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Introduction: Changes in blood coagulation during exposure to high altitude are not well understood and studies of activation and consumption of specific coagula-tion factors in hypoxic humans have yielded conflicting results. In this study we used thrombelastometry (TEM) which allows a global evaluation of clot formation and lysis process to study blood coagulation profiles in volunteers exposed to pro-longed hypobaric hypoxia at extreme altitudes. Material and methods: We conducted a prospective, observational study in 39 healthy volunteers during a research expedition up to an altitude of 7050 m. Plasma based thrombelastometric measurements and standard coagulation parameters were performed at different altitudes. Results: TEM measurements showed an increase in clotting time (CT) and maxi-mum clot firmness (MCF) at high altitudes, paralleled by an increase in international normalized ratio (INR) and activated partial thromboplastin time (aPTT). Fibrinogen concentration increased until 6022 m. D-Dimer and Thrombin-Antithrombin complex (TAT) increased with time exposed to severe hypoxia. For both measurements highest levels were found at 4844 m after acclimatization; in contrast, lower values were observed again at 7050m in the group of summiteers. Activated protein C resistance (APC-R) was slightly lowered at all altitudes. Conclusion: Our results suggest that activation of the coagulation and fibrinolytic system occurs with increasing hypobaric hypoxia with concurrent use of coagula-tion factors indicating the occurrence of a consumption-coagulopathy phenotype.

Background: In clinical practice, blood pressure is used as a resuscitation goal on a daily basis, with the aim of maintaining adequate perfusion and oxygen delivery to target organs. Compromised perfusion is often indicated as a key factor in the pathophysiology of anastomotic leakage. This study was aimed at assessing the extent to which the microcirculation of the bowel coheres with blood pressure during abdominal surgery. Methods: We performed a prospective and observational cohort study. In patients undergoing abdominal surgery, the serosal microcirculation of either the small intestine or the colon was visualized using handheld vital microscopy (HVM). From the acquired HVM image sequences, red blood cell velocity (RBCv) and total vessel density (TVD) were calculated using MicroTools and AVA software, respectively. The association between microcirculatory parameters and blood pressure was assessed using Pearson's correlation analysis. We considered a two-sided P-value of 2. Mean arterial pressure (MAP) was 71 ± 12 mm Hg during microcirculatory imaging. MAP was not correlated with RBCv (Pearson's r = −0.049, P = 0.800) or TVD (Pearson's r = 0.310, P = 0.110). Conclusion: In 28 patients undergoing abdominal surgery, we found no association between serosal intestinal microcirculatory parameters and blood pressure.

Background: Sonographic assessment of optical nerve sheath diameter (ONSD) has the potential for non-invasive monitoring of intracranial pressure (ICP). Hyperventilation (HV) -induced hypocapnia is used in the management of patients with traumatic brain injury (TBI) to reduce ICP. This study investigates, whether sonography is a reliable tool to detect dynamic changes in ONSD. Methods: This prospective single center trial included patients with TBI and neuromonitoring within 36 h after injury. Data collection and ONSD measurements were performed at baseline and during moderate HV for 50 min. Patients not suffering from TBI were recruited as control group. Results: Ten patients with TBI (70% males, mean age 35 ± 14 years) with a median of first GCS of 5.9 and ten control patients (40% males, mean age 45 ± 16 years) without presumed intracranial hypertension were included. During HV, ICP decreased significantly (p < .0001) in the TBI group. An ONSD response was found for HV (p = .05). Conclusion: We observed a dynamic decrease of ONSD during moderate HV. This suggests a potential use of serial ONSD measurements when applying HV in cases of suspected intracranial hypertension.

COVID-19 displays diverse disease severities and symptoms including acute systemic inflammation and hypercytokinemia, with subsequent dysregulation of immune cells. Bacterial superinfections in COVID-19 can further complicate the disease course and are associated with increased mortality. However, there is limited understanding of how SARS-CoV-2 pathogenesis and hypercytokinemia impede the innate immune function against bacterial superinfections. We assessed the influence of COVID-19 plasma hypercytokinemia on the functional responses of myeloid immune cells upon bacterial challenges from acute-phase COVID-19 patients and their corresponding recovery-phase. We show that a severe hypercytokinemia status in COVID-19 patients correlates with the development of bacterial superinfections. Neutrophils and monocytes derived from COVID-19 patients in their acute-phase showed an impaired intracellular microbicidal capacity upon bacterial challenges. The impaired microbicidal capacity was reflected by abrogated MPO and reduced NETs production in neutrophils along with reduced ROS production in both neutrophils and monocytes. Moreover, we observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes, in line with suppressed autocrine and paracrine cytokine signaling. This phenotype was characterized by a high expression of CD66b, CXCR4 and low expression of CXCR1, CXCR2 and CD15 in neutrophils and low expression of HLA-DR, CD86 and high expression of CD163 and CD11b in monocytes. Furthermore, the impaired antibacterial effector function was mediated by synergistic effect of the cytokines TNF-α, IFN-γ and IL-4. COVID-19 patients receiving dexamethasone showed a significant reduction of overall inflammatory markers in the plasma as well as exhibited an enhanced immune response towards bacterial challenge ex vivo. Finally, broad anti-inflammatory treatment was associated with a reduction in CRP, IL-6 levels as well as length of ICU stay and ventilation-days in critically ill COVID-19 patients. Our data provides insights into the transient functional dysregulation of myeloid immune cells against subsequent bacterial infections in COVID-19 patients and describe a beneficial role for the use of dexamethasone in these patients., Author summary COVID-19 caused by SARS-CoV-2 induces immune-paralysis characterized by misdirected host responses and altered levels of inflammatory mediators. Additionally, bacterial superinfections can further exacerbate the disease. Here, we report an in-depth functional characterization of the effector response and phenotypic properties of neutrophils and monocytes derived from critically ill COVID-19 patients towards bacterial superinfection. We show that elevated levels of specific cytokine clusters, positively correlate with the development of bacterial superinfections in these patients. Neutrophils and monocytes of critically ill COVID-19 patients showed impaired bactericidal capacity, which was mediated by elevated inflammatory mediators in the plasma. The observed impaired bactericidal capacity in critically ill COVID-19 patients was due to reduced classical effector functions of neutrophils and monocytes. Interestingly, lower levels of overall inflammatory mediators as well as reduction in length of ICU stay and ventilation-days in critically ill COVID-19 patients treated with dexamethasone was observed. These data suggest that the exhaustion and paralysis of the cellular innate immunity against bacterial challenge in critically ill COVID-19 patients is driven by a misdirected host-response, characterized by a hyperinflammatory environment including dysregulated cytokine levels. These results further emphasize the utility and importance of dampening these inflammatory mediators via broad anti-inflammatory therapy in COVID-19 patients, which improves the antibacterial effector functions of neutrophils and monocytes.

Background The modifications to the standard intensive care unit (ICU) organization that had to be urgently implemented worldwide to overcome the surge of ICU admissions due to patients with a severe coronavirus disease 2019 (COVID-19) have resulted in increased workload and patients-to-nurse ratio. The aim of this study was to investigate whether level of critical care staffing could be associated with an increased risk of ICU mortality (primary endpoint), length of stay, mechanical ventilation and the evolution of disease (secondary study endpoints) in critically ill patients with COVID-19. Methods Retrospective multicenter analysis of the international Risk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry that prospectively enrolls patients developing critical illness due to COVID-19 in several countries worldwide. The analysis was limited to the period between March 1st, 2020 and May 31st, 2020, to ICUs in Switzerland that have collected additional data on nurse and physician staffing. Hierarchical regression models were used to investigate crude and adjusted effects of critical care staffing ratio on study endpoints. We adjusted for diseases severity and weekly caseload. Results Among the 38 Swiss participating ICUs, 17 recorded critical care staffing information. The study population included 437 patients and 2342 daily assessments of patient-to-nurse/physician ratio. Median of daily patient-to-nurse ratio started at 1.0 ([IQR] 0.5–1.5; calendar week 9) and peaked at 2.4 (IQR 0.4-2.0; calendar week 16), while the median of daily patient-to-physician ratio started at 4.0 (IQR 2.1-5.0; calendar week 9) and peaked at 6.8 (IQR 6.3–7.3; calendar week 19). Neither the patient-to-nurse ratio [adjusted Odds Ratio (OR) 1.28, 95% confidence interval (CI) 0.85–1.94; doubling of ratio] nor the patient-to-physician ratio [adjusted OR 1.08, 95% CI 0.87–1.32; doubling of ratio] was associated with ICU mortality. We found no association of critical care staffing on the investigated secondary study endpoints in adjusted models. COnclusion The Swiss health care system successfully overcame the first wave of the COVID-19 pandemic with regards to the unprecedented demand for ICU treatments. The reduced availability of critical care staffing resources per critically ill patient in Swiss ICUs did not translate in an overall increased risk of mortality.

Background : Accurate risk stratification of critically ill patients with coronavirus disease 2019 (COVID-19) is essential for optimizing resource allocation, delivering targeted interventions, and maximizing patient survival probability. Machine learning (ML) techniques are attracting increased interest for the development of prediction models as they excel in the analysis of complex signals in data-rich environments such as critical care. Methods : We retrieved data on patients with COVID-19 admitted to an intensive care unit (ICU) between March and October 2020 from the RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry. We applied the Extreme Gradient Boosting (XGBoost) algorithm to the data to predict as a binary outcome the increase or decrease in patients’ Sequential Organ Failure Assessment (SOFA) score on day 5 after ICU admission. The model was iteratively cross-validated in different subsets of the study cohort. Results : The final study population consisted of 675 patients. The XGBoost model correctly predicted a decrease in SOFA score in 320/385 (83%) critically ill COVID-19 patients, and an increase in the score in 210/290 (72%) patients. The area under the mean receiver operating characteristic curve for XGBoost was significantly higher than that for the logistic regression model {0.86 vs. 0.69, P

Purpose: This study aims to compare protocol adherence, neurological outcome and adverse effects associated with a controlled hypothermia versus a controlled normothermia protocol in patients successfully resuscitated after cardiac arrest. Methods: In this retrospective single-center study in a university intensive care unit in Switzerland, post-cardiac arrest patients were compared before and after a protocol change from targeted temperature management at 33 °C (TTM-33) to 36 °C (TTM-36) using an intravascular cooling device. Protocol adherence was assessed as the primary outcome. Secondary outcomes were in-hospital mortality, neurological outcome and adverse effects. Results: 373 patients after cardiac arrest were screened, of whom a total of 133 patients were included. Protocol adherence was lower in the TTM-33 group (47% vs 87% of patients, p < 0.01). In-hospital mortality (59% vs 45%, p = 0.15) and neurological outcome (modified Rankin Score < 4 in 33% vs 39% and CPC-Score < 3 in 33% vs 39% of patients, p = 0.60 and 0.97) were similar. Overall incidence of adverse effects was comparable, with bradycardic arrhythmias occurring more frequently in the TTM-33 group. Conclusion: Protocol adherence was higher in the TTM-36 group. In-hospital mortality and neurological outcome were similar, while bradycardic arrhythmias were encountered more often in TTM-33.

The impact of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic on pediatric intensive care units (PICUs) is difficult to quantify. We conducted a retrospective cohort study in all eight Swiss PICUs between 02-24-2020 and 06-15-2020 to characterize the logistical and medical aspects of the pandemic and their impact on Swiss PICUs. Out of the 1113 patients under the age of 20, who were tested positive for SARS-CoV-2 in Switzerland during the study period, 6% (63/1113) had to be hospitalized. All nine patients requiring intensive care had pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and constituted 14% (9/63) of all hospitalized patients. The patients presented with multiple organ dysfunction, needed longer stays in PICUs (p < 0.0001) and longer positive pressure ventilation (p = 0.025) than the regular PICU patients. They caused a higher workload (total Nine Equivalents of nursing Manpower use Score (NEMS) points, p = 0.0008) and were classified to higher workload categories (p < 0.0001) than regular PICU patients (n = 4881) in 2019. PICU burden was also influenced by different logistical factors such as cancellation of planned surgeries and staff recruitment to adult wards.Conclusions The different logistical and medical factors associated with the pandemic influenced the workload of the individual PICUs differently, depending on the presence of the single factors and their temporal relationship. The experiences of the study period help further to organize Swiss PICUs during the current pandemic to reduce the workload and optimize occupancy.

BACKGROUND: Diaphragmatic respiratory effort during mechanical ventilation is an important determinant of patient outcome, but direct measurement of diaphragmatic contractility requires specialized instrumentation and technical expertise. We sought to determine whether routinely collected clinical variables can predict diaphragmatic contractility and stratify the risk of diaphragm atrophy. METHODS: We conducted a secondary analysis of a prospective cohort study on diaphragm ultrasound in mechanically ventilated subjects. Clinical variables, such as breathing frequency, ventilator settings, and blood gases, were recorded longitudinally. Machine learning techniques were used to identify variables predicting diaphragm contractility and stratifying the risk of diaphragm atrophy (> 10% decrease in thickness from baseline). Performance of the variables was evaluated in mixed-effects logistic regression and random-effects tree models using the area under the receiver operating characteristic curve. RESULTS: Measurements were available for 761 study days in 191 subjects, of whom 73 (38%) developed diaphragm atrophy. No routinely collected clinical variable, alone or in combination, could accurately predict either diaphragm contractility or the development of diaphragm atrophy (model area under the receiver operating characteristic curve 0.63–0.75). The risk of diaphragm atrophy was not significantly different according to the presence or absence of patient-triggered breaths (38.3% vs 38.6%; odds ratio 1.01, 95% CI 0.05–2.03). Diaphragm thickening fraction < 15% during either of the first 2 d of the study was associated with a higher risk of atrophy (44.6% vs 26.1%; odds ratio 2.28, 95% CI 1.05–4.95). CONCLUSIONS: Diaphragmatic contractility and the risk of diaphragm atrophy could not be reliably determined from routinely collected clinical variables and ventilator settings. A single measurement of diaphragm thickening fraction measured within 48 h of initiating mechanical ventilation can be used to stratify the risk of diaphragm atrophy during mechanical ventilation.

The impact of secondary bacterial infections (superinfections) in COVID-19 is not well understood. In this prospective, monocentric cohort study we aim to investigate the impact of superinfections in COVID-19 patients with acute respiratory distress syndrome. Patients are assessed for concomitant microbial infections by longitudinal analysis of tracheobronchial secretions, bronchoalveolar lavages and blood cultures. In 45 critically ill patients, we identify 19 patients with superinfections (42.2%). Superinfections are detected on day 10 after intensive care admission. The proportion of participants alive and off invasive mechanical ventilation at study day 28 (ventilator-free days (VFDs) at 28 days) is substantially lower in patients with superinfection (subhazard ratio 0.37, 95%-CI 0.15-0.90, p=0.028). Patients with pulmonary superinfections have a higher incidence of bacteraemia, virus reactivations, yeast colonization, and required intensive care treatment for a longer time. Superinfections are frequent and associated with reduced VFDs at 28 days despite a high rate of empirical antibiotic therapy., Graphical Abstract, Buehler et al. show that detection of bacterial pulmonary superinfection is associated with a more severe disease course in COVID-19 patients, especially a lower likelihood of being alive and off invasive mechanical ventilation at study day 28 (ventilator-free days at 28 days).

RationaleThe COVID-19 pandemic induces considerable strain on intensive care unit resources.ObjectivesWe aim to provide early predictions of individual patients’ intensive care unit length of stay, which might improve resource allocation and patient care during the on-going pandemic.MethodsWe developed a new semiparametric distributional index model depending on covariates which are available within 24h after intensive care unit admission. The model was trained on a large cohort of acute respiratory distress syndrome patients out of the Minimal Dataset of the Swiss Society of Intensive Care Medicine. Then, we predict individual length of stay of patients in the RISC-19-ICU registry.MeasurementsThe RISC-19-ICU Investigators for Switzerland collected data of 557 critically ill patients with COVID-19.Main ResultsThe model gives probabilistically and marginally calibrated predictions which are more informative than the empirical length of stay distribution of the training data. However, marginal calibration was worse after approximately 20 days in the whole cohort and in different subgroups. Long staying COVID-19 patients have shorter length of stay than regular acute respiratory distress syndrome patients. We found differences in LoS with respect to age categories and gender but not in regions of Switzerland with different stress of intensive care unit resources.ConclusionA new probabilistic model permits calibrated and informative probabilistic prediction of LoS of individual patients with COVID-19. Long staying patients could be discovered early. The model may be the basis to simulate stochastic models for bed occupation in intensive care units under different casemix scenarios.

Supplemental Digital Content is available in the text., OBJECTIVES: In this study, we hypothesized that coronavirus disease 2019 patients exhibit sublingual microcirculatory alterations caused by inflammation, coagulopathy, and hypoxemia. DESIGN: Multicenter case-controlled study. SETTING: Two ICUs in The Netherlands and one in Switzerland. PATIENTS: Thirty-four critically ill coronavirus disease 2019 patients were compared with 33 healthy volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The microcirculatory parameters quantified included total vessel density (mm × mm–2), functional capillary density (mm × mm–2), proportion of perfused vessels (%), capillary hematocrit (%), the ratio of capillary hematocrit to systemic hematocrit, and capillary RBC velocity (μm × s–1). The number of leukocytes in capillary-postcapillary venule units per 4-second image sequence (4 s–1) and capillary RBC microaggregates (4 s–1) was measured. In comparison with healthy volunteers, the microcirculation of coronavirus disease 2019 patients showed increases in total vessel density (22.8 ± sd 5.1 vs 19.9 ± 3.3; p < 0.0001) and functional capillary density (22.2 ± 4.8 vs 18.8 ± 3.1; p < 0.002), proportion of perfused vessel (97.6 ± 2.1 vs 94.6 ± 6.5; p < 0.01), RBC velocity (362 ± 48 vs 306 ± 53; p < 0.0001), capillary hematocrit (5.3 ± 1.3 vs 4.7 ± 0.8; p < 0.01), and capillary-hematocrit-to-systemic-hematocrit ratio (0.18 ± 0.0 vs 0.11 ± 0.0; p < 0.0001). These effects were present in coronavirus disease 2019 patients with Sequential Organ Failure Assessment scores less than 10 but not in patients with Sequential Organ Failure Assessment scores greater than or equal to 10. The numbers of leukocytes (17.6 ± 6.7 vs 5.2 ± 2.3; p < 0.0001) and RBC microaggregates (0.90 ± 1.12 vs 0.06 ± 0.24; p < 0.0001) was higher in the microcirculation of the coronavirus disease 2019 patients. Receiver-operating-characteristics analysis of the microcirculatory parameters identified the number of microcirculatory leukocytes and the capillary-hematocrit-to-systemic-hematocrit ratio as the most sensitive parameters distinguishing coronavirus disease 2019 patients from healthy volunteers. CONCLUSIONS: The response of the microcirculation to coronavirus disease 2019-induced hypoxemia seems to be to increase its oxygen-extraction capacity by increasing RBC availability. Inflammation and hypercoagulation are apparent in the microcirculation by increased numbers of leukocytes and RBC microaggregates.

RationaleThe COVID-19 pandemic induces considerable strain on intensive care unit resources.ObjectivesWe aim to provide early predictions of individual patients' intensive care unit length of stay, which might improve resource allocation and patient care during the on-going pandemic.MethodsWe developed a new semiparametric distributional index model depending on covariates which are available within 24h after intensive care unit admission. The model was trained on a large cohort of acute respiratory distress syndrome patients out of the Minimal Dataset of the Swiss Society of Intensive Care Medicine. Then, we predict individual length of stay of patients in the RISC-19-ICU registry.MeasurementsThe RISC-19-ICU Investigators for Switzerland collected data of 557 critically ill patients with COVID-19.Main resultsThe model gives probabilistically and marginally calibrated predictions which are more informative than the empirical length of stay distribution of the training data. However, marginal calibration was worse after approximately 20 days in the whole cohort and in different subgroups. Long staying COVID-19 patients have shorter length of stay than regular acute respiratory distress syndrome patients. We found differences in LoS with respect to age categories and gender but not in regions of Switzerland with different stress of intensive care unit resources.ConclusionA new probabilistic model permits calibrated and informative probabilistic prediction of LoS of individual patients with COVID-19. Long staying patients could be discovered early. The model may be the basis to simulate stochastic models for bed occupation in intensive care units under different casemix scenarios.

COVID-19 displays diverse disease severities and symptoms. Elevated inflammation mediated by hypercytokinemia induces a detrimental dysregulation of immune cells. However, there is limited understanding of how SARS-CoV-2 pathogenesis impedes innate immune signaling and function against secondary bacterial infections. We assessed the influence of COVID-19 hypercytokinemia on the functional responses of neutrophils and monocytes upon bacterial challenges from acute and corresponding recovery COVID-19 ICU patients. We show that severe hypercytokinemia in COVID-19 patients correlated with bacterial superinfections. Neutrophils and monocytes from acute COVID-19 patients showed severely impaired microbicidal capacity, reflected by abrogated ROS and MPO production as well as reduced NETs upon bacterial challenges. We observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes leading to a suppressive autocrine and paracrine signaling during bacterial challenges. Our data provide insights into the innate immune status of COVID-19 patients mediated by their hypercytokinemia and its transient effect on immune dysregulation upon subsequent bacterial infections

BACKGROUND: With recent advances in technology, patients with acute respiratory distress syndrome (ARDS) and severe acute exacerbations of chronic obstructive pulmonary disease (ae-COPD) could benefit from extracorporeal CO2 removal (ECCO2R). However, current evidence in these indications is limited. A European ECCO2R Expert Round Table Meeting was convened to further explore the potential for this treatment approach. METHODS: A modified Delphi-based method was used to collate European experts' views to better understand how ECCO2R therapy is applied, identify how patients are selected and how treatment decisions are made, as well as to identify any points of consensus. RESULTS: Fourteen participants were selected based on known clinical expertise in critical care and in providing respiratory support with ECCO2R or extracorporeal membrane oxygenation. ARDS was considered the primary indication for ECCO2R therapy (n = 7), while 3 participants considered ae-COPD the primary indication. The group agreed that the primary treatment goal of ECCO2R therapy in patients with ARDS was to apply ultra-protective lung ventilation via managing CO2 levels. Driving pressure (≥ 14 cmH2O) followed by plateau pressure (Pplat; ≥ 25 cmH2O) was considered the most important criteria for ECCO2R initiation. Key treatment targets for patients with ARDS undergoing ECCO2R included pH (> 7.30), respiratory rate ( 7.30-7.35), respiratory rate (, SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives: Reliable automated handheld vital microscopy image sequence analysis and the identification of disease states and effects of therapy are prerequisites for the routine use of quantitative sublingual microcirculation measurements at the point-of-care. The present study aimed to clinically validate the recently introduced MicroTools software in a large multicentral database of perioperative and critically ill patients and to use this automatic algorithm to data-mine and identify the sublingual microcirculatory variable changes in response to disease and therapy. Design: Retrospective algorithm-based image analysis and data-mining within a large international database of sublingual capillary microscopy. Algorithm-based analysis was compared with manual analysis for validation. Thereafter, MicroTools was used to identify the functional microcirculatory alterations associated with disease conditions and identify therapeutic options for recruiting functional microcirculatory variables. Setting: Ten perioperative/ICU/volunteer studies in six international teaching hospitals. Patients: The database encompass 267 adult and pediatric patients undergoing surgery, treatment for sepsis, and heart failure in the ICU and healthy volunteers. Interventions: Perioperative and ICU standard of care. Measurements and Main Results: One thousand five hundred twenty-five handheld vital microscopy image sequences containing 149,257 microscopy images were analyzed. 3.89 × 1012 RBC positions were tracked by the algorithm in real time, and offline manual analysis was performed. Good correlation and trending ability were found between manual and automatic total and functional capillary density (r = 0.6–0.8; p < 0.0001). RBC tracking within the database demonstrated changes in functional capillary density and/or RBC velocity in septic shock, heart failure, hypovolemia, obstructive shock, and hemodilution and thus detected the presence of a disease condition. Therapies recruiting the microcirculatory diffusion and convection capacity associated with systemic vasodilation and an increase in cardiac output were separately identified. Conclusions: Algorithm-based analysis of the sublingual microcirculation closely matched manual analysis across a broad spectrum of populations. It successfully identified a methodology to quantify microcirculatory alterations associated with disease and the success of capillary recruitment, improving point-of-care application of microcirculatory-targeted resuscitation procedures.

Background: While superinfections are associated with unfavourable disease course, their impact on clinical outcomes in critically ill COVID-19 patients remains largely unknown. We aimed to investigate the impact of superinfections in critically ill patients with COVID-19. Methods: In this prospective single centre cohort study in an intensive care unit (ICU) setting patients aged ≥ 18 years with COVID-19 Acute Respiratory Distress Syndrome (CARDS) and confirmed SARS-CoV-2 infection were assessed for concomitant microbial infections by longitudinal analysis of tracheobronchial secretions (TBS), bronchoalveolar lavages (BAL) and blood. Our primary outcome was ventilator-free survival on day 28 in patients with and without clinically relevant superinfection. Further outcomes included the association of superinfection with ICU length of stay, incidence of bacteremia, viral reactivations, and fungal colonization. Findings: In a total of 45 critically ill COVID-19 patients, we identified 19 patients with superinfections (42·2%) by longitudinal analysis of 433 TBS, 35 BAL and 455 blood samples, respectively. On average, superinfections were detected on day 10 after ICU admission despite the majority of patients already being on empiric antibiotic therapy. The most frequently isolated clinically relevant bacteria were Enterobacter/Citrobacter , Klebsiella spp., Streptococcus pneumoniae, Escherichia coli and Pseudomonas aeruginosa. Ventilator-free survival (VFS) at 28 days was substantially lower in patients with superinfection (subhazard ratio 0·37, 95%-CI 0·15-0·90, p=0·028). Patients with pulmonary superinfections more often had bacteraemia, virus reactivations, yeast colonization, and needed ICU treatment for a significantly longer time. Interpretation: The detection of superinfections was frequent and associated with reduced ventilator-free survival. A more severe disease course in critically ill COVID-19 patients with superinfections thus seems likely, also reflected by a substantially increased ICU length of stay despite empirical broad-spectrum antimicrobial therapy. Longitudinal microbiologic sampling in COVID-19 patients could allow targeted antimicrobial therapy, and therefore minimize the use of broad-spectrum and reserve antibiotics. Funding: Promedica-Foundation, unrestricted grant. Declaration of Interests: All other authors have no conflict of interest. Ethics Approval Statement: The study was approved by the local ethics committee of the Canton of Zurich, Switzerland (Kantonale Ethikkommission Zurich BASEC ID 2020 - 00646).

Advances in medical technology and IT infrastructure have led to increased availability of continuous patient data that allows investigation of the longitudinal progression of novel and known diseases in unprecedented detail. However, to accurately describe any underlying pathophysiology with longitudinal data, the individual patient trajectories have to be synchronized based on temporal markers. In this study, we use longitudinal data from 28 critically ill ICU COVID-19 patients to compare the commonly used alignment markers “onset of symptoms”, “hospital admission” and “ICU admission” with a novel objective method based on the peak value of inflammatory marker C-reactive protein (CRP). By applying our CRP-based method to align the progression of neutrophils and lymphocytes, we were able to define a pathophysiological window that allowed further risk stratification in our COVID-19 patient cohort. Our data highlights that proper synchronization of patient data is crucial to differentiate severity subgroups and to allow reliable interpatient comparisons.

PURPOSE OF REVIEW: Identification of insufficient tissue perfusion is fundamental to recognizing circulatory shock in critically ill patients, and the primary target to restore adequate oxygen delivery. However, the concept of tissue perfusion remains ill-defined and out-of-reach for clinicians as point-of-care resuscitation target. Even though handheld vital microscopy (HVM) provides the technical prerequisites to collect information on tissue perfusion in the sublingual microcirculation, challenges in image analysis prevent quantification of tissue perfusion and manual analysis steps prohibit point-of-care application. The present review aims to discuss recent advances in algorithm-based HVM analysis and the physiological basis of tissue perfusion-based resuscitation parameters. RECENT FINDINGS: Advanced computer vision algorithm such as MicroTools independently quantify microcirculatory diffusion and convection capacity by HVM and provide direct insight into tissue perfusion, leading to our formulation a functional parameter, tissue red blood cell (RBC) perfusion (tRBCp). Its definition is discussed in terms of the physiology of oxygen transport to the tissue and its expected effect as a point-of-care resuscitation target. Further refinements to microcirculatory monitoring include multiwavelength HVM techniques and maximal recruitable microcirculatory diffusion and convection capacity. SUMMARY: tRBCp as measured using algorithm-based HVM analysis with an automated software called MicroTools, represents a promising candidate to assess microcirculatory delivery of oxygen for microcirculation-based resuscitation in critically ill patients at the point-of-care.

The coronavirus disease 2019 (COVID-19) pandemic is overwhelming healthcare systems worldwide. There is no evidence from randomised clinical trials that any potential therapy improves outcome in COVID-19 pneumonia, and therapeutic strategies have been based on a progressively increasing knowledge of the clinical presentation of the disease. Some clinicians have found the clinical features of COVID-19 pneumonia to be similar to high-altitude pulmonary oedema (HAPE) [1], and such theory has been amplified via social media. We question this relationship., COVID-19 pneumonia is a viral infection; high-altitude pulmonary oedema is a non-cardiogenic oedema. Some clinicians have found the clinical features similar. It is important to clarify such misconceptions to prevent erroneous treatment strategies https://bit.ly/2KOBi3F

PEGylated carboxyhemoglobin (PEGHbCO), which has carbon monoxide-releasing properties and plasma expansion and oxygen-carrying properties, may improve both skeletal microcirculatory flow and renal cortical microcirculatory Po2 (CµPo2) and, subsequently, limit endotoxemia-induced acute kidney injury. Anesthetized, ventilated Wistar albino rats ( n = 44) underwent endotoxemic shock. CµPo2 was measured in exposed kidneys using a phosphorescence-quenching method. Rats were randomly assigned to the following five groups: 1) unresuscitated lipopolysaccharide (LPS), 2) LPS + Ringer’s acetate (RA), 3) LPS + RA + 0.5 µg·kg·−1min−1 norepinephrine (NE), 4) LPS + RA + 320 mg/kg PEGHbCO, and 5) LPS + RA + PEGHbCO + NE. The total volume was 30 mL/kg in each group. A time control animal group was used. Skeletal muscle microcirculation was assessed by handheld intravital microscopy. Kidney immunohistochemistry and myeloperoxidase-stained leukocytes in glomerular and peritubular areas were analyzed. Endotoxemia-induced histological damage was assessed. Plasma levels of IL-6, heme oxygenase-1, malondialdehyde, and syndecan-1 were assessed by ELISA. CµPo2 was higher in the LPS + RA + PEGHbCO-resuscitated group, at 35 ± 6mmHg compared with 21 ± 12 mmHg for the LPS+RA group [mean difference: −13.53, 95% confidence interval: (−26.35; −0.7156), P = 0.035]. The number of nonflowing, intermittent, or sluggish capillaries was smaller in groups infused with PEGHbCO compared with RA alone ( P < 0.05), while the number of normally perfused vessels was greater ( P < 0.05). The addition of NE did not further improve CµPo2 or microcirculatory parameters. Endotoxemia-induced kidney immunohistochemistry and histological alterations were not mitigated by PEGHbCO 1 h after resuscitation. Renal leukocyte infiltration and plasma levels of biomarkers were similar across groups. PEGHbCO enhanced CµPo2 while restoring skeletal muscle microcirculatory flow in previously nonflowing capillaries. PEGHbCO should be further evaluated as a resuscitation fluid in mid- to long-term models of sepsis-induced acute kidney injury.

This paper briefly reviews the physiological components of the microcirculation, focusing on its function in homeostasis and its central function in the realization of oxygen transport to tissue cells. Its pivotal role in the understanding of circulatory compromise in states of shock and renal compromise is discussed. Our introduction of hand-held vital microscopes (HVM) to clinical medicine has revealed the importance of the microcirculation as a central target organ in states of critical illness and inadequate response to therapy. Technical and methodological developments have been made in hardware and in software including our recent introduction and validation of automatic analysis software called MicroTools, which now allows point-of-care use of HVM imaging at the bedside for instant availability of functional microcirculatory parameters needed for microcirculatory targeted resuscitation procedures to be a reality. This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Primary resuscitation fluid to treat hemorrhagic shock remains controversial. Use of hydroxyethyl starches raised concerns of acute kidney injury. Polyethylene-glycolated carboxyhemoglobin, which has carbon monoxide–releasing molecules and oxygen-carrying properties, was hypothesized to sustain cortical renal microcirculatory Po2 after hemorrhagic shock and reduce kidney injury. Methods Anesthetized and ventilated rats (n = 42) were subjected to pressure-controlled hemorrhagic shock for 1 h. Renal cortical Po2 was measured in exposed kidneys using a phosphorescence quenching method. Rats were randomly assigned to six groups: polyethylene-glycolated carboxyhemoglobin 320 mg · kg−1, 6% hydroxyethyl starch (130/0.4) in Ringer’s acetate, blood retransfusion, diluted blood retransfusion (~4 g · dl−1), nonresuscitated animals, and time control. Nitric oxide and heme oxygenase 1 levels were determined in plasma. Kidney immunohistochemistry (histologic scores of neutrophil gelatinase-associated lipocalin and tumor necrosis factor-α) and tubular histologic damages analyses were performed. Results Blood and diluted blood restored renal Po2 to 51 ± 5 mmHg (mean difference, −18; 95% CI, −26 to −11; P < 0.0001) and 47 ± 5 mmHg (mean difference, −23; 95% CI, −31 to −15; P < 0.0001), respectively, compared with 29 ± 8 mmHg for hydroxyethyl starch. No differences between polyethylene-glycolated carboxyhemoglobin and hydroxyethyl starch were observed (33 ± 7 mmHg vs. 29 ± 8 mmHg; mean difference, −5; 95% CI, −12 to 3; P = 0.387), but significantly less volume was administered (4.5 [3.3–6.2] vs. 8.5[7.7–11.4] ml; mean rank difference, 11.98; P = 0.387). Blood and diluted blood increased the plasma bioavailability of nitric oxide compared with hydroxyethyl starch (mean rank difference, −20.97; P = 0.004; and −17.13; P = 0.029, respectively). No changes in heme oxygenase 1 levels were observed. Polyethylene-glycolated carboxyhemoglobin limited tubular histologic damages compared with hydroxyethyl starch (mean rank difference, 60.12; P = 0.0012) with reduced neutrophil gelatinase-associated lipocalin (mean rank difference, 84.43; P < 0.0001) and tumor necrosis factor-α (mean rank difference, 49.67; P = 0.026) histologic scores. Conclusions Polyethylene-glycolated carboxyhemoglobin resuscitation did not improve renal Po2 but limited tubular histologic damages and neutrophil gelatinase-associated lipocalin upregulation after hemorrhage compared with hydroxyethyl starch, whereas a lower volume was required to sustain macrocirculation.

What is the central question of this study? High-altitude hypoxia increases muscle sympathetic nerve activity (MSNA), but whether intravenous infusion of dopamine, to blunt the responsiveness of the carotid chemoreceptors, reduces MSNA at high altitude is not known. What is the main finding and its importance? Muscle sympathetic nerve activity was elevated after 15-17 days of high-altitude hypoxia (3454 m) compared with values at 'sea level' (432 m). However, intravenous dopamine infusion to blunt the responsiveness of the carotid chemoreceptors did not significantly decrease MSNA either at sea level or at high altitude, suggesting that high-altitude sympathoexcitation arises via a different mechanism. High-altitude hypoxia causes pronounced sympathoexcitation, but the underlying mechanisms remain unclear. We tested the hypothesis that i.v. infusion of dopamine to attenuate carotid chemoreceptor responsiveness would reduce muscle sympathetic nerve activity (MSNA) at high altitude. Nine healthy individuals [mean (SD); 26 (4) years of age] were studied at 'sea level' (SL; Zurich) and at high altitude (ALT; 3454 m; 15-17 days after arrival), both while breathing the ambient air and during an acute incremental hypoxia test (eight 3 min stages; partial pressure of end-tidal O2 90-45 mmHg). Intravenous infusions of dopamine (3 μg kg-1 min-1 ) and placebo (saline) were administered on both study days, according to a single-blind randomized cross-over design. Sojourn to high altitude decreased the partial pressure of end-tidal O2 (to ∼60 mmHg) and increased minute ventilation [VE; mean ± SEM, SL versus ALT: saline, 8.6 ± 0.5 versus 11.3 ± 0.6 l min-1 ; dopamine, 8.2 ± 0.5 versus 10.6 ± 0.8 l min-1 ; P < 0.05] and MSNA burst frequency by ∼80% [SL versus ALT: saline, 16 ± 3 versus 28 ± 4 bursts min-1 ; dopamine, 16 ± 4 versus 31 ± 4 bursts min-1 ; P < 0.05) when breathing the ambient air, but were not different with dopamine. Increases in MSNA burst frequency and VE during the acute incremental hypoxia test were greater at ALT than SL (P < 0.05). Dopamine did not affect the magnitude of the MSNA burst frequency response to acute incremental hypoxia at either SL or ALT. However, VE was lower with dopamine than saline administration throughout the acute incremental hypoxia test at ALT. These data indicate that i.v. infusion of low-dose dopamine to blunt the responsiveness of the carotid chemoreceptors does not significantly decrease MSNA at high altitude.

Chronic hypoxia increases resting heart rate (HR), but the underlying mechanism remains incompletely understood. We investigated the relative contributions of the sympathetic and parasympathetic ne ...

Matthias Peter Hilty, Andrea Mueller, Daniela Flück, Christoph Siebenmann, Peter Rasmussen, Stefanie Keiser, Katja Auinger, Carsten Lundby, and Marco Maggiorini. Effect of increased blood flow on the pulmonary circulation before and during high altitude acclimatization. High Alt Med Biol. 17:305-314, 2016.-Introduction and Methods: Acute exposure to high altitude increases pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR). The evolution of Ppa and PVR with continuous hypoxic exposure remains, however, elusive. To test the hypothesis that altitude exposure leads to a persistent elevation in Ppa and PVR throughout acclimatization in seven healthy male subjects, echocardiography was performed at sea level (SL; 488 m) weekly during a 4-week sojourn at 3454 m (HA1-HA4) and upon return (SL2). Pulmonary artery catheterization and bilateral thigh cuff release maneuver were performed at SL and HA3 to study the properties of pulmonary circulation after 3 weeks of acclimatization.Pulmonary artery catheter determined that systolic Ppa (mean ± SEM) was increased from 20 ± 1 at SL to 27 ± 2 mmHg at HA3 (p 0.01). Echocardiography assessed that systolic Ppa remained equally increased throughout acclimatization (26 ± 2, 25 ± 2, 25 ± 2, and 24 ± 2 mmHg at HA1-HA4; p = 0.93) and returned to baseline upon return (17 ± 2, 18 ± 1 mmHg at SL, SL2; p = 0.3). The same was shown for PVR. Right heart function remained unaffected. Thigh cuff release maneuvers at SL and HA3 resulted in similar increase in cardiac output (2.5 ± 0.5 and 2.2 ± 0.4 L/min; p = 0.61) without affecting mean Ppa.Prolonged altitude exposure leads to a persistent increase in Ppa and PVR without affecting right heart function and is fully reversible within 1 week after return to SL. The thigh cuff release maneuver-induced increase in cardiac output suggests a preserved ability of pulmonary circulation to cope with sudden remarkable increase in pulmonary blood flow throughout acclimatization.

Bed rest leads to rapid impairments in glucose tolerance. Plasma volume and thus dilution space for glucose are also reduced with bed rest, but the potential influence on glucose tolerance has not been investigated. Accordingly, the aim was to investigate whether bed rest-induced impairments in glucose tolerance are related to a concomitant reduction in plasma volume. This hypothesis was tested mechanistically by restoring plasma volume with albumin infusion after bed rest and parallel determination of glucose tolerance. Fifteen healthy volunteers (age 24 ± 3 yr, body mass index 23 ± 2 kg/m2, maximal oxygen uptake 44 ± 8 ml·min−1·kg−1; means ± SD) completed 4 days of strict bed rest. Glucose tolerance [oral glucose tolerance test (OGTT)] and plasma and blood volumes (carbon monoxide rebreathing) were assessed before and after 3 days of bed rest. On the fourth day of bed rest, plasma volume was restored by means of an albumin infusion prior to an OGTT. Plasma volume was reduced by 9.9 ± 3.0% on bed rest day 3 and area under the curve for OGTT was augmented by 55 ± 67%. However, no association ( R2= 0.09, P = 0.33) between these simultaneously occurring responses was found. While normalization of plasma volume by matched albumin administration (408 ± 104 ml) transiently decreased ( P < 0.05) resting plasma glucose concentration (5.0 ± 0.4 to 4.8 ± 0.3 mmol/l), this did not restore glucose tolerance. Bed rest-induced alterations in dilution space may influence resting glucose values but do not affect area under the curve for OGTT.

Acute kidney injury (AKI) is one of the most frequent complications in critically ill patients and in the perioperative setting. The anatomical structure and the microvasculature of the kidney makes it highly vulnerable to hypoxia. Although fluid therapy is considered crucial in situations where improvement of cardiac output is needed, it can also contribute to AKI development when administered inappropriately. Hemodilution and anemia during cardio-pulmonary bypass have been demonstrated to be risk factors for AKI and they are likely to be a consequence of fluid administration. In order to assess the perfusion of the kidneys it is necessary to investigate the determinants of delivery of oxygen at the microcirculatory level. Indeed, fluids can decrease the capillary hematocrit and the functional capillary density, affecting the renal oxygenation and increasing the risk of AKI. Monitoring sublingual microcirculation can be a reliable tool to guide fluid administration, aiming to prevent or improve perioperative AKI.

Direct assessment of capillary perfusion has been prioritized in hemodynamic management of critically ill patients in addition to optimizing blood flow on the global scale. Sublingual handheld vital microscopy has enabled online acquisition of moving image sequences of the microcirculation, including the flow of individual red blood cells in the capillary network. However, due to inherent content complexity, manual image sequence analysis remained gold standard, introducing inter-observer variability and precluding real-time image analysis for clinical therapy guidance. Here we introduce an advanced computer vision algorithm for instantaneous analysis and quantification of morphometric and kinetic information related to capillary blood flow in the sublingual microcirculation. We evaluated this technique in a porcine model of septic shock and resuscitation and cardiac surgery patients. This development is of high clinical relevance because it enables implementation of point-of-care goal-directed resuscitation procedures based on correction of microcirculatory perfusion in critically ill and perioperative patients., Matthias Hilty et al. develop MicroTools, a computer vision algorithm that analyzes image sequences obtained from handheld vital microscopy. MicroTools can provide morphometric and kinetic information about the sublingual microcirculation in real-time, making this tool highly relevant in clinical settings.

KEY POINTS A physiological response to increase microcirculatory oxygen extraction capacity at high altitude is to recruit capillaries. In the present study, we report that high altitude-induced sublingual capillary recruitment is an intrinsic mechanism of the sublingual microcirculation that is independent of changes in cardiac output, arterial blood pressure or systemic vascular hindrance. Using a topical nitroglycerin challenge to the sublingual microcirculation, we show that high altitude-related capillary recruitment is a functional response of the sublingual microcirculation as opposed to an anatomical response associated with angiogenesis. The concurrent presence of a low capillary density and high microvascular reactivity to topical nitroglycerin at sea level was found to be associated with a failure to reach the summit, whereas the presence of a high baseline capillary density with the ability to further increase maximum recruitable capillary density upon ascent to an extreme altitude was associated with summit success. ABSTRACT A high altitude (HA) stay is associated with an increase in sublingual capillary total vessel density (TVD), suggesting microvascular recruitment. We hypothesized that microvascular recruitment occurs independent of cardiac output changes, that it relies on haemodynamic changes within the microcirculation as opposed to structural changes and that microcirculatory function is related to individual performance at HA. In 41 healthy subjects, sublingual handheld vital microscopy and echocardiography were performed at sea level (SL), as well as at 6022 m (C2) and 7042 m (C3), during ascent to 7126 m within 21 days. Sublingual topical nitroglycerin was applied to measure microvascular reactivity and maximum recruitable TVD (TVDNG ). HA exposure decreased resting cardiac output, whereas TVD (mean ± SD) increased from 18.81 ± 3.92 to 20.92 ± 3.66 and 21.25 ± 2.27 mm mm-2 (P

High altitude (HA) exposure facilitates a rapid contraction of plasma volume (PV) and a slower occurring expansion of hemoglobin mass (Hbmass). The kinetics of the Hbmassexpansion has never been examined by multiple repeated measurements, and this was our primary study aim. The second aim was to investigate the mechanisms mediating the PV contraction. Nine healthy, normally trained sea-level (SL) residents (8 males, 1 female) sojourned for 28 days at 3,454 m. Hbmasswas measured and PV was estimated by carbon monoxide rebreathing at SL, on every 4th day at HA, and 1 and 2 wk upon return to SL. Four weeks at HA increased Hbmassby 5.26% (range 2.5-11.1%; P < 0.001). The individual Hbmassincreases commenced with up to 12 days of delay and reached a maximal rate of 4.04 ± 1.02 g/day after 14.9 ± 5.2 days. The probability for Hbmassto plateau increased steeply after 20–24 days. Upon return to SL Hbmassdecayed by −2.46 ± 2.3 g/day, reaching values similar to baseline after 2 wk. PV, aldosterone concentration, and renin activity were reduced at HA ( P < 0.001) while the total circulating protein mass remained unaffected. In summary, the Hbmassresponse to HA exposure followed a sigmoidal pattern with a delayed onset and a plateau after ∼3 wk. The decay rate of Hbmassupon descent to SL did not indicate major changes in the rate of erythrolysis. Moreover, our data support that PV contraction at HA is regulated by the renin-angiotensin-aldosterone axis and not by changes in oncotic pressure.

Humans cannot live at very high altitude for reasons, which are not completely understood. Since these reasons are not restricted to cardiorespiratory changes alone, changes in the endocrine system might also be involved. Therefore, hormonal changes during prolonged hypobaric hypoxia were comprehensively assessed to determine effects of altitude and hypoxia on stress, thyroid and gonadal hypothalamus–pituitary hormone axes. Twenty-one male and 19 female participants were examined repetitively during a high-altitude expedition. Cortisol, prolactin, thyroid-stimulating hormone (TSH), fT4 and fT3 and in males follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total testosterone were analysed as well as parameters of hypoxemia, such as SaO2 and paO2 at 550 m (baseline) (n = 40), during ascent at 4844 m (n = 38), 6022 m (n = 31) and 7050 m (n = 13), at 4844 m (n = 29) after acclimatization and after the expedition (n = 38). Correlation analysis of hormone concentrations with oxygen parameters and with altitude revealed statistical association in most cases only with altitude. Adrenal, thyroid and gonadal axes were affected by increasing altitude. Adrenal axis and prolactin were first supressed at 4844 m and then activated with increasing altitude; thyroid and gonadal axes were directly activated or suppressed respectively with increasing altitude. Acclimatisation at 4844 m led to normalization of adrenal and gonadal but not of thyroid axes. In conclusion, acclimatization partly leads to a normalization of the adrenal, thyroid and gonadal axes at around 5000 m. However, at higher altitude, endocrine dysregulation is pronounced and might contribute to the physical degradation found at high altitude.