Acute respiratory distress from left diaphragmatic dysfunction

COUNTERPOINT: Should Corticosteroids Be Routine Treatment in Early ARDS? No

Defining Right Ventricular Dysfunction in Acute Respiratory Distress Syndrome

ARDS: progress unlikely with non-biological definition

“… 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

Nitric oxide as mediator, marker and modulator of microvascular damage in ARDS.

Acute lung injury (ALI) affects an estimated 190,000 persons per year in U.S. intensive care units (ICUs), but little is known about its prevalence in the emergency department (ED). The objective was to describe the prevalence of ALI among mechanically ventilated adult nontrauma patients in the ED. The hypothesis was that the prevalence of ALI in adult ED patients would be low. This was a retrospective cohort study of admitted nontrauma patients presenting to an academic ED. Two trained investigators abstracted data from patient records using a standardized form. The use of mechanical ventilation in the ED was identified in two phases. First, all ED patients were screened for the current procedural terminology (CPT) code for endotracheal intubation (CPT 31500) from January 1, 2003, to December 31, 2006. Second, each patient record was reviewed to verify the use of mechanical ventilation. ALI was defined in accordance with a modified version of the American-European Consensus Conference criteria as: 1) hypoxemia defined as PaO(2) /FiO(2) ratio ≤300 mm Hg on all arterial blood gases (ABGs) in the ED and the first 24 hours of admission, 2) the presence of bilateral infiltrates on chest radiograph, and 3) the absence of left atrial hypertension. Data are presented in absolute numbers and percentages. Interobserver agreement was evaluated using the kappa statistic. Of the 552 patients who received mechanical ventilation in the ED and were subsequently admitted, a total of 134 (24.3%, 95% confidence interval [CI] = 20.8% to 28.0%) met hypoxemia criteria. Of these, 34 had evidence of left atrial hypertension, 52 did not have chest radiograph findings consistent with ALI, and two did not have a chest radiograph performed; the remaining 46 met ALI criteria. An additional two patients who died in the ED had clinical evidence of ALI. Thus, 48 of 552, or 8.7% (95% CI = 6.6% to 11.3%), met criteria for ALI. The kappa value for determination of ALI was 0.84 (95% CI = 0.54 to 1.0). The prevalence of ALI was nearly 9% in adult nontrauma patients receiving mechanical ventilation in the ED. Further study is required to determine which types of patients present to the ED with ALI, the extent to which lung protective ventilation is used, and the need for ED ventilator management algorithms.

Biology and pathology of fibroproliferation following the acute respiratory distress syndrome.

Prognosis of adult respiratory distress syndrome in pediatric patients

PRONE POSITIONING IN COVID-19 VS NON-COVID-19 ARDS IN THE EARLY COVID-19 PANDEMIC

Acute respiratory distress syndrome, also known as diffuse alveolar damage, is an acute injury to the lungs. Patients experience severe shortness of breath and require mechanical ventilation. It is not a specific disease, but an acute lung dysfunction associated with a variety of disorders: pneumonia, shock, sepsis, and trauma. A similar lesion occurs in newborn infants, called hyaline disease of the newborn. It occurs in premature babies and has the same pathophysiological mechanism as acute respiratory distress syndrome. Hyaline membranes are a pathologic feature of acute respiratory distress syndrome, consisting of basophilic structures that coat alveolar surfaces. They prevent oxygen exchange and are the basis of the lethality of this disorder. The syndrome is associated with very high levels of hyaluronan in broncho-alveolar lavage specimens. We postulate that the hyaline membranes of acute respiratory distress syndrome are hyaluronan-rich structures associated with serum hyaluronan-binding proteins such as fibrinogen and fibrin. Potent infectious influenza viruses are recurrent pandemics and potential terrorist threats. Lethality of influenza infection correlates with the presence of hyaline membranes. Installation of hyaluronidase as an aerosol would provide a new treatment for acute respiratory respiratory distress syndrome, for which there has been no new treatment in 45 years. The pig is the only species other than humans that develop hyaline membranes. Employing this treatment in the porcine model would provide a direct test of the hypothesis.

Comparison of Clinical Characteristics Between “True ARDS” and “Imitator ARDS”: A Retrospective Study

Objective To investigate the variation and potential function of pre-B cell colony enhancing factor (PBEF) in obesity rats with acute respiratory distress syndrome (ARDS). Methods Forty healthy male Sprague-Dawley (SD) rats were randomly divided into control group, obesity group, ARDS group, and obesity ARDS group, with 10 rats in each group. Rats in the two obesity groups were fed with high-fat diet, and the rats in other groups were fed with normal fodder. After successful obesity models were reproduced as the mean weight of rats in obesity model groups was up over 20% compared to other groups, the rats in two ARDS groups were injected with lipopolysaccharide (LPS) through tail vein to reproduce ARDS models, and the rats in other groups were injected with the same volume of saline. The lung tissues were harvested at 8 hours after ARDS model reproduction to determine lung dry/wet weight (D/W) ratio; real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression of PBEF mRNA, and the proteins expressions of PBEF and nuclear factor-κB p50 (NF-κB p50) were detected by Western Blot; the distribution and expression of PBEF was also examined by immunohistochemical staining. Pathological changes of lung tissues were observed after hematoxylin-eosin (HE) staining. Results Obesity rat models were set up successfully with 6 weeks of high fat diet. The D/W ratio of rats in obesity, ARDS, and obesity ARDS groups was significantly lower than that of control group (0.195±0.005, 0.179±0.003, 0.153±0.011 vs. 0.224±0.007, all P < 0.05), and D/W ratio in obesity ARDS group was significantly lower than that of ARDS group, indicating that the lung water content of ARDS rats and non ARDS rats could be influenced by obesity. In obesity group, ARDS group and obesity ARDS group, the expression of PBEF mRNA in lung tissues was increased in turn [it was (1.77±0.22), (3.29±0.14), (5.52±0.14) folds of that in control group respectively, all P < 0.01], and the proteins expression of PBEF and NF-κB p50 in lung tissues were also increased in turn [PBEF protein was (1.75±0.16), (2.71±0.19), (3.83±0.18) folds of that of control group, and NF-κB p50 protein was (1.56±0.12), (1.95±0.12), (2.48±0.24) folds of that of control group respectively, all P < 0.01], and there were significant differences between any two groups. There was almost no PBEF expression in lung tissues of control group detected by immunohistochemical staining, and a little PBEF expression in obesity group, the obvious increased PBEF expression was found in ARDS group, as well as PBEF expressed strikingly in alveolar walls exudates and alveolar spaces exudates of obesity ARDS group. It was shown by HE staining there were no significant pathological changes in lung tissue of rats in the control group; a few inflammatory cells infiltrated in lung tissue of obesity group, thicken alveoli septum and a number of the red cells infiltrated in alveolar spaces were found in ARDS group; the inflammation degree in lung tissue is most serious, a huge amount of exudates, red cells and inflammatory cells in alveolar spaces were found in the obesity ARDS group. Conclusions PBEF might be involved in the process of the development of ARDS in obese rats through the regulation of activity of NF-κB. Key words: Obesity; Acute respiratory distress syndrome; Pre-B cell colony enhancing factor; Nuclear factor-κB

Both persistent accumulation and activation of neutrophils may contribute to the most severe form of acute lung injury, acute respiratory distress syndrome. We analyzed the expression of neutrophil-derived S100A12 and the proinflammatory receptor for advanced glycation end products (RAGE) in patients with acute respiratory distress syndrome. Additional in vivo and in vitro experiments were performed to further analyze the contribution of S100A12 to pulmonary inflammation. We included 14 patients with acute respiratory distress syndrome and eight controls. In addition, 16 healthy subjects were included in an experimental lipopolysaccharide challenge model. Concentrations of S100A12 and soluble RAGE were analyzed in bronchoalveolar lavage fluid. The expression of S100A12 and RAGE in lung biopsies from patients was analyzed by immunohistochemistry. S100A12 was also analyzed in bronchoalveolar lavage fluid from eight healthy subjects after challenge with lipopolysaccharide and compared with eight controls who received placebo inhalation. Effects of S100A12 on endothelial cells were analyzed in vitro. Patients with acute respiratory distress syndrome had significantly enhanced pulmonary S100A12 expression and higher S100A12 protein concentrations in bronchoalveolar lavage fluid than controls. Levels of soluble RAGE were not significantly elevated in acute respiratory distress syndrome. S100A12 concentrations decreased with time from disease onset. In healthy volunteers, S100A12 was elevated in bronchoalveolar lavage fluid after lipopolysaccharide inhalation. In vitro experiments confirmed strong proinflammatory effects of human S100A12. S100A12 and its receptor RAGE are found at high concentrations in pulmonary tissue and bronchoalveolar lavage fluid in acute lung injury. S100A12 expression may reflect neutrophil activation during lung inflammation and contribute to pulmonary inflammation and endothelial activation via binding to RAGE.

Veno-Pulmonary Arterial Extracorporeal Membrane Oxygenation in Severe Acute Respiratory Distress Syndrome: Should We Consider Mechanical Support of the Pulmonary Circulation From the Outset?

Objective To investigate the roles of CD3+,CD4+,CD8+T lymphocytes and CD19+B lymphocytes on the pathogenesis of acute respiratory distress syndrome(ARDS). Methods According to Berlin definition Of ARDS in 2012, 34 patients with ARDS admitted in the Department of ICU of Central Hospital of Baoji from January,2016 to January,2017 were enrolled in this study as study group(ARDS group). At the same time, 22 healthy subjects were recruited as control group. Clinical data of ARDS patients were collected, and the survivors were followed up. The ARDS patients were divided into moderate group(n=20) and severe group (n=14) according to clinical settings on the first day after diagnosis of ARDS and Berlin Definition of ARDS in 2012, and at the same time they were also divided into two groups according to the outcome followed up for 28 days: non-survival group(n=14) and survival group(n=20). Sample of 3 mL peripheral venous blood of ARDS patients was collected on an empty stomach in the early morning on the first day after diagnosis of ARDS and the blood samples of healthy subjects were also collected on the first day to measure the level of CD3+,CD4+,CD8+ T cells and CD19+ B cell in peripheral venous blood by flow cytometry. Comparison of CD3+,CD4+,CD8+ T cells and CD19+ B cell numbers were carried out between ARDS group and control group on the first day after diagnosis of ARDS, and between moderate group and severe group as well as between survival group and non-survival group. The risk factors associated with ARDS were analyzed using logistic regression analysis. Results On the first day after diagnosis of ARDS, there were significant differences in serum Lac and pre-albumin between survival group and non-survival group(P 0.05). There were statistically significant differences in numbers of CD3+, CD4+, CD8+T cells and CD19+B cell between moderate group and severe group and as well as between survival group and non-survival group(P<0.05). Logistic regression analysis showed that CD19+ B cell (OR=0.614,95%CI:0.416-0.907, P=0.014) level on the first day after diagnosis of ARDS was related with the risk of prognosis of ARDS. The ROC of CD19+ B cell had area under curve(AUC)of 0.907, and the cut-off value of CD19+ B cell in the survival followed up for 28 day's was 12.59%. Conclusions CD3+,CD4+,CD8+ T cells and CD19+B cell level of peripheral venous serum in ARDS patients can be helpful for the assess of ARDS severity of patients in the early stage, and for prognosis judgment, especially CD19+ B cell is more remarkable. Key words: Acute respiratory distress syndrome; CD3+; CD4+; CD8+; CD19+; Pathogenesis