Latest advances in glucose-responsive microneedle-based systems for transdermal insulin delivery.

The development of a self-regulated minimally invasive system for insulin delivery can be considered as the holy grail in the field of diabetes mellitus. A delivery system capable of releasing insulin in response to blood glucose levels would significantly improve the quality of life of diabetic patients, eliminating the need for frequent finger-prick tests and providing better glycaemic control with lower risk of hypoglycaemia. In this context, the latest advances in glucose-responsive microneedle-based transdermal insulin delivery are here compiled with a thorough analysis of the delivery mechanisms and challenges lying ahead in their clinical translation. Two main groups of microneedle-based systems have been developed so far: glucose oxidase-containing and phenylboronic acid-containing systems. Both strategies in combination have also been tested and two other novel strategies are under development, namely electronic closed-loop and glucose transporter-based systems. Results from preclinical studies conducted using these different types of glucose-triggered release systems are comprehensively discussed. Altogether, this analysis from both a mechanistic and translational perspective will provide rationale and/or guidance for future trends in the research hotspot of glucose-responsive microneedle-based insulin delivery systems.

An overview of in vitro 3D models of the blood-brain barrier as a tool to predict the in vivo permeability of nanomedicines.

The blood-brain barrier (BBB) prevents efficient drug delivery to the central nervous system. As a result, brain diseases remain one of the greatest unmet medical needs. Understanding the tridimensional structure of the BBB helps gain insight into the pathology of the BBB and contributes to the development of novel therapies for brain diseases. Therefore, 3D models with an ever-growing sophisticated complexity are being developed to closely mimic the human neurovascular unit. Among these 3D models, hydrogel-, spheroid- and organoid-based static BBB models have been developed, and so have microfluidic-based BBB-on-a-chip models. The different 3D preclinical models of the BBB, both in health and disease, are here reviewed, from their development to their application for permeability testing of nanomedicines across the BBB, discussing the advantages and disadvantages of each model. The validation with data from in vivo preclinical data is also discussed in those cases where provided.

Incidence, Outcomes and Risk Factors of Recurrent Ventilator Associated Pneumonia in COVID-19 Patients: A Retrospective Multicenter Study.

Background: High incidence of ventilator associated pneumonia (VAP) has been reported in critically ill patients with COVID-19. Among these patients, we aimed to assess the incidence, outcomes and risk factors of VAP recurrences. Methods: We conducted an observational retrospective study in three French intensive care units (ICUs). Patients admitted for a documented COVID-19 from March 2020 to May 2021 and requiring mechanical ventilation (MV) for ≥48 h were included. The study main outcome was the incidence of VAP recurrences. Secondary outcomes were the duration of MV, ICU and hospital length of stay and mortality according to VAP and recurrences. We also assessed the factors associated with VAP recurrences. Results: During the study period, 398 patients met the inclusion criteria. A total of 236 (59%) of them had at least one VAP episode during their ICU stay and 109 (46%) of these patients developed at least one recurrence. The incidence of VAP recurrence considering death and extubation as competing events was 29.6% (IC = [0.250−0.343]). Seventy-eight percent of recurrences were due to the same bacteria (relapses). Patients with a VAP recurrence had a longer duration of MV as compared with one VAP and no VAP patients (41 (25−56) vs. 16 (8−30) and 10 (5−18) days; p < 0.001) and a longer ICU length of stay (46 (29−66) vs. 22 (12−36) and 14 (9−25) days; p < 0.001). The 90-day mortality was higher in the recurrence group as compared with the no VAP group only (31.2 vs. 21.0% (p = 0.021)). In a multivariate analysis including bacterial co-infection at admission, the use of immunosuppressive therapies and the bacteria responsible for the first VAP episode, the duration of MV was the only factor independently associated with VAP recurrence. Conclusion: In COVID-19 associated respiratory failure, recurrences affected 46% of patients with a first episode of VAP. VAP recurrences were mainly relapses and were associated with a prolonged duration of MV and ICU length of stay but not with a higher mortality. MV duration was the only factor associated with recurrences.

Sistemas de liberación prolongada de opioides: Analgesia y dependencia / Extended-release delivery systems of opioids: Analgesia and dependence

El consumo de analgésicos opioides ha experimentado un vertiginoso ascenso en las últimas décadas a nivel mundial. Este elevado consumo está relacionado con el aumento del número de prescripciones de opioides para el tratamiento del dolor crónico y por el aumento de la dependencia a opioides. Los analgésicos opioides tienen una corta duración de acción, siendo necesarias múltiples administraciones para obtener analgesia prolongada. El empleo de formulaciones de liberación prolongada permite espaciar los intervalos posológicos y estabilizar las concentraciones máximas de fármaco en sangre, favoreciendo el cumplimiento terapéutico y reduciendo el riesgo de desarrollar adicción. Sin embargo, estas formulaciones llevan dosis más altas de analgésicos opioides que las hacen más susceptibles de ser alteradas. Así, los avances en tecnología farmacéutica más recientes se han orientado hacia la aplicación de recursos tecnológicos disuasorios de su utilización por vías de administración alternativas con fines no terapéuticos. A su vez, los sistemas de liberación modificada también juegan un papel esencial en el tratamiento de la adicción a opioides: con el desarrollo de sistemas de administración parenteral capaces de prolongar la liberación de opioides durante meses se consigue superar una de las mayores dificultades para alcanzar el éxito del tratamiento en este tipo de pacientes como es el cumplimiento terapéutico. En este artículo se realiza una revisión bibliográfica de los diferentes sistemas de liberación prolongada de opioides que se encuentran actualmente autorizados en Europa y/o en Estados Unidos para el tratamiento del dolor y de la dependencia a opioides. (AU)

The consumption of opioid analgesics has increased drastically in the last decades worldwide. This high consumption is linked with a surge in the number of opioid prescriptions for the treatment of chronic pain and a surge in opioid misuse and addiction. Opioid analgesics have a short duration of action, making necessary frequent administrations to provide extended analgesia. The use of prolonged-release formulations enables dosing intervals to be spaced out and drug blood levels to be stabilized, improving therapeutic compliance, and reducing the likelihood of developing addiction. However, these formulations contain higher doses of opioid analgesics which make them more susceptible to be manipulated. Hence, the most recent advances in pharmaceutical technology have been oriented towards the application of abuse deterrent technologies aiming to prevent their administration through alternative routes. Moreover, prolonged- release systems also play an essential role in the treatment of opioid addictions with the development of parenteral dosage forms capable of prolonging opioid release for months that help overcome one of the most important drawbacks in achieving treatment success, namely, patient compliance. We review herein the different prolonged-release opioid dosage forms currently approved in Europe and/or the United States for the treatment of pain and opioid dependence. (AU)

Effects of a Chair Positioning Session on Awake Non-Intubated COVID-19 Pneumonia Patients: A Multicenter, Observational, and Pilot Study Using Lung Ultrasound.

BACKGROUND: LUS is a validated tool for the management of COVID-19 pneumonia. Chair positioning (CP) may have beneficial effects on oxygenation and lung aeration, and may be an easier alternative to PP. This study assessed the effects of a CP session on oxygenation and lung aeration (LA) changes in non-intubated COVID-19 patients. METHODS: A retrospective multicenter study was conducted in an ICU. We analyzed data from LUS exams and SpO2:FiO2 performed before/after a CP session in non-intubated COVID-19 patients. Patients were divided into groups of responders or non-responders in terms of oxygenation or LA. RESULTS: Thirty-three patients were included in the study; fourteen (44%) were oxygenation non-responders and eighteen (56%) were oxygenation responders, while thirteen (40.6%) and nineteen (59.4%) patients were classified as LA non-responders and responders, respectively. Changes in oxygenation and LA before/after a CP session were not correlated (r = -0.19, p = 0.3, 95% CI: -0.5-0.17). The reaeration scores did not differ between oxygenation responders and non-responders (1 (-0.75-3.75) vs. 4 (-1-6), p = 0.41). The LUS score was significantly correlated with SpO2:FiO2 before a CP session (r = 0.37, p = 0.04, 95% CI: 0.03-0.64) but not after (r = 0.17, p = 0.35, 95% CI: -0.19-0.50). CONCLUSION: A CP session was associated with improved oxygenation and LA in more than half of the non-intubated COVID-19 patients.

Impact of Dexamethasone and Inhaled Nitric Oxide on Severe Acute Kidney Injury in Critically Ill Patients with COVID-19.

Background: Acute kidney injury (AKI) is the second most frequent condition after acute respiratory distress syndrome (ARDS) in critically ill patients with severe COVID-19 and is strongly associated with mortality. The aim of this multicentric study was to assess the impact of the specific treatments of COVID-19 and ARDS on the risk of severe AKI in critically ill COVID-19 patients. Methods: In this cohort study, data from consecutive patients older than 18 years admitted to 6 ICUs for COVID-19-related ARDS requiring invasive mechanical ventilation were included. The incidence and severity of AKI, defined according to the 2012 KDIGO definition, were monitored during the entire ICU stay until day 90. Patients older than 18 years admitted to the ICU for COVID-19-related ARDS requiring invasive mechanical ventilation were included. Results: 164 patients were included in the final analysis; 97 (59.1%) displayed AKI, of which 39 (23.8%) had severe stage 3 AKI, and 21 (12.8%) required renal replacement therapy (RRT). In univariate analysis, severe AKI was associated with angiotensin-converting enzyme inhibitors (ACEI) exposure (p = 0.016), arterial hypertension (p = 0.029), APACHE-II score (p = 0.004) and mortality at D28 (p = 0.008), D60 (p < 0.001) and D90 (p < 0.001). In multivariate analysis, the factors associated with the onset of stage 3 AKI were: exposure to ACEI (OR: 4.238 (1.307−13.736), p = 0.016), APACHE II score (without age) (OR: 1.138 (1.044−1.241), p = 0.003) and iNO (OR: 5.694 (1.953−16.606), p = 0.001). Prone positioning (OR: 0.234 (0.057−0.967), p = 0.045) and dexamethasone (OR: 0.194 (0.053−0.713), p = 0.014) were associated with a decreased risk of severe AKI. Conclusions: Dexamethasone was associated with the prevention of the risk of severe AKI and RRT, and iNO was associated with severe AKI and RRT in critically ill patients with COVID-19. iNO should be used with caution in COVID-19-related ARDS.

Pre-Ischemic Hypothermic Oxygenated Perfusion Alleviates Protective Molecular Markers of Ischemia-Reperfusion Injury in Rat Liver.

To expand the pool of organs, hypothermic oxygenated perfusion (HOPE), one of the most promising perfusion protocols, is currently performed after cold storage (CS) at transplant centers (HOPE-END). We investigated a new timing for HOPE, hypothesizing that performing HOPE before CS (HOPE-PRE) could boost mitochondrial protection allowing the graft to better cope with the accumulation of oxidative stress during CS. We analyzed liver injuries at 3 different levels. Histologic analysis demonstrated that, compared to classical CS (CTRL), the HOPE-PRE group showed significantly less ischemic necrosis compared to CTRL vs HOPE-END. From a biochemical standpoint, transaminases were lower after 2 hours of reperfusion in the CTRL vs HOPE-PRE group, which marked decreased liver injury. qPCR analysis on 37 genes involved in ischemia-reperfusion injury revealed protection in HOPE-PRE and HOPE-END compared to CTRL mediated through similar pathways. However, the CTRL vs HOPE-PRE group demonstrated an increased transcriptional level for protective genes compared to the CTRL vs HOPE-END group. This study provides insights on novel biomarkers that could be used in the clinic to better characterize graft quality improving transplantation outcomes.

Anti-cardiolipin IgG autoantibodies associate with circulating extracellular DNA in severe COVID-19.

Whereas the detection of antiphospholipid autoantibodies (aPL) in COVID-19 is of increasing interest, their role is still unclear. We analyzed a large aPL panel in 157 patients with COVID-19 according to the disease severity. We also investigated a potential association between aPL and extracellular DNA (exDNA, n = 85) or circulating markers of neutrophil extracellular traps (NET) such as citrullinated histones H3 (CitH3, n = 49). A total of 157 sera of patients infected by SARS-CoV-2 were collected. A large aPL panel including lupus anticoagulant, anti-cardiolipin and anti-beta-2 glycoprotein I (IgG, IgM and IgA), anti-phosphatidylethanolamine IgA, anti-prothrombin (IgG and IgM) was retrospectively analyzed according to the disease severity. We found a total aPL prevalence of 54.8% with almost half of the cases having aCL IgG. Within an extended panel of aPL, only aCL IgG were associated with COVID-19 severity. Additionally, severe patients displayed higher CitH3 levels than mild patients. Interestingly, we highlighted a significant association between the levels of aCL IgG and exDNA only in aCL positive patients with severe disease. In conclusion, we showed a significant link between aPL, namely aCL IgG, and circulating exDNA in patients with severe form of COVID-19, that could exacerbate the thrombo-inflammatory state related to disease severity.

Embolization therapy with microspheres for the treatment of liver cancer: State-of-the-art of clinical translation.

Embolization with microspheres is a therapeutic strategy based on the selective occlusion of the blood vessels feeding a tumor. This procedure is intraarterially performed in the clinical setting for the treatment of liver cancer. The practice has evolved over the last decade through the incorporation of drug loading ability, biodegradability and imageability with the subsequent added functionality for the physicians and improved clinical outcomes for the patients. This review highlights the evolution of the embolization systems developed through the analysis of the marketed embolic microspheres for the treatment of malignant hepatocellular carcinoma, namely the most predominant form of liver cancer. Embolic microspheres for the distinct modalities of embolization (i.e., bland embolization, chemoembolization and radioembolization) are here comprehensively compiled with emphasis on material characteristics and their impact on microsphere performance. Moreover, the future application of the embolics under clinical investigation is discussed along with the scientific and regulatory challenges ahead in the field. STATEMENT OF SIGNIFICANCE: Embolization therapy with microspheres is currently used in the clinical setting for the treatment of most liver cancer conditions. The progressive development of added functionalities on embolic microspheres (such as biodegradability, imageability or drug and radiopharmaceutical loading capability) provides further benefit to patients and widens the therapeutic armamentarium for physicians towards truly personalized therapies. Therefore, it is important to analyze the possibilities that advanced biomaterials offer in the field from a clinical translational perspective to outline the future trends in therapeutic embolization.

Ultra-early initiation of postoperative rehabilitation in the post-anaesthesia care unit after major thoracic surgery: case-control study.

BACKGROUND: Physiotherapy is a major cornerstone of enhanced rehabilitation after surgery (ERAS) and reduces the development of atelectasis after thoracic surgery. By initiating physiotherapy in the post-anaesthesia care unit (PACU), the aim was to evaluate whether the ultra-early initiation of rehabilitation (in the first hour following tracheal extubation) would improve the outcomes of patients undergoing elective thoracic surgery. METHODS: A case-control study with a before-and-after design was conducted. From a historical control group, patients were paired at a 3:1 ratio with an intervention group. This group consisted of patients treated with the ultra-early rehabilitation programme after elective thoracic surgery (clear fluids, physiotherapy, and ambulation). The primary outcome was the incidence of postoperative atelectasis and/or pneumonia during the hospital stay. RESULTS: After pairing, 675 patients were allocated to the historical control group and 225 patients to the intervention group. A significant decrease in the incidence of postoperative atelectasis and/or pneumonia was found in the latter (11.4 versus 6.7 per cent respectively; P = 0.042) and remained significant on multivariate analysis (OR 0.53, 95 per cent c.i. 0.26 to 0.98; P = 0.045). A subgroup analysis of the intervention group showed that early ambulation during the PACU stay was associated with a further significant decrease in the incidence of postoperative atelectasis and/or pneumonia (2.2 versus 9.5 per cent; P = 0.012). CONCLUSIONS: Ultra-early rehabilitation in the PACU was associated with a decrease in the incidence of postoperative atelectasis and/or pneumonia after major elective thoracic surgery.

Left ventricular longitudinal strain variations assessed by speckle-tracking echocardiography after a passive leg raising maneuver in patients with acute circulatory failure to predict fluid responsiveness: A prospective, observational study.

BACKGROUND: An association was reported between the left ventricular longitudinal strain (LV-LS) and preload. LV-LS reflects the left cardiac function curve as it is the ratio of shortening over diastolic dimension. The aim of this study was to determine the sensitivity and specificity of LV-LS variations after a passive leg raising (PLR) maneuver to predict fluid responsiveness in intensive care unit (ICU) patients with acute circulatory failure (ACF). METHODS: Patients with ACF were prospectively included. Preload-dependency was defined as a velocity time integral (VTI) variation greater than 10% between baseline (T0) and PLR (T1), distinguishing the preload-dependent (PLD+) group and the preload-independent (PLD-) group. A 7-cycles, 4-chamber echocardiography loop was registered at T0 and T1, and strain analysis was performed off-line by a blind clinician. A general linear model for repeated measures was used to compare the LV-LS variation (T0 to T1) between the two groups. RESULTS: From June 2018 to August 2019, 60 patients (PLD+ = 33, PLD- = 27) were consecutively enrolled. The VTI variations after PLR were +21% (±8) in the PLD+ group and -1% (±7) in the PLD- group (p<0.01). Mean baseline LV-LS was -11.3% (±4.2) in the PLD+ group and -13.0% (±4.2) in the PLD- group (p = 0.12). LV-LS increased in the whole population after PLR +16.0% (±4.0) (p = 0.04). The LV-LS variations after PLR were +19.0% (±31) (p = 0.05) in the PLD+ group and +11.0% (±38) (p = 0.25) in the PLD- group, with no significant difference between the two groups (p = 0.08). The area under the curve for the LV-LS variations between T0 and T1 was 0.63 [0.48-0.77]. CONCLUSION: Our study confirms that LV-LS is load-dependent; however, the variations in LV-LS after PLR is not a discriminating criterion to predict fluid responsiveness of ICU patients with ACF in this cohort.

Association between mortality and highly antimicrobial-resistant bacteria in intensive care unit-acquired pneumonia.

Data on the relationship between antimicrobial resistance and mortality remain scarce, and this relationship needs to be investigated in intensive care units (ICUs). The aim of this study was to compare the ICU mortality rates between patients with ICU-acquired pneumonia due to highly antimicrobial-resistant (HAMR) bacteria and those with ICU-acquired pneumonia due to non-HAMR bacteria. We conducted a multicenter, retrospective cohort study using the French National Surveillance Network for Healthcare Associated Infection in ICUs ("REA-Raisin") database, gathering data from 200 ICUs from January 2007 to December 2016. We assessed all adult patients who were hospitalized for at least 48 h and presented with ICU-acquired pneumonia caused by S. aureus, Enterobacteriaceae, P. aeruginosa, or A. baumannii. The association between pneumonia caused by HAMR bacteria and ICU mortality was analyzed using the whole sample and using a 1:2 matched sample. Among the 18,497 patients with at least one documented case of ICU-acquired pneumonia caused by S. aureus, Enterobacteriaceae, P. aeruginosa, or A. baumannii, 3081 (16.4%) had HAMR bacteria. The HAMR group was associated with increased ICU mortality (40.3% vs. 30%, odds ratio (OR) 95%, CI 1.57 [1.45-1.70], P < 0.001). This association was confirmed in the matched sample (3006 HAMR and 5640 non-HAMR, OR 95%, CI 1.39 [1.27-1.52], P < 0.001) and after adjusting for confounding factors (OR ranged from 1.34 to 1.39, all P < 0.001). Our findings suggest that ICU-acquired pneumonia due to HAMR bacteria is associated with an increased ICU mortality rate, ICU length of stay, and mechanical ventilation duration.

A Novel Oxygen Carrier (M101) Attenuates Ischemia-Reperfusion Injuries during Static Cold Storage in Steatotic Livers.

The combined impact of an increasing demand for liver transplantation and a growing incidence of nonalcoholic liver disease has provided the impetus for the development of innovative strategies to preserve steatotic livers. A natural oxygen carrier, HEMO2life®, which contains M101 that is extracted from a marine invertebrate, has been used for static cold storage (SCS) and has shown superior results in organ preservation. A total of 36 livers were procured from obese Zucker rats and randomly divided into three groups, i.e., control, SCS-24H and SCS-24H + M101 (M101 at 1 g/L), mimicking the gold standard of organ preservation. Ex situ machine perfusion for 2 h was used to evaluate the quality of the livers. Perfusates were sampled for functional assessment, biochemical analysis and subsequent biopsies were performed for assessment of ischemia-reperfusion markers. Transaminases, GDH and lactate levels at the end of reperfusion were significantly lower in the group preserved with M101 (p < 0.05). Protection from reactive oxygen species (low MDA and higher production of NO2-NO3) and less inflammation (HMGB1) were also observed in this group (p < 0.05). Bcl-1 and caspase-3 were higher in the SCS-24H group (p < 0.05) and presented more histological damage than those preserved with HEMO2life®. These data demonstrate, for the first time, that the addition of HEMO2life® to the preservation solution significantly protects steatotic livers during SCS by decreasing reperfusion injury and improving graft function.

Management of SARS-CoV-2 pneumonia in intensive care unit: An observational retrospective study comparing two bundles.

PURPOSE: To compare the effects of two therapeutic bundles of management in SARS-CoV2 ICU patients. MATERIALS AND METHODS: Our retrospective, observational study was performed in a university ICU from March to June 2020 (first wave) and from September 2020 to January 2021 (second wave). In first wave, patients received bundle 1 including early invasive ventilation, hydroxychloroquine, cefotaxime and azithromycin. In second wave, bundle 2 included non-invasive oxygenation support and dexamethasone. The main outcome was in-hospital mortality. Secondary outcomes included ICU and hospital length of stay, ICU supportive therapies, viral clearance and antimicrobial resistance emergence. RESULTS: 129 patients with SARS-CoV-2 pneumonia were admitted to our ICU. Thirty-five were treated according to bundle 1 and 76 to bundle 2. In-hospital mortality was similar in the two groups (23%, p = 1). The hospital (p = 0.003) and ICU (p = 0.01) length of stay and ventilator-free days at 28 days (p = 0.03) were significantly reduced in bundle 2. Increasing age, vasopressor use and PaO2/FiO2 ratio < 125 were associated with in-hospital mortality. CONCLUSION: Within the limitations of our study, changes in therapeutic bundles for SARS-Cov-2 ICU patients might have no effect on in-hospital mortality but were associated with less exposure to mechanical ventilation and reduced hospital length of stay.

Impact of dexamethasone on the incidence of ventilator-associated pneumonia and blood stream infections in COVID-19 patients requiring invasive mechanical ventilation: a multicenter retrospective study.

BACKGROUND: Dexamethasone decreases mortality in patients with severe coronavirus disease 2019 (COVID-19) and has become the standard of care during the second wave of pandemic. Dexamethasone is an immunosuppressive treatment potentially increasing the risk of secondary hospital acquired infections in critically ill patients. We conducted an observational retrospective study in three French intensive care units (ICUs) comparing the first and second waves of pandemic to investigate the role of dexamethasone in the occurrence of ventilator-associated pneumonia (VAP) and blood stream infections (BSI). Patients admitted from March to November 2020 with a documented COVID-19 and requiring mechanical ventilation (MV) for ≥ 48 h were included. The main study outcomes were the incidence of VAP and BSI according to the use of dexamethasone. Secondary outcomes were the ventilator-free days (VFD) at day-28 and day-60, ICU and hospital length of stay and mortality. RESULTS: Among the 151 patients included, 84 received dexamethasone, all but one during the second wave. VAP occurred in 63% of patients treated with dexamethasone (DEXA+) and 57% in those not receiving dexamethasone (DEXA-) (p = 0.43). The cumulative incidence of VAP, considering death, duration of MV and late immunosuppression as competing factors was not different between groups (p = 0.59). A multivariate analysis did not identify dexamethasone as an independent risk factor for VAP occurrence. The occurrence of BSI was not different between groups (29 vs. 30%; p = 0.86). DEXA+ patients had more VFD at day-28 (9 (0-21) vs. 0 (0-11) days; p = 0.009) and a reduced ICU length of stay (20 (11-44) vs. 32 (17-46) days; p = 0.01). Mortality did not differ between groups. CONCLUSIONS: In this cohort of COVID-19 patients requiring invasive MV, dexamethasone was not associated with an increased incidence of VAP or BSI. Dexamethasone might not explain the high rates of VAP and BSI observed in critically ill COVID-19 patients.

Can Thoracic Ultrasound on Admission Predict the Outcome of Critically Ill Patients with SARS-CoV-2? A French Multi-Centric Ancillary Retrospective Study.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks have led to massive admissions to intensive care units (ICUs). An ultrasound examination of the thorax is widely performed on admission in these patients. The primary objective of our study was to assess the performance of the lung ultrasound score (LUS) on ICU admission to predict the 28-day mortality rate in patients with SARS-CoV-2. The secondary objective was to asses the performance of thoracic ultrasound and biological markers of cardiac injury to predict mortality. METHODS: This multicentre, retrospective, observational study was conducted in six ICUs of four university hospitals in France from 15 March to 3 May 2020. Patients admitted to ICUs because of SARS-CoV-2-related acute respiratory failure and those who received an LUS examination at admission were included. The area under the receiver-operating characteristics (ROC) curve was determined for the LUS score to predict the 28-day mortality rate. The same analysis was performed for the Simplified Acute Physiology Score, left ventricular ejection fraction, cardiac output, brain natriuretic peptide and ultra-sensitive troponin levels at admission. RESULTS: In 57 patients, the 28-day mortality rate was 21%. The area under the ROC curve of the LUS score value on ICU admission was 0.68 [95% CI 0.54-0.82; p = 0.05]. In non-intubated patients on ICU admission (n = 40), the area under the ROC curves was 0.84 [95% CI 0.70-0.97; p = 0.005]. The best cut-off of 22 corresponded to 85% specificity and 83% sensitivity. CONCLUSIONS: LUS scores on ICU admission for SARS-CoV-2 did not efficiently predict the 28-day mortality rate. Performance was better for non-intubated patients at admission. Performance of biological cardiac markers may be equivalent to the LUS score.

Sistemas de liberación prolongada de opioides: Analgesia y dependencia / Extended-release delivery systems of opioids: Analgesia and dependence

El consumo de analgésicos opioides ha experimentado un vertiginoso ascenso en las últimas décadas a nivel mundial. Este elevado consumo está relacionado con el aumento del número de prescripciones de opioides para el tratamiento del dolor crónico y por el aumento de la dependencia a opioides. Los analgésicos opioides tienen una corta duración de acción, siendo necesarias múltiples administraciones para obtener analgesia prolongada. El empleo de formulaciones de liberación prolongada permite espaciar los intervalos posológicos y estabilizar las concentraciones máximas de fármaco en sangre, favoreciendo el cumplimiento terapéutico y reduciendo el riesgo de desarrollar adicción. Sin embargo, estas formulaciones llevan dosis más altas de analgésicos opioides que las hacen más susceptibles de ser alteradas. Así, los avances en tecnología farmacéutica más recientes se han orientado hacia la aplicación de recursos tecnológicos disuasorios de su utilización por vías de administración alternativas con fines no terapéuticos. A su vez, los sistemas de liberación modificada también juegan un papel esencial en el tratamiento de la adicción a opioides: con el desarrollo de sistemas de administración parenteral capaces de prolongar la liberación de opioides durante meses se consigue superar una de las mayores dificultades para alcanzar el éxito del tratamiento en este tipo de pacientes como es el cumplimiento terapéutico. En este artículo se realiza una revisión bibliográfica de los diferentes sistemas de liberación prolongada de opioides que se encuentran actualmente autorizados en Europa y/o en Estados Unidos para el tratamiento del dolor y de la dependencia a opioides

The consumption of opioid analgesics has increased drastically in the last decades worldwide. This high consumption is linked with a surge in the number of opioid prescriptions for the treatment of chronic pain and a surge in opioid misuse and addiction. Opioid analgesics have a short duration of action, making necessary frequent administrations to provide extended analgesia. The use of prolonged-release formulations enables dosing intervals to be spaced out and drug blood levels to be stabilized, improving therapeutic compliance, and reducing the likelihood of developing addiction. However, these formulations contain higher doses of opioid analgesics which make them more susceptible to be manipulated. Hence, the most recent advances in pharmaceutical technology have been oriented towards the application of abuse deterrent technologies aiming to prevent their administration through alternative routes. Moreover, prolonged- release systems also play an essential role in the treatment of opioid addictions with the development of parenteral dosage forms capable of prolonging opioid release for months that help overcome one of the most important drawbacks in achieving treatment success, namely, patient compliance. We review herein the different prolonged-release opioid dosage forms currently approved in Europe and/or the United States for the treatment of pain and opioid dependence