Clinical Patterns of Rocuronium and Cisatracurium Use in Acute Respiratory Distress Syndrome: A Retrospective Cohort Study

BackgroundWhether age would impact the outcomes in subjects with acute respiratory distress syndrome (ARDS) remains unclear. Herein, we study the effect of age as a predictor of mortality in ARDS.Materials and methodsWe categorized consecutive subjects with ARDS as either ARDSelderly (age >65 years) or ARDSnonelderly (age ≤65 years) admitted to the respiratory intensive care unit (ICU) of a tertiary care hospital in North India between January 2007 and December 2019. We compared the baseline clinical and demographic characteristics, lung mechanics, and mortality between the two groups. We also analyzed the factors predicting ICU survival using multivariate logistic regression analysis.ResultsWe included 625 patients (ARDSelderly, 140 [22.4%] and ARDSnonelderly, 485 [77.6%]) with a mean (standard deviation) age (56.3% males) of 40.6 (17.8) years. The ARDSelderly were more likely (p = 0.0001) to have the presence of any comorbid illness compared to ARDSnonelderly. The elderly subjects had significantly higher pulmonary ARDS than the younger group. The severity of ARDS was however, similarly distributed between the two study arms. There were 224 (35.8%) deaths, and the mortality was significantly higher (p = 0.012) in the ARDSelderly than the to ARDSnonelderly (ARDSelderly vs ARDSnonelderly, 45 vs 33.2%). On multivariate logistic regression analysis, the baseline sequential organ failure assessment scores, presence of pulmonary ARDS, and the development of new organ dysfunction were the independent predictors of mortality.ConclusionThe outcomes in subjects with ARDS are dependent on the severity of illness at admission and the etiology of ARDS rather than the age alone.How to cite this articleSehgal IS, Agarwal R, Dhooria S, Prasad KT, Muthu V, Aggarwal AN. Etiology and Outcomes of ARDS in the Elderly Population in an Intensive Care Unit in North India. Indian J Crit Care Med 2021;25(6):648–654.

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

In Response.

Background:Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions.Methods and Findings:In this study, we compared COVID-19 ARDS (n=43) and bacterial sepsis-induced (non-COVID-19) ARDS (n=24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within- ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation.Conclusion:We present a first comprehensive molecular characterization of differences between two ARDS etiologies – COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.

Objectives The aim of this study is to investigate the effect of glucocorticoids in adult patients with acute respiratory distress syndrome (ARDS) by meta-analysis. Methods PubMed, Cochrane Library, Embase, CNKI, Wanfang Database, and Chinese Biomedical literature database were searched. A randomized controlled trial (RCTS) on glucocorticoid therapy in adult patients with ARDS was conducted from the time of database construction to December 2021. The content is about the randomized controlled trial (RCT) of glucocorticoid treatment for adult patients with ARDS, without limiting the dose and course of glucocorticoid treatment. The quality of the included RCTS was evaluated by using the bias risk assessment tool of the Cochrane Collaboration network, and the basic information, clinical features, and target outcomes of the literature were extracted. The effects of glucocorticoids on mortality and oxygenation index (PaO2/FiO2) in adult ARDS patients were evaluated by meta-analysis. Results A total of 1,441 ARDS patients in 10 RCTs were finally included, including 734 patients in the glucocorticoid treatment group (hormone group) and 707 patients in the conventional treatment group (control group). The 10 studies included have a good overall design and high quality. Compared with controls, glucocorticoid use was significantly associated with a decrease in mortality in adult ARDS patients (relative risk (RR) = 0.73, 95% confidence interval (95% CI) = 0.59–0.90, P = 0.003). Analysis showed that glucocorticoids significantly reduced the mortality in ARDS patients treated with medium and low doses of steroids (RR = 0.73, 95% CI = 0.58–0.92, P = 0.007). In patients with early administration of steroids, intervention with glucocorticoids was significantly associated with the decreased mortality in adult ARDS patients compared with controls (RR = 0.74, 95% CI 0.56–0.99, P = 0.04). Among patients with more than 7 days of hormone therapy, treatment with glucocorticoids was significantly associated with decreased mortality in adult ARDS patients (RR = 0.66, 95% CI = 0.50–0.88, P = 0.005) compared with controls. Glucocorticoids tended to improve PaO2/FiO2 in adult ARDS patients compared with controls, but the difference was not statistically significant (weighted mean difference (WMD) = 11.60, 95% = CI = 15.02–38.22, P = 0.39). Conclusion Glucocorticoid therapy can reduce mortality in adult ARDS patients, and the benefit is more pronounced in patients with medium- and low-dose hormone therapy, early hormone administration, and hormone therapy for more than 7 days. However, no improvement in PaO2/FiO2 by glucocorticoid treatment was found, which needs to be confirmed by further studies.

To compare a time-controlled adaptive ventilation strategy, set in airway pressure release ventilation mode, versus a protective mechanical ventilation strategy in pulmonary and extrapulmonary acute respiratory distress syndrome with similar mechanical impairment. Animal study. Laboratory investigation. Forty-two Wistar rats. Pulmonary acute respiratory distress syndrome and extrapulmonary acute respiratory distress syndrome were induced by instillation of Escherichia coli lipopolysaccharide intratracheally or intraperitoneally, respectively. After 24 hours, animals were randomly assigned to receive 1 hour of volume-controlled ventilation (n = 7/etiology) or time-controlled adaptive ventilation (n = 7/etiology) (tidal volume = 8 mL/kg). Time-controlled adaptive ventilation consisted of the application of continuous positive airway pressure 2 cm H2O higher than baseline respiratory system peak pressure for a time (Thigh) of 0.75-0.85 seconds. The release pressure (Plow = 0 cm H2O) was applied for a time (Tlow) of 0.11-0.18 seconds. Tlow was set to target an end-expiratory flow to peak expiratory flow ratio of 75%. Nonventilated animals (n = 7/etiology) were used for Diffuse Alveolar Damage and molecular biology markers analyses. Time-controlled adaptive ventilation increased mean respiratory system pressure regardless of acute respiratory distress syndrome etiology. The Diffuse Alveolar Damage score was lower in time-controlled adaptive ventilation compared with volume-controlled ventilation in pulmonary acute respiratory distress syndrome and lower in time-controlled adaptive ventilation than nonventilated in extrapulmonary acute respiratory distress syndrome. In pulmonary acute respiratory distress syndrome, volume-controlled ventilation, but not time-controlled adaptive ventilation, increased the expression of amphiregulin, vascular cell adhesion molecule-1, and metalloproteinase-9. Collagen density was higher, whereas expression of decorin was lower in time-controlled adaptive ventilation than nonventilated, independent of acute respiratory distress syndrome etiology. In pulmonary acute respiratory distress syndrome, but not in extrapulmonary acute respiratory distress syndrome, time-controlled adaptive ventilation increased syndecan expression. In pulmonary acute respiratory distress syndrome, time-controlled adaptive ventilation led to more pronounced beneficial effects on expression of biomarkers related to overdistension and extracellular matrix homeostasis.

Rebuttal From Dr Hall

There are conflicting results regarding whether corticosteroids have better efficacy than placebo in acute respiratory distress syndrome (ARDS) patients. Therefore, we aim to further evaluate the efficacy and safety of corticosteroids in adult ARDS patients. The databases, including Medline, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, were searched from their inception to May 2, 2020. Randomized controlled trials (RCTs) and observational cohort studies were selected to assess the use of corticosteroids in adult ARDS patients. The quality of the results was judged by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The inverse-variance method with random or fixed effects modeling was used to compute pooled odds ratio (OR), standardized mean difference (SMD), and their 95% confidence interval (CI). Eight eligible RCTs and six cohort studies were included. The use of corticosteroids was associated with reduced mortality (OR 0.57, 95% CI 0.43-0.76, I2=35.1%, P=0.148) in ARDS patients, and the result was confirmed in the included cohort studies (OR 0.51, 95% CI 0.27-0.95, I2=66.7%, P=0.010). The subgroup analysis stratified by the initiation time and duration of corticosteroid use showed that early ARDS and prolonged corticosteroid use had significant survival benefits in the RCTs. The low-dose corticosteroid use was also associated with significantly more ventilator-free days and a reduced rate of new infections in ARDS patients. The low-dose corticosteroid therapy may be safe and reduce mortality, especially in patients with prolonged treatment and early ARDS.

The biologic effects of variable ventilation may depend on the etiology of acute respiratory distress syndrome. We compared variable and conventional ventilation in experimental pulmonary and extrapulmonary acute respiratory distress syndrome. Prospective, randomized, controlled experimental study. University research laboratory. Twenty-four Wistar rats. Acute respiratory distress syndrome was induced by Escherichia coli lipopolysaccharide administered intratracheally (pulmonary acute respiratory distress syndrome, n = 12) or intraperitoneally (extrapulmonary acute respiratory distress syndrome, n = 12). After 24 hours, animals were randomly assigned to receive conventional (volume-controlled ventilation, n = 6) or variable ventilation (n = 6). Nonventilated animals (n = 4 per etiology) were used for comparison of diffuse alveolar damage, E-cadherin, and molecular biology variables. Variable ventilation was applied on a breath-to-breath basis as a sequence of randomly generated tidal volume values (n = 600; mean tidal volume = 6 mL/kg), with a 30% coefficient of variation (normal distribution). After randomization, animals were ventilated for 1 hour and lungs were removed for histology and molecular biology analysis. Variable ventilation improved oxygenation and reduced lung elastance compared with volume-controlled ventilation in both acute respiratory distress syndrome etiologies. In pulmonary acute respiratory distress syndrome, but not in extrapulmonary acute respiratory distress syndrome, variable ventilation 1) decreased total diffuse alveolar damage (median [interquartile range]: volume-controlled ventilation, 12 [11-17] vs variable ventilation, 9 [8-10]; p < 0.01), interleukin-6 expression (volume-controlled ventilation, 21.5 [18.3-23.3] vs variable ventilation, 5.6 [4.6-12.1]; p < 0.001), and angiopoietin-2/angiopoietin-1 ratio (volume-controlled ventilation, 2.0 [1.3-2.1] vs variable ventilation, 0.7 [0.6-1.4]; p < 0.05) and increased relative angiopoietin-1 expression (volume-controlled ventilation, 0.3 [0.2-0.5] vs variable ventilation, 0.8 [0.5-1.3]; p < 0.01). In extrapulmonary acute respiratory distress syndrome, only volume-controlled ventilation increased vascular cell adhesion molecule-1 messenger RNA expression (volume-controlled ventilation, 7.7 [5.7-18.6] vs nonventilated, 0.9 [0.7-1.3]; p < 0.05). E-cadherin expression in lung tissue was reduced in volume-controlled ventilation compared with nonventilated regardless of acute respiratory distress syndrome etiology. In pulmonary acute respiratory distress syndrome, E-cadherin expression was similar in volume-controlled ventilation and variable ventilation; in extrapulmonary acute respiratory distress syndrome, however, it was higher in variable ventilation than in volume-controlled ventilation. Variable ventilation improved lung function in both pulmonary acute respiratory distress syndrome and extrapulmonary acute respiratory distress syndrome. Variable ventilation led to more pronounced beneficial effects in biologic marker expressions in pulmonary acute respiratory distress syndrome compared with extrapulmonary acute respiratory distress syndrome but preserved E-cadherin in lung tissue only in extrapulmonary acute respiratory distress syndrome, thus suggesting lower damage to epithelial cells.

Introduction: We describe our outcomes in patients with Acute Respiratory Failure (ARF) prior to and during the Coronavirus-19 (COVID-19) pandemic with regards to salvage therapies for ARF Methods: In our single center retrospective matched cohort study, we collected demographic variables, comorbid conditions, laboratory data, variables on the ventilator, vasopressor use, use of prone ventilation, neuromuscular blockade, and inhaled pulmonary vasodilators. Data was collected from electronic health records for all patients for whom a consultation for Extra Corporeal Membranous Oxygenation (ECMO) for ARF was sought from January 2018 to April 2022. Results: Two hundred and fifty-three patients (253) received consultation for ECMO for ARF. Of those 189 patients were non COVID-19 related ARF and 141 met the criteria for acute respiratory distress syndrome (ARDS), 64 patients had ARF due to COVID-19, of which 63 patients met criteria for ARDS. Consultation for ECMO was obtained after 3.94 ± 4.75 days of ARDS and 3.86 ± 4.91 of Mechanical Ventilation (MV) vs 4.92 ± 4.67 days of ARDS and 6.11 ± 4.82 of MV in patients with non-COVID ARF and COVID-19 ARF respectively (p < 0.0001). Patients with non-COVID-19 ARF tended to have higher lactate, more vasopressor needs and were on higher tidal volumes. Prone positioning (67% vs 14.8%; p=0.0001), corticosteroid use (85.9% vs 50.2%, p=0.001) and neuromuscular blockade (87.5% vs 61.3%; p= 0.001) were used more in the COVID-19 ARF group when compared to non-COVID ARF group. There were no statistically significant differences between the two groups in their PRESERVE score, RESP score, Oxygenation Index (OI) or the percentage of patients deemed candidates and initiated on VV-ECMO. In the non-COVID-19 ARF group 30% patients were extubated versus 3.1% patients (p=0.001) in the COVID-19 ARF group, and 32 % patients received tracheostomy versus 47% patients received tracheostomy (p=0.04) in the COVID-19 ARF group. Conclusions: Patients with ARF and ARDS received ECMO consultation later in the disease course and the use of salvage therapies was more pronounced during the COVID-19 pandemic. There was no difference in risk prognostication scores or use of ECMO in either group. Protocolized ARDS management can help avoid ECMO, subsequent complications and limit resource utilization.

Delirium is a common complication in patients with acute respiratory distress syndrome (ARDS) and is associated with poor clinical outcomes. However, studies investigating the associations between easily accessible biomarkers and early mortality or the risk of early invasive mechanical ventilation in this population remain poorly defined. This study aimed to investigate the association between the ratio of arterial partial pressure of oxygen to red cell distribution width (PaO2/RDW) and short-term outcomes in ICU patients with delirium associated with ARDS. Data were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 3.1), a large, publicly available critical care database that contains de-identified health records of patients admitted to Beth Israel Deaconess Medical Center. Adult ARDS patients with at least one positive Confusion Assessment Method for the ICU (CAM-ICU) evaluation were included. The primary outcome was all-cause mortality within seven days after delirium onset, and the secondary outcome was the initiation of invasive mechanical ventilation after ICU admission. Cox proportional hazards and cause-specific Cox regression models were applied to evaluate the associations between the PaO2/RDW ratio and clinical outcomes. Restricted cubic spline (RCS) modeling was used to explore potential nonlinear relationships, and subgroup analyses were performed to assess consistency across clinical strata. A total of 4,116 patients with ARDS were initially identified, and 1,665 patients with delirium were ultimately included in the final analysis. Compared with the highest PaO2/RDW tertile, patients in the lowest tertile had significantly higher risks of 7-day (adjusted HR = 2.12, 95% CI 1.46-3.09, P < 0.001) and 30-day mortality (adjusted HR = 1.72, 95% CI 1.33-2.22, P < 0.001). The lowest tertile was also associated with an increased risk of invasive mechanical ventilation (adjusted HR = 2.68, 95% CI 1.16-6.22, P = 0.021). Restricted cubic spline analysis revealed a U-shaped association between the PaO2/RDW ratio and 7-day mortality, with the lowest estimated hazard at approximately 6.7. Subgroup analyses showed consistent associations across age, sex, and comorbidity strata without significant interactions (P for interaction > 0.05). The PaO2/RDW ratio was independently associated with 7-day mortality after delirium onset and with the early risk of invasive mechanical ventilation among ICU patients with delirium associated with ARDS. As an easily obtainable composite index, the PaO2/RDW ratio may serve as a convenient and informative biomarker for early risk assessment and clinical decision-making in critical care settings.

To systematically review the role of corticosteroids in prevention of acute respiratory distress syndrome (ARDS) in high-risk patients, and in treatment of established ARDS. Primary articles were identified by English-language Pubmed/MEDLINE, Cochrane central register of controlled trials, and Cochrane systemic review database search (1960–June 2009) using the MeSH headings: ARDS, adult respiratory distress syndrome, ARDS, corticosteroids, and methylprednisolone (MP). The identified studies were reviewed and information regarding role of corticosteroids in prevention and treatment of ARDS was evaluated. Nine trials have evaluated the role of corticosteroid drugs in management of ARDS at various stages. Of the 9, 4 trials evaluated role of corticosteroids in prevention of ARDS, while other 5 trials were focused on treatment after variable periods of onset of ARDS. Trials with preventive corticosteroids, mostly using high doses of MP, showed negative results with patients in treatment arm, showing higher mortality and rate of ARDS development. While trials of corticosteroids in early ARDS showed variable results, somewhat, favoring use of these agents to reduce associated morbidities. In late stage of ARDS, these drugs have no benefits and are associated with adverse outcome. Use of corticosteroids in patients with early ARDS showed equivocal results in decreasing mortality; however, there is evidence that these drugs reduce organ dysfunction score, lung injury score, ventilator requirement, and intensive care unit stay. However, most of these trials are small, having a significant heterogeneity regarding study design, etiology of ARDS, and dosage of corticosteroids. Further research involving large-scale trials on relatively homogeneous cohort is necessary to establish the role of corticosteroids for this condition.

Therapeutic Value of a Lung Protective Ventilation Strategy in Acute Lung Injury

Acute respiratory distress syndrome (ARDS) is characterized by severe pulmonary inflammation, increased blood–gas barrier permeability, and hypoxemia, resulting in high mortality rates. Despite extensive research, there is still no specific therapy for ARDS and management remains supportive, mostly in the form of protective mechanical ventilation. These limited therapeutic options result from the complexity of ARDS pathophysiology, which involves multiple, overlapping signaling pathways depending on etiology. ARDS models are important to elucidate the mechanisms underlying pathogenesis, progression, and resolution of this syndrome, as well as to develop therapeutic approaches [1]. This brief review will address the main features of human ARDS that may be modeled experimentally, major current models of ARDS, and what these models have taught us concerning pathophysiology and new therapeutic strategies. An ideal model for ARDS research should reproduce the parameters found in human ARDS. However, since models that perfectly mimic human ARDS are lacking, a committee was organized to determine which features characterize ARDS in animals and identify the optimal methods to assess these features [2]. ARDS triggers are numerous, as are the animal models used to study this syndrome. The many etiologies of ARDS can be broadly classified into two categories: direct insults to the lung epithelium (pulmonary ARDS) and indirect insults to vascular endothelium (extrapulmonary ARDS), determined by an acute systemic inflammatory response [3]. Pulmonary ARDS can be induced experimentally by administration of bacteria or bacterial products such as lipopolysaccharide (LPS), hydrochloric acid or gastric particulates, high inspired fractions of oxygen, depletion of surfactant by repeated saline lavage, induction of ischemia/reperfusion by hilar clamping, or mechanical stretch secondary to injurious mechanical ventilation. Extrapulmonary ARDS can be induced using standard models of sepsis (cecal ligation and puncture [CLP], intravenous administration of bacteria or LPS, mesenteric ischemia/reperfusion), paraquat, and oleic acid. More recently, two-hit models were developed using saline lavage or LPS followed by mechanical ventilation, CLP followed by hemorrhage, or peritoneal sepsis combined with gut ischemia/reperfusion [4] (Table 1). Selection of ARDS models depends on local availability, cost, number of animals (if survival is the study endpoint, rodents are ideal), blood sampling requirements (if multiple samples are needed, large animals should be used), and measurement of inflammatory mediators, receptors, or other proteins (large animals lack specific reagents to measure these parameters).

BackgroundDelirium is a common complication in patients with acute respiratory distress syndrome (ARDS) and is associated with poor clinical outcomes. However, studies investigating the associations between easily accessible biomarkers and early mortality or the risk of early invasive mechanical ventilation in this population remain poorly defined. This study aimed to investigate the association between the ratio of arterial partial pressure of oxygen to red cell distribution width (PaO2/RDW) and short-term outcomes in ICU patients with delirium associated with ARDS.MethodsData were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 3.1), a large, publicly available critical care database that contains de-identified health records of patients admitted to Beth Israel Deaconess Medical Center. Adult ARDS patients with at least one positive Confusion Assessment Method for the ICU (CAM-ICU) evaluation were included. The primary outcome was all-cause mortality within seven days after delirium onset, and the secondary outcome was the initiation of invasive mechanical ventilation after ICU admission. Cox proportional hazards and cause-specific Cox regression models were applied to evaluate the associations between the PaO2/RDW ratio and clinical outcomes. Restricted cubic spline (RCS) modeling was used to explore potential nonlinear relationships, and subgroup analyses were performed to assess consistency across clinical strata.ResultsA total of 4,116 patients with ARDS were initially identified, and 1,665 patients with delirium were ultimately included in the final analysis. Compared with the highest PaO2/RDW tertile, patients in the lowest tertile had significantly higher risks of 7-day (adjusted HR = 2.12, 95% CI 1.46–3.09, P < 0.001) and 30-day mortality (adjusted HR = 1.72, 95% CI 1.33–2.22, P < 0.001). The lowest tertile was also associated with an increased risk of invasive mechanical ventilation (adjusted HR = 2.68, 95% CI 1.16–6.22, P = 0.021). Restricted cubic spline analysis revealed a U-shaped association between the PaO2/RDW ratio and 7-day mortality, with the lowest estimated hazard at approximately 6.7. Subgroup analyses showed consistent associations across age, sex, and comorbidity strata without significant interactions (P for interaction > 0.05).ConclusionsThe PaO2/RDW ratio was independently associated with 7-day mortality after delirium onset and with the early risk of invasive mechanical ventilation among ICU patients with delirium associated with ARDS. As an easily obtainable composite index, the PaO2/RDW ratio may serve as a convenient and informative biomarker for early risk assessment and clinical decision-making in critical care settings.