT scans were obtained at 5 and 45 cm H2O airway pressure. Nine patients did not fulfill acute respiratory distress syndrome criteria of the novel Berlin definition. Patients were then classified according to PaO2/FIO2 assessed at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure. At clinical positive end-expiratory pressure (11±3 cm H2O), patients with severe acute respiratory distress syndrome had a greater lung tissue weight and recruitability than patients with mild or moderate acute respiratory distress syndrome (p<0.001). At 5 cm H2O, 54% of patients with mild acute respiratory distress syndrome at clinical positive end-expiratory pressure were reclassified to either moderate or severe acute respiratory distress syndrome. In these patients, lung recruitability and clinical positive end-expiratory pressure were higher than in patients who remained in the mild subgroup (p<0.05). When patients were classified at 5 cm H2O, but not at clinical or 15 cm H2O, lung recruitability linearly increases with acute respiratory distress syndrome severity (5% [2-12%] vs 12% [7-18%] vs 23% [12-30%], respectively, p<0.001). The potentially recruitable lung was the only CT-derived variable independently associated with ICU mortality (p=0.007). The Berlin definition of acute respiratory distress syndrome assessed at 5 cm H2O allows a better evaluation of lung recruitability and edema than at higher positive end-expiratory pressure clinically set.