Perfusion deficits may underlie lung and kidney injury in severe COVID-19 disease: insights from a multicenter international cohort study.

BACKGROUND: Lung perfusion defects, mainly due to endothelial and coagulation activation, are a key contributor to COVID-19 respiratory failure. COVID-19 patients may also develop acute kidney injury (AKI) because of renal perfusion deficit. We aimed to explore AKI-associated factors and the independent prediction of standardized minute ventilation (MV)-a proxy of alveolar dead space-on AKI onset and persistence in COVID-19 mechanically ventilated patients. METHODS: This is a multicenter observational cohort study. We enrolled 157 COVID-19 patients requiring mechanical ventilation and intensive care unit (ICU) admission. We collected clinical information, ventilation, and laboratory data. AKI was defined by the 2012 KDIGO guidelines and classified as transient or persistent according to serum creatinine criteria persistence within 48 h. Ordered univariate and multivariate logistic regression analyses were employed to identify variables associated with AKI onset and persistence. RESULTS: Among 157 COVID-19 patients on mechanical ventilation, 47% developed AKI: 10% had transient AKI, and 37% had persistent AKI. The degree of hypoxia was not associated with differences in AKI severity. Across increasing severity of AKI groups, despite similar levels of paCO2, we observed an increased MV and standardized MV, a robust proxy of alveolar dead space. After adjusting for other clinical and laboratory covariates, standardized MV remained an independent predictor of AKI development and persistence. D-dimer levels were higher in patients with persistent AKI. CONCLUSIONS: In critically ill COVID-19 patients with respiratory failure, increased wasted ventilation is independently associated with a greater risk of persistent AKI. These hypothesis-generating findings may suggest that perfusion derangements may link the pathophysiology of both wasted ventilation and acute kidney injury in our population.

Dynamic inflation prevents and standardized lung recruitment reverts volume loss associated with percutaneous tracheostomy during volume control ventilation: results from a Neuro-ICU population.

To determine how percutaneous tracheostomy (PT) impacts on respiratory system compliance (Crs) and end-expiratory lung volume (EELV) during volume control ventilation and to test whether a recruitment maneuver (RM) at the end of PT may reverse lung derecruitment. This is a single center, prospective, applied physiology study. 25 patients with acute brain injury who underwent PT were studied. Patients were ventilated in volume control ventilation. Electrical impedance tomography (EIT) monitoring and respiratory mechanics measurements were performed in three steps: (a) baseline, (b) after PT, and (c) after a standardized RM (10 sighs of 30 cmH2O lasting 3 s each within 1 min). End-expiratory lung impedance (EELI) was used as a surrogate of EELV. PT determined a significant EELI loss (mean reduction of 432 arbitrary units p = 0.049) leading to a reduction in Crs (55 ± 13 vs. 62 ± 13 mL/cmH2O; p < 0.001) as compared to baseline. RM was able to revert EELI loss and restore Crs (68 ± 15 vs. 55 ± 13 mL/cmH2O; p < 0.001). In a subgroup of patients (N = 8, 31%), we observed a gradual but progressive increase in EELI. In this subgroup, patients did not experience a decrease of Crs after PT as compared to patients without dynamic inflation. Dynamic inflation did not cause hemodynamic impairment nor raising of intracranial pressure. We propose a novel and explorative hyperinflation risk index (HRI) formula. Volume control ventilation did not prevent the PT-induced lung derecruitment. RM could restore the baseline lung volume and mechanics. Dynamic inflation is common during PT, it can be monitored real-time by EIT and anticipated by HRI. The presence of dynamic inflation during PT may prevent lung derecruitment.

Algor-ethics: charting the ethical path for AI in critical care.

The integration of Clinical Decision Support Systems (CDSS) based on artificial intelligence (AI) in healthcare is groundbreaking evolution with enormous potential, but its development and ethical implementation, presents unique challenges, particularly in critical care, where physicians often deal with life-threating conditions requiring rapid actions and patients unable to participate in the decisional process. Moreover, development of AI-based CDSS is complex and should address different sources of bias, including data acquisition, health disparities, domain shifts during clinical use, and cognitive biases in decision-making. In this scenario algor-ethics is mandatory and emphasizes the integration of 'Human-in-the-Loop' and 'Algorithmic Stewardship' principles, and the benefits of advanced data engineering. The establishment of Clinical AI Departments (CAID) is necessary to lead AI innovation in healthcare, ensuring ethical integrity and human-centered development in this rapidly evolving field.

Role of hemolysis on pulmonary arterial compliance and right ventricular systolic function after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with intravascular hemolysis which depletes endogenous nitric oxide (NO). The impact of hemolysis on pulmonary arterial compliance (PAC) and right ventricular systolic function has not been explored yet. We hypothesized that decreased NO availability is associated with worse PAC and right ventricular systolic function after CPB. METHODS: This is a secondary analysis of an observational cohort study in patients undergoing cardiac surgery with CPB at Massachusetts General Hospital, USA (2014-2015). We assessed PAC (stroke volume/pulmonary artery pulse pressure ratio), and right ventricular function index (RVFI) (systolic pulmonary arterial pressure/cardiac output), as well as NO consumption at 15 min, 4 h and 12 h after CPB. Patients were stratified by CPB duration. Further, we assessed the association between changes in NO consumption with PAC and RVFI between 15min and 4 h after CPB. RESULTS: PAC was lowest at 15min after CPB and improved over time (n = 50). RVFI was highest -worse right ventricular function- at CPB end and gradually decreased. Changes in hemolysis, PAC and RVFI differed over time by CPB duration. PAC inversely correlated with total pulmonary resistance (TPR). TPR and PAC positively and negatively correlated with RVFI, respectively. NO consumption between 15min and 4 h after CPB correlated with changes in PAC (-0.28 ml/mmHg, 95%CI -0.49 to -0.01, p = 0.012) and RVFI (0.14 mmHg*L-1*min, 95%CI 0.10 to 0.18, p < 0.001) after multivariable adjustments. CONCLUSION: PAC and RVFI are worse at CPB end and improve over time. Depletion of endogenous NO may contribute to explain changes in PAC and RVFI after CPB.

Pulmonary shunt in critical care: a practical approach with clinical scenarios.

BACKGROUND: Pulmonary shunt refers to the passage of venous blood into the arterial blood system bypassing the alveoli-blood gas exchange. Pulmonary shunt is defined by a drop in the physiologic coupling of lung ventilation and lung perfusion. This may consequently lead to respiratory failure. MAIN BODY: The pulmonary shunt assessment is often neglected. From a mathematical point of view, pulmonary shunt can be assessed by estimating the degree of mixing between oxygenated and deoxygenated blood. To compute the shunt, three key components are analyzed: the oxygen (O2) content in the central venous blood before gas exchange, the calculated O2 content in the pulmonary capillaries after gas exchange, and the O2 content in the arterial system, after the mixing of shunted and non-shunted blood. Computing the pulmonary shunt becomes of further importance in patients on extracorporeal membrane oxygenation (ECMO), as arterial oxygen levels may not directly reflect the gas exchange of the native lung. CONCLUSION: In this review, the shunt analysis and its practical clinical applications in different scenarios are discussed by using an online shunt simulator.

The "ZEEP-PEEP test" to evaluate the response to positive end-expiratory pressure delivered by helmet: A prospective physiologic study.

Introduction: The improvement in oxygenation after helmet application in hypoxemic patients may be explained by the alveolar recruitment obtained with positive end expiratory pressure (PEEP) or by the administration of a more accurate inspiratory fraction of oxygen (FiO2). We have designed the "ZEEP-PEEP test", capable to distinguish between the FiO2-related or PEEP-related oxygenation improvement. Our primary aim was to describe the use of this test during helmet CPAP to assess the oxygenation improvement attributable to PEEP application. Material and methods: We performed a prospective physiological study including adult critically ill patients. Respiratory and hemodynamic parameters were recorded before helmet application (PRE step), after helmet application without PEEP (ZEEP step) and after the application of the PEEP valve (PEEP step), while maintaining a constant FiO2. We defined as "PEEP responders" patients showing a PaO2/FiO2 ratio improvement ≥10% after PEEP application. Results: 93 patients were enrolled. Compared to the PRE step, PaO2/FiO2 ratio was significantly improved during helmet CPAP both at ZEEP and PEEP step (189 ± 55, 219 ± 74 and 241 ± 82 mmHg, respectively, p < 0.01). Both PEEP responders (41%) and non-responders showed a significant improvement of PaO2/FiO2 ratio after the application of helmet at ZEEP, PEEP responders also showed a significant improvement of oxygenation after PEEP application (208 ± 70 vs 267 ± 85, p < 0.01). Conclusions: Helmet CPAP improved oxygenation. This improvement was not only due to the PEEP effect, but also to the increase of the effective inspired FiO2. Performing the ZEEP-PEEP test may help to identify patients who benefit from PEEP.

The occurrence of pressure injuries and related risk factors in patients undergoing extracorporeal membrane oxygenation for respiratory failure: A retrospective single centre study.

INTRODUCTION: Limited data is available regarding the incidence of pressure injuries in patients who have undergone Extracorporeal Membrane Oxygenation (ECMO), a life-saving technique that provides respiratory support for hypoxemia that does not respond to conventional treatment. AIM: To assess the incidence of pressure injuries and identify the risk factors in Acute Respiratory Distress Syndrome patients receiving ECMO. METHODS: A retrospective observational study utilizing prospectively collected data was performed in an Italian intensive care unit, between 1 January 2012 and 30 April 2022 enrolling all consecutive patients with Acute Respiratory Distress Syndrome who underwent ECMO. RESULTS: One hundred patients were included in this study. 67 patients (67%) developed pressure injuries during their intensive care unit stay, with a median of 2 (1-3) sites affected. The subgroup of patients with pressure injuries was more hypoxic before ECMO implementation, received more frequent continuous renal replacement therapy and prone positioning, and showed prolonged ECMO duration, intensive care unit and hospital length of stay compared to patients without pressure injuries. The logistic model demonstrated an independent association between the pO2/FiO2 ratio prior to ECMO initiation, the utilization of the prone positioning during ECMO, and the occurrence of pressure injuries. CONCLUSIONS: The incidence of pressure injuries was elevated in patients with Adult Respiratory Distress Syndrome who received ECMO. The development of pressure injuries was found to be independently associated with hypoxemia before ECMO initiation and the utilization of prone positioning during ECMO. IMPLICATIONS FOR CLINICAL PRACTICE: Patients who require ECMO for respiratory failure are at a high risk of developing pressure injuries. To ensure optimal outcomes during ECMO implementation and treatment, it is vital to implement preventive measures and to closely monitor skin health in at-risk areas.

Successful Versus Failed Transition From Controlled Ventilation to Pressure Support Ventilation in COVID-19 Patients: A Retrospective Cohort Study.

OBJECTIVES: In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation (PSV) is a key objective when the patient's respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes. DESIGN: Retrospective observational cohort study. SETTING: Twenty-four Italian ICUs from February 2020 to May 2020. PATIENTS: Mechanically ventilated ICU patients with COVID-19-induced respiratory failure. INTERVENTION: The transition period from CMV to PSV was evaluated. We defined it as "failure of assisted breathing" if the patient returned to CMV within the first 72 hours. MEASUREMENTS AND MAIN RESULTS: Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao2/Fio2 ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99-1.00; p = 0.003). Patients in the success group displayed a better trend in Pao2/Fio2, Paco2, plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42-3.06; p < 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d; p < 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d, p = 0.04). CONCLUSIONS: Our study emphasizes that the Pao2/Fio2 ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes.

Long term outcome in patients treated with veno-venous extracorporeal membrane oxygenation: A prospective observational study.

INTRODUCTION: Over the last few decades, the use of veno-venous extracorporeal membrane oxygenation (VV-ECMO) support for severe respiratory failure has increased. AIM: This study aimed to assess the long-term outcomes of patients treated with VV-ECMO for respiratory failure. METHODS: We performed a single-centre prospective evaluation of patients on VV-ECMO who were successfully discharged from the intensive care unit of an Italian University Hospital between January 2018 and May 2021. The enrolled patients underwent follow-up evaluations at 6 and 12 months after ICU discharge. The follow-up team performed psychological and functional assessments using the following instruments: Hospital Anxiety and Depression Scale (HADS), Post-traumatic Stress Disorder Symptom Severity Scale (PTSS-10), Euro Quality Five Domains Five Levels (EQ-5L-5D), and 6-minute walk test. RESULTS: We enrolled 33 patients who were evaluated at a follow-up clinic. The median patient age was 51 years (range: 45-58 years). The median duration of VV-ECMO support was 12 (9-19) days and the length of ICU stay was 23 (18-42) days. A HADS score higher than 14 was reported in 8 (24 %) and 7 (21 %) patients at the six- and twelve-month visit, respectively. PTSS-10 total score ≥ 35 points was present in three (9 %) and two (6 %) patients at the six- and twelve-month examination. The median EQ-5L-5D-VAS was respectively 80 (80-90) and 87.5 (70-95). The PTSS-10 score significantly decreased from six to 12 months in COVID-19 survivors (p = 0.024). CONCLUSIONS: In this cohort of patients treated with VV-ECMO, cognitive and psychological outcomes were good and comparable to those of patients with Adult Respiratory Distress Syndrome (ARDS) managed without ECMO. IMPLICATIONS FOR CLINICAL PRACTICE: The findings of this study confirm the need for long-term follow-up and rehabilitation programs for every ICU survivor after discharge. COVID-19 survivors treated with VV-ECMO had outcomes comparable to those reported in non-COVID patients.

Expiratory Muscle Activity Counteracts Positive End-Expiratory Pressure and Is Associated with Fentanyl Dose in Patients with Acute Respiratory Distress Syndrome.

Rationale: Hypoxemia during mechanical ventilation might be worsened by expiratory muscle activity, which reduces end-expiratory lung volume through lung collapse. A proposed mechanism of benefit of neuromuscular blockade in acute respiratory distress syndrome (ARDS) is the abolition of expiratory efforts. This may contribute to the restoration of lung volumes. The prevalence of this phenomenon, however, is unknown. Objectives: To investigate the incidence and amount of end-expiratory lung impedance (EELI) increase after the administration of neuromuscular blocking agents (NMBAs), clinical factors associated with this phenomenon, its impact on regional lung ventilation, and any association with changes in pleural pressure. Methods: We included mechanically ventilated patients with ARDS monitored with electrical impedance tomography (EIT) who received NMBAs in one of two centers. We measured changes in EELI, a surrogate for end-expiratory lung volume, before and after NMBA administration. In an additional 10 patients, we investigated the characteristic signatures of expiratory muscle activity depicted by EIT and esophageal catheters simultaneously. Clinical factors associated with EELI changes were assessed. Measurements and Main Results: We included 46 patients, half of whom showed an increase in EELI of >10% of the corresponding Vt (46.2%; IQR, 23.9-60.9%). The degree of EELI increase correlated positively with fentanyl dosage and negatively with changes in end-expiratory pleural pressures. This suggests that expiratory muscle activity might exert strong counter-effects against positive end-expiratory pressure that are possibly aggravated by fentanyl. Conclusions: Administration of NMBAs during EIT monitoring revealed activity of expiratory muscles in half of patients with ARDS. The resultant increase in EELI had a dose-response relationship with fentanyl dosage. This suggests a potential side effect of fentanyl during protective ventilation.

Noninvasive Ventilation Before Intubation and Mortality in Patients Receiving Extracorporeal Membrane Oxygenation for COVID-19: An Analysis of the Extracorporeal Life Support Organization Registry.

Bilevel-positive airway pressure (BiPAP) is a noninvasive respiratory support modality which reduces effort in patients with respiratory failure. However, it may increase tidal ventilation and transpulmonary pressure, potentially aggravating lung injury. We aimed to assess if the use of BiPAP before intubation was associated with increased mortality in adult patients with coronavirus disease 2019 (COVID-19) who received venovenous extracorporeal membrane oxygenation (ECMO). We used the Extracorporeal Life Support Organization Registry to analyze adult patients with COVID-19 supported with venovenous ECMO from January 1, 2020, to December 31, 2021. Patients treated with BiPAP were compared with patients who received other modalities of respiratory support or no respiratory support. A total of 9,819 patients from 421 centers were included. A total of 3,882 of them (39.5%) were treated with BiPAP before endotracheal intubation. Patients supported with BiPAP were intubated later (4.3 vs . 3.3 days, p < 0.001) and showed higher unadjusted hospital mortality (51.7% vs. 44.9%, p < 0.001). The use of BiPAP before intubation and time from hospital admission to intubation resulted as independently associated with increased hospital mortality (odds ratio [OR], 1.32 [95% confidence interval {CI}, 1.08-1.61] and 1.03 [1-1.06] per day increase). In ECMO patients with severe acute respiratory failure due to COVID-19, the extended use of BiPAP before intubation should be regarded as a risk factor for mortality.

A non-invasive continuous and real-time volumetric monitoring in spontaneous breathing subjects based on bioimpedance-ExSpiron®Xi: a validation study in healthy volunteers.

Tidal volume (TV) monitoring breath-by-breath is not available at bedside in non-intubated patients. However, TV monitoring may be useful to evaluate the work of breathing. A non-invasive device based on bioimpedance provides continuous and real-time volumetric tidal estimation during spontaneous breathing. We performed a prospective study in healthy volunteers aimed at evaluating the accuracy, the precision and the trending ability of measurements of ExSpiron®Xi as compared with the gold standard (i.e. spirometry). Further, we explored whether the differences between the 2 devices would be improved by the calibration of ExSpiron®Xi with a pre-determined tidal volume. Analysis accounted for the repeated nature of measurements within each subject. We enrolled 13 healthy volunteers, including 5 men and 8 women. Tidal volume, TV/ideal body weight (IBW) and respiratory rate (RR) measured with spirometer (TVSpirometer) and with ExSpiron®Xi (TVExSpiron) showed a robust correlation, while minute ventilation (MV) showed a weak correlation, in both non/calibrated and calibrated steps. The analysis of the agreement showed that non-calibrated TVExSpiron underestimated TVspirometer, while in the calibrated steps, TVExSpiron overestimated TVspirometer. The calibration procedure did not reduce the average absolute difference (error) between TVSpirometer and TVExSpiron. This happened similarly for TV/IBW and MV, while RR showed high accuracy and precision. The trending ability was excellent for TV, TV/IBW and RR. The concordance rate (CR) was >95% in both calibrated and non-calibrated measurements. The trending ability of minute ventilation was limited. Absolute error for both calibrated and not calibrated values of TV, TV/IBW and MV accounting for repeated measurements was variably associated with BMI, height and smoking status. Conclusions: Non-invasive TV, TV/IBW and RR estimation by ExSpiron®Xi was strongly correlated with tidal ventilation according to the gold standard spirometer technique. This data was not confirmed for MV. The calibration of the device did not improve its performance. Although the accuracy of ExSpiron®Xi was mild and the precision was limited for TV, TV/IBW and MV, the trending ability of the device was strong specifically for TV, TV/IBW and RR. This makes ExSpiron®Xi a non-invasive monitoring system that may detect real-time tidal volume ventilation changes and then suggest the need to better optimize the patient ventilatory support.

Gas Humidification During Helmet Continuous Positive Airway Pressure: A Crossover Randomized Physiologic Study in Healthy Subjects.

BACKGROUND: In the last decades, the use of the helmet interface to deliver noninvasive respiratory support has steadily increased. When delivering oxygen therapy, conditioning of inspired gas is mandatory, as the water content of medical gas is neglectable. To minimize the risk of airway damage, it is recommended to achieve an absolute humidity greater than 10 mg H2O/L. The primary aim of the study was to assess the performance of 3 different heated humidifiers to condition gas during helmet continuous positive airway pressure and to compare them with a setting without active humidification. METHODS: We performed a crossover randomized physiological study in healthy volunteers. Absolute humidity, relative humidity, and temperature were measured during 4 steps (no humidification and the 3 heated humidifiers, performed in a randomized order) and at 3 time points (after 1, 5, and 10 minutes). RESULTS: Eight subjects participated to the study. Without active humidification, absolute humidity was constantly below the recommended level. All humidifiers conditioned the inspired gases to an average absolute humidity greater than 10 mg H2O/L. Overall, the best performance, in terms of absolute humidity, was obtained with H900 (19.74 ± 0.50 mg H2O/L), followed by TurbH2O (-6.82 mg H2O/L vs H900; 95% confidence interval, -8.49 to -5.14; P < .05) and F&P 810 (-9.03 mg H2O/L vs H900; 95% confidence interval, -10.70 to -7.35; P < .05). CONCLUSIONS: Active humidification is required to achieve adequate conditioning of inspired gas during helmet continuous positive airway pressure. The choice between different humidifiers available on the market should be made according to the local needs and expertise.

Individual response in patient's effort and driving pressure to variations in assistance during pressure support ventilation.

BACKGROUND: During Pressure Support Ventilation (PSV) an inspiratory hold allows to measure plateau pressure (Pplat), driving pressure (∆P), respiratory system compliance (Crs) and pressure-muscle-index (PMI), an index of inspiratory effort. This study aims [1] to assess systematically how patient's effort (estimated with PMI), ∆P and tidal volume (Vt) change in response to variations in PSV and [2] to confirm the robustness of Crs measurement during PSV. METHODS: 18 patients recovering from acute respiratory failure and ventilated by PSV were cross-randomized to four steps of assistance above (+ 3 and + 6 cmH2O) and below (-3 and -6 cmH2O) clinically set PS. Inspiratory and expiratory holds were performed to measure Pplat, PMI, ∆P, Vt, Crs, P0.1 and occluded inspiratory airway pressure (Pocc). Electromyography of respiratory muscles was monitored noninvasively from body surface (sEMG). RESULTS: As PSV was decreased, Pplat (from 20.5 ± 3.3 cmH2O to 16.7 ± 2.9, P < 0.001) and ∆P (from 12.5 ± 2.3 to 8.6 ± 2.3 cmH2O, P < 0.001) decreased much less than peak airway pressure did (from 21.7 ± 3.8 to 9.7 ± 3.8 cmH2O, P < 0.001), given the progressive increase of patient's effort (PMI from -1.2 ± 2.3 to 6.4 ± 3.2 cmH2O) in line with sEMG of the diaphragm (r = 0.614; P < 0.001). As ∆P increased linearly with Vt, Crs did not change through steps (P = 0.119). CONCLUSION: Patients react to a decrease in PSV by increasing inspiratory effort-as estimated by PMI-keeping Vt and ∆P on a desired value, therefore, limiting the clinician's ability to modulate them. PMI appears a valuable index to assess the point of ventilatory overassistance when patients lose control over Vt like in a pressure-control mode. The measurement of Crs in PSV is constant-likely suggesting reliability-independently from the level of assistance and patient's effort.

Airway Closure in Patients With Cardiogenic Pulmonary Edema as a Cause of Driving Pressure Overestimation: The "Uncorking Effect".

Airway closure is an underestimated phenomenon reported in hypoxemic respiratory failure under mechanical ventilation, during cardiac arrest, and in patients who are obese. Because airway and alveolar pressure are not communicating, it leads to an overestimation of driving pressure and an underestimation of respiratory system compliance. Airway closure also favors denitrogenation atelectasis. To date, it has been described mainly in patients with ARDS and those with obesity. We describe three cases of airway closure in patients with hydrostatic pulmonary edema caused by cardiogenic shock, highlighting its resolution in a limited period of time (24 h) as pulmonary edema resolved. The waveforms show a biphasic reopening that we refer to as the "uncorking effect". The detection of airway closure may require setting positive end-expiratory pressure at or above the airway opening pressure to avoid the overestimation of driving pressure.

Effect of a quality improvement program on compliance to the sepsis bundle in non-ICU patients: a multicenter prospective before and after cohort study.

Objective: Sepsis and septic shock are major challenges and economic burdens to healthcare, impacting millions of people globally and representing significant causes of mortality. Recently, a large number of quality improvement programs focused on sepsis resuscitation bundles have been instituted worldwide. These educational initiatives have been shown to be associated with improvements in clinical outcomes. We aimed to evaluate the impact of a multi-faceted quality implementing program (QIP) on the compliance of a "simplified 1-h bundle" (Sepsis 6) and hospital mortality of severe sepsis and septic shock patients out of the intensive care unit (ICU). Methods: Emergency departments (EDs) and medical wards (MWs) of 12 academic and non-academic hospitals in the Lombardy region (Northern Italy) were involved in a multi-faceted QIP, which included educational and organizational interventions. Patients with a clinical diagnosis of severe sepsis or septic shock according to the Sepsis-2 criteria were enrolled in two different periods: from May 2011 to November 2011 (before-QIP cohort) and from August 2012 to June 2013 (after-QIP cohort). Measurements and main results: The effect of QIP on bundle compliance and hospital mortality was evaluated in a before-after analysis. We enrolled 467 patients in the before-QIP group and 656 in the after-QIP group. At the time of enrollment, septic shock was diagnosed in 50% of patients, similarly between the two periods. In the after-QIP group, we observed increased compliance to the "simplified rapid (1 h) intervention bundle" (the Sepsis 6 bundle - S6) at three time-points evaluated (1 h, 13.7 to 18.7%, p = 0.018, 3 h, 37.1 to 48.0%, p = 0.013, overall study period, 46.2 to 57.9%, p < 0.001). We then analyzed compliance with S6 and hospital mortality in the before- and after-QIP periods, stratifying the two patients' cohorts by admission characteristics. Adherence to the S6 bundle was increased in patients with severe sepsis in the absence of shock, in patients with serum lactate <4.0 mmol/L, and in patients with hypotension at the time of enrollment, regardless of the type of admission (from EDs or MWs). Subsequently, in an observational analysis, we also investigated the relation between bundle compliance and hospital mortality by logistic regression. In the after-QIP cohort, we observed a lower in-hospital mortality than that observed in the before-QIP cohort. This finding was reported in subgroups where a higher adherence to the S6 bundle in the after-QIP period was found. After adjustment for confounders, the QIP appeared to be independently associated with a significant improvement in hospital mortality. Among the single S6 procedures applied within the first hour of sepsis diagnosis, compliance with blood culture and antibiotic therapy appeared significantly associated with reduced in-hospital mortality. Conclusion: A multi-faceted QIP aimed at promoting an early simplified bundle of care for the management of septic patients out of the ICU was associated with improved compliance with sepsis bundles and lower in-hospital mortality.

Sustainable production and pharmaceutical applications of ß-glucan from microbial sources.

ß-glucans are a large class of complex polysaccharides found in abundant sources. Our dietary sources of ß-glucans are cereals that include oats and barley, and non-cereal sources can consist of mushrooms, microalgae, bacteria, and seaweeds. There is substantial clinical interest in ß-glucans; as they can be used for a variety of diseases including cancer and cardiovascular conditions. Suitable sources of ß-glucans for biopharmaceutical applications include bacteria, microalgae, mycelium, and yeast. Environmental factors including culture medium can influence the biomass and ultimately ß-glucan content. Therefore, cultivation conditions for the above organisms can be controlled for sustainable enhanced production of ß-glucans. This review discusses the various sources of ß-glucans and their cultivation conditions that may be optimised to exploit sustainable production. Finally, this article discusses the immune-modulatory potential of ß-glucans from these sources.