A New Global Definition of Acute Respiratory Distress Syndrome.

Background: Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings. Methods: A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would 1) identify patients with the currently accepted conceptual framework for ARDS, 2) facilitate rapid ARDS diagnosis for clinical care and research, 3) be applicable in resource-limited settings, 4) be useful for testing specific therapies, and 5) be practical for communication to patients and caregivers. Results: The committee made four main recommendations: 1) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min; 2) use PaO2:FiO2 ⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry SpO2:FiO2 ⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify hypoxemia; 3) retain bilateral opacities for imaging criteria but add ultrasound as an imaging modality, especially in resource-limited areas; and 4) in resource-limited settings, do not require positive end-expiratory pressure, oxygen flow rate, or specific respiratory support devices. Conclusions: We propose a new global definition of ARDS that builds on the Berlin definition. The recommendations also identify areas for future research, including the need for prospective assessments of the feasibility, reliability, and prognostic validity of the proposed global definition.

Evaluation of GSK2789917-induced TRPV4 inhibition in animal models of fluid induced lung injury.

Administration of bolus intravenous fluids, common in pre-hospital and hospitalised patients, is associated with increased lung vascular permeability and mortality outside underlying disease states. In our laboratory, the induction of lung injury and oedema through rapid administration of intravenous fluid in rats was reduced by a non-specific antagonist of transient receptor potential vanilloid 4 (TRPV4) channels. The aims of this study were to determine the effect of selective TRPV4 inhibition on fluid-induced lung injury (FILI) and compare the potency of FILI inhibition to that of an established model of TRPV4 agonist-induced lung oedema. In a series of experiments, rats received specific TRPV4 inhibitor (GSK2789917) at high (15 µg/kg), medium (5 µg/kg) or low (2 µg/kg) dose or vehicle prior to induction of lung injury by intravenous infusion of TRPV4 agonist (GSK1016790) or saline. GSK1016790 significantly increased lung wet weight/body weight ratio by 96% and lung wet-to-dry weight ratio by 43% in vehicle pre-treated rats, which was inhibited by GSK2789917 in a dose-dependent manner (IC50 = 3 ng/mL). Similarly, in a single-dose study, bolus saline infusion significantly increased lung wet weight/body weight by 17% and lung wet-to-dry weight ratio by 15%, which was attenuated by high dose GSK2789917. However, in a final GSK2789917 dose-response study, inhibition did not reach significance and an inhibitory potency was not determined due to the lack of a clear dose-response. In the FILI model, TRPV4 may have a role in lung injury induced by rapid-fluid infusion, indicated by inconsistent amelioration with high dose TRPV4 antagonist.

Improving health care efficiency one click at a time.

Computers are an integral component of modern hospitals. Mouse clicks are currently inherent to this use of computers. However, mouse clicks are not instantaneous. These clicks may be associated with significant costs. Estimated costs associated with 10 additional clicks per day for 20 000 staff exceed AU$500 000 annually. Workflow modifications that increase clicks should weigh the potential benefits of such changes against these costs. Future investigation of strategies to reduce low-value clicks may provide an avenue for health care savings.

A vital parameter? Systematic review of spirometry in evaluation for intensive care unit admission and intubation and ventilation for Guillain-Barré syndrome.

BACKGROUND: Patients with Guillain-Barré syndrome (GBS) may require intensive care unit (ICU) admission for intubation and ventilation (I + V). The means to predict which patients will require I + V include spirometry measures. The aims of this study were to determine, for adult patients with GBS, how effectively different spirometry parameter thresholds predict the need for ICU admission and the requirement for I + V; and what effects these different parameter thresholds have on GBS patient outcomes. METHOD: A systematic review was conducted of the databases PubMed, EMBASE, and Cochrane library in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The systematic review was registered prospectively on PROSPERO. RESULTS: Initial searches returned 1011 results, of which 8 fulfilled inclusion criteria. All included studies were observational in nature. Multiple studies suggest that a vital capacity below 60% of predicted value on admission is associated with the need for eventual I + V. No included studies evaluated peak expiratory flow rate, or interventions with different thresholds for ICU or I + V. CONCLUSIONS: There is a relationship between vital capacity and the need for I + V. However, there is limited evidence supporting specific thresholds for I + V. In addition to evaluating these factors, future research may evaluate the effect of different patient characteristics, including clinical presentation, weight, age, and respiratory comorbidities, on the effectiveness of spirometry parameters in the prediction of the need for I + V.

Does hyperglycemia affect arginine metabolites in critically ill patients? A prospective cohort and in vitro study.

BACKGROUND: Changes in the arginine metabolites asymmetric dimethyl-L-arginine (ADMA) and L-homoarginine and acute blood glucose concentrations have been shown to cause endothelial dysfunction and be independently associated with mortality in Intensive Care Unit (ICU) patients. The aim of this study was to investigate whether hyperglycemia potentially modulates these arginine metabolite concentrations to provide a mechanism that may link hyperglycemia and mortality in this patient group. METHODS: A clinical and in vitro study were undertaken. Glucose, glycosylated hemoglobin-A1c (HbA1c) and the stress hyperglycemia ratio (SHR) (to quantify absolute, chronic and relative hyperglycemia respectively) were measured in 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU. SHR was calculated by dividing the admission glucose by the estimated average glucose over the last 3 months, which was derived from HbA1c. ADMA and L-homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. The activity of dimethylarginine-dimethylaminohydrolase 1 (DDAH1), the main enzyme regulating ADMA concentrations, was assessed at varying glucose concentrations in vitro by quantifying the conversion of ADMA to citrulline in HEK293 cells that overexpress DDAH1. RESULTS: In the clinical study, plasma ADMA was not significantly associated with any measure of hyperglycemia. L-homoarginine was positively associated with glucose (ß = 0.067, p = 0.018) and SHR (ß = 0.107, p < 0.001) after correction for glomerular filtration rate. However, as L-homoarginine is a negative predictor of mortality, the direction of these associations are the opposite of those expected if hyperglycemia was affecting mortality via changes in L-homoarginine. In vitro DDAH1 activity was not significantly influenced by glucose concentrations (p = 0.506). CONCLUSION: In critically ill patients the association between relative hyperglycemia and mortality is not mediated by changes in ADMA or L-homoarginine. Trial registration ANZCTR Trial ID ACTRN12615001164583.

Monocyte chemotactic protein (MCP)-1 (CCL2) and its receptor (CCR2) are elevated in chronic heart failure facilitating lung monocyte infiltration and differentiation which may contribute to lung fibrosis.

BACKGROUND: Dyspnea, the cardinal manifestation of chronic heart failure (CHF), may reflect both pulmonary oedema and pulmonary remodeling resulting in tissue stiffening. Emerging evidence suggests that predominance of distinct phenotypes of alveolar and recruited macrophages, designated M1 and M2, may regulate the course of inflammatory tissue repair and remodeling in the lung. METHODS: In a CHF rat model, we found fibrotic reinforcement of the extracellular matrix with an increase in monocyte chemotactic protein (MCP)-1/CCL2 in bronchoalveolar lavage (BAL), corresponding to a 3-fold increase in recruited macrophages. In this clinical cross sectional study, we aimed to examine potential mediators of leukocyte activation and lung infiltration in parallel BAL and blood from CHF patients compared to non-CHF controls. RESULTS: Mini-BAL and peripheral blood samples were obtained from hospitalized CHF, acute decompensated CHF and non-CHF patients. CHF patients and decompensated CHF patients demonstrated increases from non-CHF patients in BAL MCP-1, as well as the M2 macrophage cytokines interleukin-10 and transforming growth factor-ß. BAL and plasma MCP-1 were significantly correlated; however, MCP-1 was 20-fold higher in epithelial lining fluid in BAL, indicative of an alveolar chemotactic gradient. An increase in transglutaminase 2 positive M2 macrophages in parallel with a decrease in the MCP-1 receptor, CC chemokine receptor 2 (CCR2), was apparent in BAL cells of CHF patients compared to non-CHF. CONCLUSION: These data suggest a pathway of MCP-1 mediated M2 macrophage prevalence in the lungs of CHF patients which may contribute to pulmonary fibrotic remodeling and consequent increased severity of dyspnea.

Admission serum sodium and osmolarity are not associated with the occurrence or outcomes of acute respiratory distress syndrome in critically ill.

BACKGROUND: Previous studies suggested that hypernatremia or hyperosmolarity may have protective effects in lung injury. We hypothesized that hypernatremia and/or hyperosmolarity would prevent ARDS. DESIGN: Retrospective cohort study of all admissions at medical, surgical, and multidisciplinary intensive care units in Mayo Clinic, Rochester from the year of 2009 to 2019. The occurrence of ARDS was identified using a validated computerized search strategy. The association between serum sodium/osmolarity and the occurrence of ARDS was analyzed using a multivariable logistic regression model. The relationship between serum sodium/osmolarity and outcomes of ARDS was analyzed using linear and logistic regression models. RESULTS: Among 50,498 patients, the serum sodium level on admission did not have a significant association with the occurrence of ARDS, with an adjusted odds ratio of 0.95 [95% CI (0.86, 1.05)]. There was no significant association between calculated serum osmolarity and the occurrence of ARDS, with an adjusted odds ratio of 1.03 [95% CI (1.00, 1.07)]. 1560 patients developed ARDS during the ICU stay. Their serum sodium level and osmolarity level did not have a significant association with their outcomes. CONCLUSIONS: Admission serum sodium or serum osmolarity were not associated with the occurrence or outcomes of ARDS in ICU.

Weaning Outcomes in Patients with Brain Injury.

BACKGROUND: Despite the need for specific weaning strategies in neurological patients, evidence is generally insufficient or lacking. We aimed to describe the evolution over time of weaning and extubation practices in patients with acute brain injury compared with patients who are mechanically ventilated (MV) due to other reasons. METHODS: We performed a secondary analysis of three prospective, observational, multicenter international studies conducted in 2004, 2010, and 2016 in adults who had need of invasive MV for more than 12 h. We collected data on baseline characteristics, variables related to management ventilator settings, and complications while patients were ventilated or until day 28. RESULTS: Among the 20,929 patients enrolled, we included 12,618 (60%) who started the weaning from MV, of whom 1722 (14%) were patients with acute brain injury. In the acutely brain-injured cohort, 538 patients (31%) did not undergo planned extubation, defined as the need for a tracheostomy without an attempt of extubation, accidental extubation, and death. Among the 1184 planned extubated patients with acute brain injury, 202 required reintubation (17%). Patients with acute brain injury had a higher odds for unplanned extubation (odds ratio [OR] 1.35, confidence interval for 95% [CI 95%] 1.19-1.54; p < 0.001), a higher odds of failure after the first attempt of weaning (spontaneous breathing trial or gradual reduction of ventilatory support; OR 1.14 [CI 95% 1.01-1.30; p = 0.03]), and a higher odds for reintubation (OR 1.41 [CI 95% 1.20-1.66; p < 0.001]) than patients without brain injury. Patients with hemorrhagic stroke had the highest odds for unplanned extubation (OR 1.47 [CI 95% 1.22-1.77; p < 0.001]), of failed extubation after the first attempt of weaning (OR 1.28 [CI 95% 1.06-1.55; p = 0.009]), and for reintubation (OR 1.49 [CI 95% 1.17-1.88; p < 0.001]). In relation to weaning evolution over time in patients with acute brain injury, the risk for unplanned extubation showed a downward trend; the risk for reintubation was not associated to time; and there was a significant increase in the percentage of patients who underwent extubation after the first attempt of weaning from MV. CONCLUSIONS: Patients with acute brain injury, compared with patients without brain injury, present higher odds of undergoing unplanned extubated after weaning was started, lower odds of being extubated after the first attempt, and a higher risk of reintubation.

ADMA and homoarginine independently predict mortality in critically ill patients.

BACKGROUND: Arginine metabolites are associated with cardiovascular and all-cause mortality in several patient groups. We investigated whether arginine metabolites are associated with mortality in patients with critical illness and whether associations are independent of other factors affecting prognosis in an Intensive Care Unit (ICU). METHODS: 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU were studied. Arginine, asymmetric dimethyl-l-arginine (ADMA), monomethyl-l-arginine (MMA), symmetric dimethyl-l-arginine (SDMA) and l-homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society. RESULTS: In this cohort, 163 patients (14.1%) died. ADMA (odds ratio = 1.159 (1.033-1.300) per 0.1 µmol/L increment, p = 0.012), homoarginine (odds ratio = 0.963 (0.934-0.992), p = 0.013) and risk of death score (odds ratio = 1.045 (1.037-1.053) per 1% increment, p < 0.001) were independently associated with mortality in ICU patients. The area under the receiver operator characteristic curve for risk of death score, ADMA and homoarginine combined for mortality was greater than for risk of death score alone (0.815 (95% CI 0.790-0.837) vs 0.796 (95% CI 0.781-0.820), p = 0.019). Other arginine metabolites were not independently associated with mortality. CONCLUSIONS: ADMA is positively and homoarginine negatively associated with mortality in ICU patients, independent of other clinical factors. Measuring ADMA and homoarginine may refine models to predict ICU mortality. Reducing ADMA and increasing homoarginine are potential therapeutic targets to reduce mortality in critically ill patients.

Perspectives of patients, family members, health professionals and the public on the impact of COVID-19 on mental health.

BACKGROUND: The coronavirus (COVID-19) pandemic has seen a global surge in anxiety, depression, post-traumatic stress disorder (PTSD), and stress. AIMS: This study aimed to describe the perspectives of patients with COVID-19, their family, health professionals, and the general public on the impact of COVID-19 on mental health. METHODS: A secondary thematic analysis was conducted using data from the COVID-19 COS project. We extracted data on the perceived causes and impact of COVID-19 on mental health from an international survey and seven online consensus workshops. RESULTS: We identified four themes (with subthemes in parenthesis): anxiety amidst uncertainty (always on high alert, ebb and flow of recovery); anguish of a threatened future (intense frustration of a changed normality, facing loss of livelihood, trauma of ventilation, a troubling prognosis, confronting death); bearing responsibility for transmission (fear of spreading COVID-19 in public; overwhelming guilt of infecting a loved one); and suffering in isolation (severe solitude of quarantine, sick and alone, separation exacerbating grief). CONCLUSION: We found that the unpredictability of COVID-19, the fear of long-term health consequences, burden of guilt, and suffering in isolation profoundly impacted mental health. Clinical and public health interventions are needed to manage the psychological consequences arising from this pandemic.

Hospital-acquired complications: the relative importance of hospital- and patient-related factors.

OBJECTIVE: To quantify the prevalence of hospital-acquired complications; to determine the relative influence of patient- and hospital-related factors on complication rates. DESIGN, PARTICIPANTS: Retrospective analysis of administrative data (Integrated South Australian Activity Collection; Victorian Admitted Episodes Dataset) for multiple-day acute care episodes for adults in public hospitals. SETTING: Thirty-eight major public hospitals in South Australia and Victoria, 2015-2018. MAIN OUTCOME MEASURES: Hospital-acquired complication rates, overall and by complication class, by hospital and hospital type (tertiary referral, major metropolitan service, major regional service); variance in rates (intra-class correlation coefficient, ICC) at the patient, hospital, and hospital type levels as surrogate measures of their influence on rates. RESULTS: Of 1 558 978 public hospital episodes (10 029 918 bed-days), 151 486 included a total of 214 286 hospital-acquired complications (9.72 [95% CI, 9.67-9.77] events per 100 episodes; 2.14 [95% CI, 2.13-2.15] events per 100 bed-days). Complication rates were highest in tertiary referral hospitals (12.7 [95% CI, 12.6-12.8] events per 100 episodes) and for episodes including intensive care components (37.1 [95% CI, 36.7-37.4] events per 100 episodes). For all complication classes, inter-hospital variation was determined more by patient factors (overall ICC, 0.55; 95% CI, 0.53-0.57) than by hospital factors (ICC, 0.04; 95% CI, 0.02-0.07) or hospital type (ICC, 0.01; 95% CI, 0.001-0.03). CONCLUSIONS: Hospital-acquired complications were recorded for 9.7% of hospital episodes, but patient-related factors played a greater role in determining their prevalence than the treating hospital.

Bolus intravenous 0.9% saline leads to interstitial permeability pulmonary edema in healthy volunteers.

PURPOSE: Bolus intravenous administration of 0.9% saline has been associated with the development of pulmonary edema, and increased mortality. An animal model has previously demonstrated that rapid intravenous administration of 0.9% saline was associated with non-hydrostatic lung injury with increased lung lavage protein. We hypothesized that this non-hydrostatic effect would also occur in human volunteers. METHODS: In a randomized, cross-over study of 14 healthy male subjects, the lung lavage protein concentration and cardiorespiratory effects of an intervention with rapid intravenous administration of 30 mL/kg of 0.9% saline were compared with sham intervention. Bronchoalveolar lavage (BAL) was performed after fluid administration. Doppler echocardiography, lung ultrasound, pulmonary function tests, and blood sampling were performed before and after each intervention. RESULTS: The BAL total protein concentration was greater after 0.9% saline administration than with sham (196.1 µg/mL (SD 87.6) versus 129.8 µg/mL (SD 55.4), respectively (p = 0.020). Plasma angiopoietin-2 concentration was also increased to 2.26 ng/mL (SD 0.87) after 0.9% saline administration compared with sham 1.53 ng/mL (SD 0.69) (p < 0.001). There were small increases in stroke volume (from 58 mL (IQR 51-74) to 66 mL (IQR 58-74), p = 0.045) and Doppler echocardiography left ventricle E/e' ratio (from 5.0 (IQR 4.5-6.0) to 5.7 (IQR 5.3-6.3), p = 0.007), but no changes to right ventricular function. CONCLUSION: Rapid intravenous administration of 0.9% saline leads to interstitial permeability pulmonary edema in healthy human volunteers. Further research is now warranted to understand these effects in critically ill patients.

Driving Pressure Is a Risk Factor for ARDS in Mechanically Ventilated Subjects Without ARDS.

BACKGROUND: Driving pressure (ΔP) has been described as a risk factor for mortality in patients with ARDS. However, the role of ΔP in the outcome of patients without ARDS and on mechanical ventilation has received less attention. Our objective was to evaluate the association between ΔP on the first day of mechanical ventilation with the development of ARDS. METHODS: This was a post hoc analysis of a multicenter, prospective, observational, international study that included subjects who were on mechanical ventilation for > 12 h. Our objective was to evaluate the association between ΔP on the first day of mechanical ventilation with the development of ARDS. To assess the effect of ΔP, a logistic regression analysis was performed when adjusting for other potential risk factors. Validation of the results obtained was performed by using a bootstrap method and by repeating the same analyses at day 2. RESULTS: A total of 1,575 subjects were included, of whom 65 (4.1%) developed ARDS. The ΔP was independently associated with ARDS (odds ratio [OR] 1.12, 95% CI 1.07-1.18 for each cm H2O of ΔP increase, P < .001). The same results were observed at day 2 (OR 1.14, 95% CI 1.07-1.21; P < .001) and after bootstrap validation (OR 1.13, 95% CI 1.04-1.22; P < .001). When taking the prevalence of ARDS in the lowest quartile of ΔP (≤9 cm H2O) as a reference, the subjects with ΔP > 12-15 cm H2O and those with ΔP > 15 cm H2O presented a higher probability of ARDS (OR 3.65, 95% CI 1.32-10.04 [P = .01] and OR 7.31, 95% CI, 2.89-18.50 [P < .001], respectively). CONCLUSIONS: In the subjects without ARDS, a higher level of ΔP on the first day of mechanical ventilation was associated with later development of ARDS. (ClinicalTrials.gov registration NCT02731898.).

Induced hypernatremia in patients with moderate-to-severe ARDS: a randomized controlled study.

BACKGROUND: Induced hypernatremia and hyperosmolarity is protective in animal models of lung injury. We hypothesized that increasing and maintaining plasma sodium between 145 and 150 mmol/l in patients with moderate-to-severe ARDS would be safe and will reduce lung injury. This was a prospective randomized feasibility study in moderate-to-severe ARDS, comparing standard care with intravenous hypertonic saline to achieve and maintain plasma sodium between 145 and 150 mmol/l for 7 days (HTS group). Both groups of patients were managed with lung protective ventilation and conservative fluid management. The primary outcome was 1-point reduction in lung injury score (LIS) or successful extubation by day 7. RESULTS: Forty patients were randomized with 20 in each group. Baseline characteristics of severity of illness were well balanced. Patients in the HTS group had higher plasma sodium levels during the first 7 days after randomization when compared with the control group (p = 0.04). Seventy five percent (15/20) of patients in the HTS group were extubated or had ≥ 1-point reduction in LIS compared with 35% (7/20) in the control group (p = 0.02). There was also a decrease in length of mechanical ventilation and hospital length of stay in the HTS group. CONCLUSION: We have shown clinical improvement in patients with moderate-to-severe ARDS following induced hypernatremia, suggesting that administration of hypertonic saline is a safe and feasible intervention in patients with moderate-to-severe ARDS. This suggests progress to a phase II study. Clinical Trial Registration Australian and New Zealand Clinical Trials Registry (ACTRN12615001282572).

Machine learning predicts mortality based on analysis of ventilation parameters of critically ill patients: multi-centre validation.

BACKGROUND: Mechanical Ventilation (MV) is a complex and central treatment process in the care of critically ill patients. It influences acid-base balance and can also cause prognostically relevant biotrauma by generating forces and liberating reactive oxygen species, negatively affecting outcomes. In this work we evaluate the use of a Recurrent Neural Network (RNN) modelling to predict outcomes of mechanically ventilated patients, using standard mechanical ventilation parameters. METHODS: We performed our analysis on VENTILA dataset, an observational, prospective, international, multi-centre study, performed to investigate the effect of baseline characteristics and management changes over time on the all-cause mortality rate in mechanically ventilated patients in ICU. Our cohort includes 12,596 adult patients older than 18, associated with 12,755 distinct admissions in ICUs across 37 countries and receiving invasive and non-invasive mechanical ventilation. We carry out four different analysis. Initially we select typical mechanical ventilation parameters and evaluate the machine learning model on both, the overall cohort and a subgroup of patients admitted with respiratory disorders. Furthermore, we carry out sensitivity analysis to evaluate whether inclusion of variables related to the function of other organs, improve the predictive performance of the model for both the overall cohort as well as the subgroup of patients with respiratory disorders. RESULTS: Predictive performance of RNN-based model was higher with Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) of 0.72 (± 0.01) and Average Precision (AP) of 0.57 (± 0.01) in comparison to RF and LR for the overall patient dataset. Higher predictive performance was recorded in the subgroup of patients admitted with respiratory disorders with AUC of 0.75 (± 0.02) and AP of 0.65 (± 0.03). Inclusion of function of other organs further improved the performance to AUC of 0.79 (± 0.01) and AP 0.68 (± 0.02) for the overall patient dataset and AUC of 0.79 (± 0.01) and AP 0.72 (± 0.02) for the subgroup with respiratory disorders. CONCLUSION: The RNN-based model demonstrated better performance than RF and LR in patients in mechanical ventilation and its subgroup admitted with respiratory disorders. Clinical studies are needed to evaluate whether it impacts decision-making and patient outcomes. TRIAL REGISTRATION: NCT02731898 ( https://clinicaltrials.gov/ct2/show/NCT02731898 ), prospectively registered on April 8, 2016.

Propensity-Adjusted Comparison of Mortality of Elderly Versus Very Elderly Ventilated Patients.

BACKGROUND: The growing proportion of elderly intensive care patients constitutes a public health challenge. The benefit of critical care in these patients remains unclear. We compared outcomes in elderly versus very elderly subjects receiving mechanical ventilation. METHODS: In total, 5,557 mechanically ventilated subjects were included in our post hoc retrospective analysis, a subgroup of the VENTILA study. We divided the cohort into 2 subgroups on the basis of age: very elderly subjects (age ≥ 80 y; n = 1,430), and elderly subjects (age 65-79 y; n = 4,127). A propensity score on being very elderly was calculated. Evaluation of associations with 28-d mortality was done with logistic regression analysis. RESULTS: Very elderly subjects were clinically sicker as expressed by higher SAPS II scores (53 ± 18 vs 50 ± 18, P < .001), and their rates of plateau pressure < 30 cm H2O were higher, whereas other parameters did not differ. The 28-d mortality was higher in very elderly subjects (42% vs 34%, P < .001) and remained unchanged after propensity score adjustment (adjusted odds ratio 1.31 [95% CI 1.16-1.49], P < .001). CONCLUSIONS: Age was an independent and unchangeable risk factor for death in mechanically ventilated subjects. However, survival rates of very elderly subjects were > 50%. Denial of critical care based solely on age is not justified. (ClinicalTrials.gov registration NCT02731898.).

Evolution Over Time of Ventilatory Management and Outcome of Patients With Neurologic Disease.

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease.

Potential for bacteriophage therapy for Staphylococcus aureus pneumonia with influenza A coinfection.

The ability of influenza A virus to evolve, coupled with increasing antimicrobial resistance, could trigger an influenza pandemic with great morbidity and mortality. Much of the 1918 influenza pandemic mortality was likely due to bacterial coinfection, including Staphylococcus aureus pneumonia. S. aureus resists many antibiotics. The lack of new antibiotics suggests alternative antimicrobials, such as bacteriophages, are needed. Potential delivery routes for bacteriophage therapy (BT) include inhalation and intravenous injection. BT has recently been used successfully in compassionate access pulmonary infection cases. Phage lysins, enzymes that hydrolyze bacterial cell walls and which are bactericidal, are efficacious in animal pneumonia models. Clinical trials will be needed to determine whether BT can ameliorate disease in influenza and S. aureus coinfection.

Understanding Restrictive Versus Liberal Fluid Therapy for Major Abdominal Surgery Trial Results: Did Liberal Fluids Associate With Increased Endothelial Injury Markers?

Liberal fluid strategies in critically ill patients are associated with harm, thought to be due to endothelial and glycocalyx injury. As the restrictive versus liberal fluid therapy for major abdominal surgery trial not only failed to report survival benefit with restrictive fluids but was associated with a higher rate of acute kidney injury, we hypothesized that factors other than endothelial and glycocalyx injury were likely to account for these findings. Consequently, we measured injury biomarkers in a cohort of the restrictive versus liberal fluid therapy for major abdominal surgery trial. DESIGN: The restrictive versus liberal fluid therapy for major abdominal surgery trial was an international, randomized, assessor-blinded trial comparing restrictive with liberal IV fluid regimens that represented traditional care in patients undergoing major abdominal surgery. SETTING AND PATIENTS: Cohort of restrictive versus liberal fluid therapy for major abdominal surgery bloods was collected at a single major site (161 patients) prior to, day 1 and day 3 after surgery. INTERVENTION: Bloods were blindly and randomly batch analyzed for plasma markers of endothelial/glycocalyx injury-angiopoietin-1, angiopoietin-2, soluble tyrosine-protein kinase-2 receptor, soluble intracellular adhesion molecule-1, syndecan, and tumor necrosis factor-α. Data were examined as restrictive versus liberal enrollment groups and high versus low (± 5,000 mL) fluid groups. Differences were examined by linear mixed modeling. MEASUREMENT AND MAIN RESULTS: There were no significant differences in any biomarkers between the restrictive (n = 75) and liberal (n = 86) groups. When examined as low (n = 81) and high (n = 79) fluid groups, plasma angiopoietin-2 (p = 0.009) and soluble intracellular adhesion molecule-1 (p = 0.01) were elevated in the high fluid group. There were no differences in other biomarkers. CONCLUSIONS: Although these results are consistent with previous findings of vascular injury following liberal fluid therapy, they suggest alternative mechanisms underlie the clinical outcomes from restrictive versus liberal fluid therapy for major abdominal surgery study. CLINICALTRIALSGOV IDENTIFIER: NCT01424150.