Sex-specific treatment characteristics and 30-day mortality outcomes of critically ill COVID-19 patients over 70 years of age-results from the prospective COVIP study.

PURPOSE: Older critically ill patients with COVID-19 have been the most vulnerable during the ongoing pandemic, with men being more prone to hospitalization and severe disease than women. We aimed to explore sex-specific differences in treatment and outcome after intensive care unit (ICU) admission in this cohort. METHODS: We performed a sex-specific analysis in critically ill patients ≥ 70 yr of age with COVID-19 who were included in the international prospective multicenter COVIP study. All patients were analyzed for ICU admission and treatment characteristics. We performed a multilevel adjusted regression analysis to elucidate associations of sex with 30-day mortality. RESULTS: A total of 3,159 patients (69.8% male, 30.2% female; median age, 75 yr) were included. Male patients were significantly fitter than female patients as determined by the Clinical Frailty Scale (fit, 67% vs 54%; vulnerable, 14% vs 19%; frail, 19% vs 27%; P < 0.001). Male patients more often underwent tracheostomy (20% vs 14%; odds ratio [OR], 1.57; P < 0.001), vasopressor therapy (69% vs 62%; OR, 1.25; P = 0.02), and renal replacement therapy (17% vs 11%; OR, 1.96; P < 0.001). There was no difference in mechanical ventilation, life-sustaining treatment limitations, and crude 30-day mortality (50% male vs 49% female; OR, 1.11; P = 0.19), which remained true after adjustment for disease severity, frailty, age and treatment limitations (OR, 1.17; 95% confidence interval, 0.94 to 1.45; P = 0.16). CONCLUSION: In this analysis of sex-specific treatment characteristics and 30-day mortality outcomes of critically ill patients with COVID-19 ≥ 70 yr of age, we found more tracheostomy and renal replacement therapy in male vs female patients, but no significant association of patient sex with 30-day mortality. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT04321265); registered 25 March 2020).

RéSUMé: OBJECTIF: Les patients âgés gravement malades atteints de la COVID-19 ont été les plus vulnérables pendant la pandémie actuelle, les hommes étant plus sujets à l'hospitalisation et aux maladies graves que les femmes. Nous avons cherché à explorer les différences spécifiques au sexe dans le traitement et les devenirs après l'admission à l'unité de soins intensifs (USI) dans cette cohorte. MéTHODE: Nous avons effectué une analyse spécifique au sexe chez des patients gravement malades âgés de ≥ 70 ans atteints de COVID-19 qui ont été inclus dans l'étude prospective multicentrique internationale COVIP. Tous les patients ont été analysés pour connaître les détails de leur admission à l'USI et les caractéristiques de leur traitement. Nous avons réalisé une analyse de régression ajustée à plusieurs niveaux pour élucider les associations entre le sexe et la mortalité à 30 jours. RéSULTATS: Au total, 3159 patients (69,8 % d'hommes, 30,2 % de femmes; âge médian, 75 ans) ont été inclus. Les patients de sexe masculin étaient significativement plus en forme que les patientes, tel que déterminé par l'échelle de fragilité clinique (bonne santé, 67 % vs 54 %; vulnérables, 14 % vs 19 %; fragiles, 19 % vs 27 %; P < 0,001). Les patients de sexe masculin ont plus souvent bénéficié d'une trachéostomie (20 % vs 14 %; rapport de cotes [RC], 1,57; P < 0,001), d'un traitement vasopresseur (69 % vs 62 %; RC, 1,25; P = 0,02) et d'un traitement substitutif de l'insuffisance rénale (17 % vs 11 %; RC, 1,96; P < 0,001). Il n'y avait aucune différence en matière de ventilation mécanique, de limites des traitements de maintien en vie et de mortalité brute à 30 jours (50 % d'hommes vs 49 % de femmes; RC, 1,11; P = 0,19), ce qui est demeuré le cas après ajustement pour tenir compte de la gravité de la maladie, de la fragilité, de l'âge et des limites du traitement (RC, 1,17 ; intervalle de confiance à 95 %, 0,94 à 1,45; P = 0,16). CONCLUSION: Dans cette analyse des caractéristiques de traitement spécifiques au sexe et des résultats de mortalité à 30 jours des patients gravement malades atteints de COVID-19 de ≥ 70 ans, nous avons noté un nombre plus élevé de trachéotomies et de traitements substitutifs de l'insuffisance rénale chez les hommes vs les femmes, mais aucune association significative entre le sexe des patients et la mortalité à 30 jours. ENREGISTREMENT DE L'éTUDE: www.ClinicalTrials.gov (NCT04321265); enregistré le 25 mars 2020.

Sublingual microcirculation in prehospital critical care medicine: A proof-of-concept study.

OBJECTIVE: Diagnostic and risk stratification are limited in emergencies. The measurement of microcirculation might identify patients with poor perfusion but compensated macrocirculation such as in beginning shock. This proof-of-concept study examines whether sublingual prehospital sidestream dark-field microscopy is feasible. METHODS: This prospective observational study included patients receiving medical aid by an emergency ambulance who had a spontaneous circulation and offered access to the sublingual mucosa. Sublingual measurement of microcirculation was performed using a sidestream dark field camera. Video quality was evaluated with microcirculation image quality score (microcirculation image quality score). AVA 4.3C software calculated microcirculatory parameters. RESULTS: Thirty patients (47% male) were included. The average age was 63 years (±20 years SD), the severity of the disease (quantified by National Advisory Committee on Aeronautics) was 3.4 (±0.7 SD). Macrocirculation presented within the normal range. The most frequent cause preventing the measurement was a time-critical disease (64%). In 17 patients (57%), the videos could be analyzed immediately. The average quality of the video was 2.2 ± 0.45 points ('acceptable'). There were minor restrictions of microcirculation. Microcirculation correlated with National Advisory Committee on Aeronautics, but not with the macrocirculation. No complications occurred. CONCLUSION: The prehospital sublingual measurement is safe and valid. Despite normal macrocirculation, microcirculation was impaired and correlated with National Advisory Committee on Aeronautics.

Acute and short-term fluctuations in gravity are associated with changes in circulatory plasma protein levels.

Gravitational changes between micro- and hypergravity cause several adaptations and alterations in the human body. Besides muscular atrophy and immune system impairment, effects on the circulatory system have been described, which can be associated with a wide range of blood biomarker changes. This study examined nine individuals (seven males, two females) during a parabolic flight campaign (PFC). Thirty-one parabolas were performed in one flight day, resulting in ~22 s of microgravity during each parabola. Each participant was subjected to a single flight day with a total of 31 parabolas, totaling 11 min of microgravity during one parabolic flight. Before and after (1 hour (h) and 24 h), the flights blood was sampled to examine potential gravity-induced changes of circulating plasma proteins. Proximity Extension Assay (PEA) offers a proteomic solution, enabling the simultaneous analysis of a wide variety of plasma proteins. From 2925 unique proteins analyzed, 251 (8.58%) proteins demonstrated a differential regulation between baseline, 1 h and 24 h post flight. Pathway analysis indicated that parabolic flights led to altered levels of proteins associated with vesicle organization and apoptosis up to 24 h post microgravity exposure. Varying gravity conditions are associated with poorly understood physiological changes, including stress responses and fluid shifts. We provide a publicly available library of gravity-modulated circulating protein levels illustrating numerous changes in cellular pathways relevant for inter-organ function and communication.

Cytokine absorption in critically ill old COVID-19 patients with renal failure: A retrospective analysis of 503 intensive care unit patients.

BACKGROUND: COVID-19 is associated with cytokine release in critical disease states. Thus, cytokine absorption has been proposed as a therapeutic option. This study investigated the influence of cytokine absorption on mortality in old critical patients with COVID-19 and renal failure admitted to intensive care units (ICU). METHODS: This retrospective analysis of a prospective international observation study (the COVIP study) analysed ICU patients≥70 years with COVID-19. Data on Sequential Organ Failure Assessment (SOFA) score, clinical frailty scale (CFS), ICU therapy details including renal replacement therapy (RRT) with/without cytokine absorption were collected. The cytokine absorption group was compared to patients receiving RRT without cytokine absorptionRESULTS:Among 3927 patients, 503 received RRT; among them 47 patients were treated with cytokine absorption. Mortality rates were high in both groups with increased rates in the cytokine group for ICU mortality and 30-day mortality, but not for 3-month mortality. Logistic regression analysis indicated that SOFA-score, but not cytokine absorption was associated with mortality. CONCLUSIONS: Critical COVID-19 patients with renal failure treated with cytokine absorption showed higher short term mortality rates when compared to patients with renal replacement therapy alone. Mortality is associated with disease severity, but not cytokine absorption in a multivariate analysis.

Rational and design of the REMOTE trial: An exploratory, pilot study to analyze REtinal MicrOcirculaTion in wEightlessness.

BACKGROUND: "Spaceflight associated neuro-ocular syndrome" (SANS) represents a challenging health condition in modern space medicine. Forty-eight percent of astronauts are diagnosed with SANS after long-term space missions. The pathophysiological mechanism seems to be multifactorial, and yet remains unknown. In this proof-of-concept study we plan to investigate retinal microcirculatory changes in weightlessness and aim to identify their role in the development of SANS. METHODS AND DESIGN: Healthy individuals will take part in a parabolic flight campaign, which recreates fractioned total weightlessness periods. The airplane is specifically equipped, and designed for the execution of parabolic flight maneuvers and scientific research in microgravity. Retinal microcirculation will be assessed with a modified fundus camera, which allows dynamic vessel analysis. We will additionally measure intra-ocular pressure and hemodynamic changes during each phase of the flight. Blood samples will be analyzed at baseline, one hour and 24 hours after exposure to weightlessness. CONCLUSIONS: This pilot study aims to investigate the feasibility of retinal microcirculation assessment during varying gravity. Results of this study may generate insights whether venous stasis in the eye, surrogated by the dilatation of retinal vessels and increase in intraocular pressure as signs of venous insufficiency, may potentially contribute to the development of SANS.

How spaceflight challenges human cardiovascular health.

The harsh environmental conditions in space, particularly weightlessness and radiation exposure, can negatively affect cardiovascular function and structure. In the future, preventive cardiology will be crucial in enabling safe space travel. Indeed, future space missions destined to the Moon and from there to Mars will create new challenges to cardiovascular health while limiting medical management. Moreover, commercial spaceflight evolves rapidly such that older persons with cardiovascular risk factors will be exposed to space conditions. This review provides an overview on studies conducted in space and terrestrial models, particularly head-down bedrest studies. These studies showed that weightlessness elicits a fluid shift towards the head, which likely predisposes to the spaceflight-associated neuro-ocular syndrome, neck vein thrombosis, and orthostatic intolerance after return to Earth. Moreover, cardiovascular unloading produces cardiopulmonary deconditioning, which may be associated with cardiac atrophy. In addition to limiting physical performance, the mechanism further worsens orthostatic tolerance after return to Earth. Finally, space conditions may directly affect vascular health; however, the clinical relevance of these findings in terms of morbidity and mortality is unknown. Targeted preventive measures, which are referred to as countermeasures in aerospace medicine, and technologies to identify vascular risks early on will be required to maintain cardiovascular performance and health during future space missions.

The association of the Activities of Daily Living and the outcome of old intensive care patients suffering from COVID-19.

PURPOSE: Critically ill old intensive care unit (ICU) patients suffering from Sars-CoV-2 disease (COVID-19) are at increased risk for adverse outcomes. This post hoc analysis investigates the association of the Activities of Daily Living (ADL) with the outcome in this vulnerable patient group. METHODS: The COVIP study is a prospective international observational study that recruited ICU patients ≥ 70 years admitted with COVID-19 (NCT04321265). Several parameters including ADL (ADL; 0 = disability, 6 = no disability), Clinical Frailty Scale (CFS), SOFA score, intensive care treatment, ICU- and 3-month survival were recorded. A mixed-effects Weibull proportional hazard regression analyses for 3-month mortality adjusted for multiple confounders. RESULTS: This pre-specified analysis included 2359 patients with a documented ADL and CFS. Most patients evidenced independence in their daily living before hospital admission (80% with ADL = 6). Patients with no frailty and no disability showed the lowest, patients with frailty (CFS ≥ 5) and disability (ADL < 6) the highest 3-month mortality (52 vs. 78%, p < 0.001). ADL was independently associated with 3-month mortality (ADL as a continuous variable: aHR 0.88 (95% CI 0.82-0.94, p < 0.001). Being "disable" resulted in a significant increased risk for 3-month mortality (aHR 1.53 (95% CI 1.19-1.97, p 0.001) even after adjustment for multiple confounders. CONCLUSION: Baseline Activities of Daily Living (ADL) on admission provides additional information for outcome prediction, although most critically ill old intensive care patients suffering from COVID-19 had no restriction in their ADL prior to ICU admission. Combining frailty and disability identifies a subgroup with particularly high mortality. TRIAL REGISTRATION NUMBER: NCT04321265.

Early evaluation of organ failure using MELD-XI in critically ill elderly COVID-19 patients.

PURPOSECritically ill elderly patients who suffer from Sars-CoV-2 disease are at high risk for organ failure. The modified MELD-XI score has not been evaluated for outcome prediction in these most vulnerable patients.METHODSThe Corona Virus disease (COVID19) in Very Elderly Intensive Care Patients study (COVIP, NCT04321265) prospectively recruited patients on intensive care units (ICU), who were = 70 years. Data were collected from March 2020 to February 2021. The MELD-XI score was calculated using the highest serum bilirubin and creatinine on ICU admission. Univariate and multivariable logistic regression analyses were performed to assess associations between the MELD-XI score and mortality. The primary outcome was 30-day-mortality, the secondary outcomes were ICU- and 3-month-mortality.RESULTSIn total, data from 2,993 patients were analyzed. Most patients had a MELD-XI <12 on admission (76%). The patients with MELD-XI = 12 had a significantly higher 30-day-, ICU- and 3-month-mortality (44%vs 64%, and 42%vs. 59%, and 57%vs. 76%, p < 0.001). After adjustment for multiple confounders, MELD-XI = 12 remained significantly associated with 30-day- (aOR 1.572, CI 1.268-1.949, p < 0.001), ICU-, and 3-month-mortality.CONCLUSIONIn critically ill elderly intensive care patients with COVID-19, the MELD-XI score constitutes a valuable tool for an early outcome prediction.

Comprehensive Analysis of Macrocirculation and Microcirculation in Microgravity During Parabolic Flights.

BACKGROUND: Profound knowledge about cardiovascular physiology in the setting of microgravity can help in the course of preparations for human space missions. So far, influences of microgravity on the cardiovascular system have been demonstrated, particularly pertaining to venous fluid shifts. Yet, little is known about the mechanisms of these adaptations on continuous macrocirculatory level and regarding the microcirculation. METHODS: Twelve healthy volunteers were subjected to alternating microgravity and hypergravity in the course of parabolic flight maneuvers. Under these conditions, as well as in normal gravity, the sublingual microcirculation was assessed by intravital sidestream dark field microscopy. Furthermore, hemodynamic parameters such as heart rate, blood pressure, and cardiac output were recorded by beat-to-beat analysis. In these settings, data acquisition was performed in seated and in supine postures. RESULTS: Systolic [median 116 mmHg (102; 129) interquartile range (IQR) vs. 125 mmHg (109; 136) IQR, p = 0.01] as well as diastolic [median 72 mmHg (61; 79) IQR vs. 80 mmHg (69; 89) IQR, p = 0.003] blood pressure was reduced, and cardiac output [median 6.9 l/min (6.5; 8.8) IQR vs. 6.8 l/min (6.2; 8.5) IQR, p = 0.0002] increased in weightlessness compared to normal gravitation phases in the seated but not in the supine posture. However, microcirculation represented by perfused proportion of vessels and by total vessel density was unaffected in acute weightlessness. CONCLUSION: Profound changes of the macrocirculation were found in seated postures, but not in supine postures. However, microcirculation remained stable in all postures.

Sublingual microcirculation detects impaired perfusion in dehydrated older patients.

BACKGROUND: Dehydration occurs frequently in older patients and constitutes a significant clinical problem. OBJECTIVE: This proof-of-concept study examines whether 1) sublingual measurement in dehydrated old patients is feasible, 2) frailty and incompliance in old, awake patients affects video-quality, 3) dehydration impacts microcirculationMETHODS:This prospective observational study included clinically dehydrated patients aged ≥65 years immediately after admission. Dehydration was assessed clinically. A sidestream dark field camera (SDF) was used for measurement. Video-quality was evaluated with MIQS (microcirculation image quality score). Both AVA 4.3C- and AVA POEM-software analyzed the videos. Seventeen patients ≥65 years not showing dehydration served as control. RESULTS: Thirteen patients (8 female) were included. The average age was 83±8 years. The mini-mental test was 17±15 points, the Clinical Frailty Scale 4±3, the Barthel-Index 59±39. None of these parameters correlated with MIQS (3.4±4.2 SD ("acceptable")). Dehydrated patients had a slightly impaired microcirculation, with a significantly lower percentage of perfused small vessels compared to control (83.1±7.7% versus 88.0±6.0%, P < 0.05). After rehydration, there was acute improvement in the microcirculation. CONCLUSIONS: Sublingual microcirculatory SDF-measurement is both, safe and valid for dehydrated old patients - regardless of frailty, age or cognitive performance. Dehydration leads to an impaired microcirculation.

Failure of Lactate Clearance Predicts the Outcome of Critically Ill Septic Patients.

PURPOSE: Early lactate clearance is an important parameter for prognosis assessment and therapy control in sepsis. Patients with a lactate clearance >0% might differ from patients with an inferior clearance in terms of intensive care management and outcomes. This study analyzes a large collective with regards to baseline risk distribution and outcomes. METHODS: In total, 3299 patients were included in this analysis, consisting of 1528 (46%) ≤0% and 1771 (54%) >0% patients. The primary endpoint was intensive care unit (ICU) mortality. Multilevel logistic regression analyses were used to compare both groups: A baseline model (model 1) with lactate clearance as a fixed effect and ICU as a random effect was installed. For model 2, patient characteristics (model 2) were included. For model 3, intensive care treatment (mechanical ventilation and vasopressors) was added to the model. Models 1 and 2 were used to evaluate the primary and secondary outcomes, respectively. Model 3 was only used to evaluate the primary outcomes. Adjusted odds ratios (aORs) with respective 95% confidence intervals (CI) were calculated. RESULTS: The cohorts had no relevant differences regarding the gender, BMI, age, heart rate, body temperature, and baseline lactate. Neither the primary infection focuses nor the ethnic background differed between both groups. In both groups, the most common infection sites were of pulmonary origin, the urinary tract, and the gastrointestinal tract. Patients with lactate clearance >0% evidenced lower sepsis-related organ failure assessment (SOFA) scores (7 ± 6 versus 9 ± 6; p < 0.001) and creatinine (1.53 ± 1.49 versus 1.80 ± 1.67; p < 0.001). The ICU mortality differed significantly (14% versus 32%), and remained this way after multivariable adjustment for patient characteristics and intensive care treatment (aOR 0.43 95% CI 0.36-0.53; p < 0.001). In the additional sensitivity analysis, the lack of lactate clearance was associated with a worse prognosis in each subgroup. CONCLUSION: In this large collective of septic patients, the 6 h lactate clearance is an independent method for outcome prediction.