Safety and Outcome of High-Flow Nasal Oxygen Therapy Outside ICU Setting in Hypoxemic Patients With COVID-19.

OBJECTIVE: High-flow nasal oxygen (HFNO) therapy is frequently applied outside ICU setting in hypoxemic patients with COVID-19. However, safety concerns limit more widespread use. We aimed to assess the safety and clinical outcomes of initiation of HFNO therapy in COVID-19 on non-ICU wards. DESIGN: Prospective observational multicenter pragmatic study. SETTING: Respiratory wards and ICUs of 10 hospitals in The Netherlands. PATIENTS: Adult patients treated with HFNO for COVID-19-associated hypoxemia between December 2020 and July 2021 were included. Patients with treatment limitations were excluded from this analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes included intubation and mortality rate, duration of hospital and ICU stay, severity of respiratory failure, and complications. Using propensity-matched analysis, we compared patients who initiated HFNO on the wards versus those in ICU. Six hundred eight patients were included, of whom 379 started HFNO on the ward and 229 in the ICU. The intubation rate in the matched cohort ( n = 214 patients) was 53% and 60% in ward and ICU starters, respectively ( p = 0.41). Mortality rates were comparable between groups (28-d [8% vs 13%], p = 0.28). ICU-free days were significantly higher in ward starters (21 vs 17 d, p < 0.001). No patient died before endotracheal intubation, and the severity of respiratory failure surrounding invasive ventilation and clinical outcomes did not differ between intubated ward and ICU starters (respiratory rate-oxygenation index 3.20 vs 3.38; Pa o2 :F io2 ratio 65 vs 64 mm Hg; prone positioning after intubation 81 vs 78%; mortality rate 17 vs 25% and ventilator-free days at 28 d 15 vs 13 d, all p values > 0.05). CONCLUSIONS: In this large cohort of hypoxemic patients with COVID-19, initiation of HFNO outside the ICU was safe, and clinical outcomes were similar to initiation in the ICU. Furthermore, the initiation of HFNO on wards saved time in ICU without excess mortality or complicated course. Our results indicate that HFNO initiation outside ICU should be further explored in other hypoxemic diseases and clinical settings aiming to preserve ICU capacity and healthcare costs.

Airborne virus shedding of the alpha, delta, omicron SARS-CoV-2 variants and influenza virus in hospitalized patients.

Airborne transmission is an important transmission route for the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological data indicate that certain SARS-CoV-2 variants, like the omicron variant, are associated with higher transmissibility. We compared virus detection in air samples between hospitalized patients infected with different SARS-CoV-2 variants or influenza virus. The study was performed during three separate time periods in which subsequently the alpha, delta, and omicron SARS-CoV-2 variants were predominant. In total, 79 patients with coronavirus disease 2019 (COVID-19) and 22 patients with influenza A virus infection were included. Collected air samples were positive in 55% of patients infected with the omicron variant in comparison to 15% of those infected with the delta variant (p < 0.01). In multivariable analysis, the SARS-CoV-2 omicron BA.1/BA.2 variant (as compared to the delta variant) and the viral load in nasopharynx were both independently associated with air sample positivity, but the alpha variant and COVID-19 vaccination were not. The proportion of positive air samples patients infected with the influenza A virus was 18%. In conclusion, the higher air sample positivity rate of the omicron variant compared to previous SARS-CoV-2 variants may partially explain the higher transmission rates seen in epidemiological trends.

DeltaScan for the Assessment of Acute Encephalopathy and Delirium in ICU and non-ICU Patients, a Prospective Cross-Sectional Multicenter Validation Study.

OBJECTIVES: To measure the diagnostic accuracy of DeltaScan: a portable real-time brain state monitor for identifying delirium, a manifestation of acute encephalopathy (AE) detectable by polymorphic delta activity (PDA) in single-channel electroencephalograms (EEGs). DESIGN: Prospective cross-sectional study. SETTING: Six Intensive Care Units (ICU's) and 17 non-ICU departments, including a psychiatric department across 10 Dutch hospitals. PARTICIPANTS: 494 patients, median age 75 (IQR:64-87), 53% male, 46% in ICUs, 29% delirious. MEASUREMENTS: DeltaScan recorded 4-minute EEGs, using an algorithm to select the first 96 seconds of artifact-free data for PDA detection. This algorithm was trained and calibrated on two independent datasets. METHODS: Initial validation of the algorithm for AE involved comparing its output with an expert EEG panel's visual inspection. The primary objective was to assess DeltaScan's accuracy in identifying delirium against a delirium expert panel's consensus. RESULTS: DeltaScan had a 99% success rate, rejecting 6 of the 494 EEG's due to artifacts. Performance showed and an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.86 (95% CI: 0.83-0.90) for AE (sensitivity: 0.75, 95%CI=0.68-0.81, specificity: 0.87 95%CI=0.83-0.91. The AUC was 0.71 for delirium (95%CI=0.66-0.75, sensitivity: 0.61 95%CI=0.52-0.69, specificity: 72, 95%CI=0.67-0.77). Our validation aim was an NPV for delirium above 0.80 which proved to be 0.82 (95%CI: 0.77-0.86). Among 84 non-delirious psychiatric patients, DeltaScan differentiated delirium from other disorders with a 94% (95%CI: 87-98%) specificity. CONCLUSIONS: DeltaScan can diagnose AE at bedside and shows a clear relationship with clinical delirium. Further research is required to explore its role in predicting delirium-related outcomes.

Rapid Evaluation of Coronavirus Illness Severity (RECOILS) in intensive care: Development and validation of a prognostic tool for in-hospital mortality.

BACKGROUND: The prediction of in-hospital mortality for ICU patients with COVID-19 is fundamental to treatment and resource allocation. The main purpose was to develop an easily implemented score for such prediction. METHODS: This was an observational, multicenter, development, and validation study on a national critical care dataset of COVID-19 patients. A systematic literature review was performed to determine variables possibly important for COVID-19 mortality prediction. Using a logistic multivariable model with a LASSO penalty, we developed the Rapid Evaluation of Coronavirus Illness Severity (RECOILS) score and compared its performance against published scores. RESULTS: Our development (validation) cohort consisted of 1480 (937) adult patients from 14 (11) Dutch ICUs admitted between March 2020 and April 2021. Median age was 65 (65) years, 31% (26%) died in hospital, 74% (72%) were males, average length of ICU stay was 7.83 (10.25) days and average length of hospital stay was 15.90 (19.92) days. Age, platelets, PaO2/FiO2 ratio, pH, blood urea nitrogen, temperature, PaCO2, Glasgow Coma Scale (GCS) score measured within +/-24 h of ICU admission were used to develop the score. The AUROC of RECOILS score was 0.75 (CI 0.71-0.78) which was higher than that of any previously reported predictive scores (0.68 [CI 0.64-0.71], 0.61 [CI 0.58-0.66], 0.67 [CI 0.63-0.70], 0.70 [CI 0.67-0.74] for ISARIC 4C Mortality Score, SOFA, SAPS-III, and age, respectively). CONCLUSIONS: Using a large dataset from multiple Dutch ICUs, we developed a predictive score for mortality of COVID-19 patients admitted to ICU, which outperformed other predictive scores reported so far.

Intensive Care Unit-Specific Virtual Reality for Critically Ill Patients With COVID-19: Multicenter Randomized Controlled Trial.

BACKGROUND: Although psychological sequelae after intensive care unit (ICU) treatment are considered quite intrusive, robustly effective interventions to treat or prevent these long-term sequelae are lacking. Recently, it was demonstrated that ICU-specific virtual reality (ICU-VR) is a feasible and acceptable intervention with potential mental health benefits. However, its effect on mental health and ICU aftercare in COVID-19 ICU survivors is unknown. OBJECTIVE: This study aimed to explore the effects of ICU-VR on mental health and on patients' perceived quality of, satisfaction with, and rating of ICU aftercare among COVID-19 ICU survivors. METHODS: This was a multicenter randomized controlled trial. Patients were randomized to either the ICU-VR (intervention) or the control group. All patients were invited to an COVID-19 post-ICU follow-up clinic 3 months after hospital discharge, during which patients in the intervention group received ICU-VR. One month and 3 months later (4 and 6 months after hospital discharge), mental health, quality of life, perceived quality, satisfaction with, and rating of ICU aftercare were scored using questionnaires. RESULTS: Eighty-nine patients (median age 58 years; 63 males, 70%) were included. The prevalence and severity of psychological distress were limited throughout follow-up, and no differences in psychological distress or quality of life were observed between the groups. ICU-VR improved satisfaction with (mean score 8.7, SD 1.6 vs 7.6, SD 1.6 [ICU-VR vs control]; t64=-2.82, P=.006) and overall rating of ICU aftercare (mean overall rating of aftercare 8.9, SD 0.9 vs 7.8, SD 1.7 [ICU-VR vs control]; t64=-3.25; P=.002) compared to controls. ICU-VR added to the quality of ICU aftercare according to 81% of the patients, and all patients would recommend ICU-VR to other ICU survivors. CONCLUSIONS: ICU-VR is a feasible and acceptable innovative method to improve satisfaction with and rating of ICU aftercare and adds to its perceived quality. We observed a low prevalence of psychological distress after ICU treatment for COVID-19, and ICU-VR did not improve psychological recovery or quality of life. Future research is needed to confirm our results in other critical illness survivors to potentially facilitate ICU-VR's widespread availability and application during follow-up. TRIAL REGISTRATION: Netherlands Trial Register NL8835; https://www.trialregister.nl/trial/8835. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-021-05271-z.

Predictors for extubation failure in COVID-19 patients using a machine learning approach.

INTRODUCTION: Determining the optimal timing for extubation can be challenging in the intensive care. In this study, we aim to identify predictors for extubation failure in critically ill patients with COVID-19. METHODS: We used highly granular data from 3464 adult critically ill COVID patients in the multicenter Dutch Data Warehouse, including demographics, clinical observations, medications, fluid balance, laboratory values, vital signs, and data from life support devices. All intubated patients with at least one extubation attempt were eligible for analysis. Transferred patients, patients admitted for less than 24 h, and patients still admitted at the time of data extraction were excluded. Potential predictors were selected by a team of intensive care physicians. The primary and secondary outcomes were extubation without reintubation or death within the next 7 days and within 48 h, respectively. We trained and validated multiple machine learning algorithms using fivefold nested cross-validation. Predictor importance was estimated using Shapley additive explanations, while cutoff values for the relative probability of failed extubation were estimated through partial dependence plots. RESULTS: A total of 883 patients were included in the model derivation. The reintubation rate was 13.4% within 48 h and 18.9% at day 7, with a mortality rate of 0.6% and 1.0% respectively. The grandient-boost model performed best (area under the curve of 0.70) and was used to calculate predictor importance. Ventilatory characteristics and settings were the most important predictors. More specifically, a controlled mode duration longer than 4 days, a last fraction of inspired oxygen higher than 35%, a mean tidal volume per kg ideal body weight above 8 ml/kg in the day before extubation, and a shorter duration in assisted mode (< 2 days) compared to their median values. Additionally, a higher C-reactive protein and leukocyte count, a lower thrombocyte count, a lower Glasgow coma scale and a lower body mass index compared to their medians were associated with extubation failure. CONCLUSION: The most important predictors for extubation failure in critically ill COVID-19 patients include ventilatory settings, inflammatory parameters, neurological status, and body mass index. These predictors should therefore be routinely captured in electronic health records.

The Dutch Data Warehouse, a multicenter and full-admission electronic health records database for critically ill COVID-19 patients.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic has underlined the urgent need for reliable, multicenter, and full-admission intensive care data to advance our understanding of the course of the disease and investigate potential treatment strategies. In this study, we present the Dutch Data Warehouse (DDW), the first multicenter electronic health record (EHR) database with full-admission data from critically ill COVID-19 patients. METHODS: A nation-wide data sharing collaboration was launched at the beginning of the pandemic in March 2020. All hospitals in the Netherlands were asked to participate and share pseudonymized EHR data from adult critically ill COVID-19 patients. Data included patient demographics, clinical observations, administered medication, laboratory determinations, and data from vital sign monitors and life support devices. Data sharing agreements were signed with participating hospitals before any data transfers took place. Data were extracted from the local EHRs with prespecified queries and combined into a staging dataset through an extract-transform-load (ETL) pipeline. In the consecutive processing pipeline, data were mapped to a common concept vocabulary and enriched with derived concepts. Data validation was a continuous process throughout the project. All participating hospitals have access to the DDW. Within legal and ethical boundaries, data are available to clinicians and researchers. RESULTS: Out of the 81 intensive care units in the Netherlands, 66 participated in the collaboration, 47 have signed the data sharing agreement, and 35 have shared their data. Data from 25 hospitals have passed through the ETL and processing pipeline. Currently, 3464 patients are included in the DDW, both from wave 1 and wave 2 in the Netherlands. More than 200 million clinical data points are available. Overall ICU mortality was 24.4%. Respiratory and hemodynamic parameters were most frequently measured throughout a patient's stay. For each patient, all administered medication and their daily fluid balance were available. Missing data are reported for each descriptive. CONCLUSIONS: In this study, we show that EHR data from critically ill COVID-19 patients may be lawfully collected and can be combined into a data warehouse. These initiatives are indispensable to advance medical data science in the field of intensive care medicine.

Effect of Low-Normal vs High-Normal Oxygenation Targets on Organ Dysfunction in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Hyperoxemia may increase organ dysfunction in critically ill patients, but optimal oxygenation targets are unknown. Objective: To determine whether a low-normal Pao2 target compared with a high-normal target reduces organ dysfunction in critically ill patients with systemic inflammatory response syndrome (SIRS). Design, Setting, and Participants: Multicenter randomized clinical trial in 4 intensive care units in the Netherlands. Enrollment was from February 2015 to October 2018, with end of follow-up to January 2019, and included adult patients admitted with 2 or more SIRS criteria and expected stay of longer than 48 hours. A total of 9925 patients were screened for eligibility, of whom 574 fulfilled the enrollment criteria and were randomized. Interventions: Target Pao2 ranges were 8 to 12 kPa (low-normal, n = 205) and 14 to 18 kPa (high-normal, n = 195). An inspired oxygen fraction greater than 0.60 was applied only when clinically indicated. Main Outcomes and Measures: Primary end point was SOFARANK, a ranked outcome of nonrespiratory organ failure quantified by the nonrespiratory components of the Sequential Organ Failure Assessment (SOFA) score, summed over the first 14 study days. Participants were ranked from fastest organ failure improvement (lowest scores) to worsening organ failure or death (highest scores). Secondary end points were duration of mechanical ventilation, in-hospital mortality, and hypoxemic measurements. Results: Among the 574 patients who were randomized, 400 (70%) were enrolled within 24 hours (median age, 68 years; 140 women [35%]), all of whom completed the trial. The median Pao2 difference between the groups was -1.93 kPa (95% CI, -2.12 to -1.74; P < .001). The median SOFARANK score was -35 points in the low-normal Pao2 group vs -40 in the high-normal Pao2 group (median difference, 10 [95% CI, 0 to 21]; P = .06). There was no significant difference in median duration of mechanical ventilation (3.4 vs 3.1 days; median difference, -0.15 [95% CI, -0.88 to 0.47]; P = .59) and in-hospital mortality (32% vs 31%; odds ratio, 1.04 [95% CI, 0.67 to 1.63]; P = .91). Mild hypoxemic measurements occurred more often in the low-normal group (1.9% vs 1.2%; median difference, 0.73 [95% CI, 0.30 to 1.20]; P < .001). Acute kidney failure developed in 20 patients (10%) in the low-normal Pao2 group and 21 patients (11%) in the high-normal Pao2 group, and acute myocardial infarction in 6 patients (2.9%) in the low-normal Pao2 group and 7 patients (3.6%) in the high-normal Pao2 group. Conclusions and Relevance: Among critically ill patients with 2 or more SIRS criteria, treatment with a low-normal Pao2 target compared with a high-normal Pao2 target did not result in a statistically significant reduction in organ dysfunction. However, the study may have had limited power to detect a smaller treatment effect than was hypothesized. Trial Registration: ClinicalTrials.gov Identifier: NCT02321072.

Physiological Effects of High-Flow Tracheal Oxygen in Tracheostomized Patients Weaning From Mechanical Ventilation.

BACKGROUND: High-flow tracheal oxygen (HFTO) is being used as supportive therapy during weaning in tracheostomized patients difficult to wean from invasive mechanical ventilation. There is, however, no clinical evidence for such a strategy. Therefore, we conducted a systematic review to summarize studies evaluating the physiologic effects of HFTO during tracheostomy-facilitated weaning and to identify potential areas for future research in this field. METHODS: Observational and interventional studies on critically ill subjects weaning from mechanical ventilation via tracheostomy published until December 22, 2022, were eligible. Studies on high-flow oxygen, only in children, non-human models or animals, on clinical outcome only, abstracts without full-text availability, case reports, and reviews were excluded. Main outcomes were end-expiratory lung volume (EELV) and tidal volume using electrical impedance tomography, respiratory effort assessed by esophageal manometry, work of breathing and neuroventilatory drive as assessed by electrical activity of the diaphragm (EAdi) signal, airway pressure (Paw), oxygenation (PaO2 /FIO2 or SpO2 /FIO2 ), breathing frequency, tidal volume, and PaCO2 . RESULTS: In total, 1,327 references were identified, of which 5 were included. In all studies, HFTO was administered with flow 50 L/min and compared to conventional O2 therapy in a crossover design. The total average duration of invasive ventilation at time of measurements ranged from 11-27 d. In two studies, PaO2 /FIO2 and mean Paw were higher with HFTO. EELV, tidal volumes, esophageal pressure swings, and EAdi were similar during high-flow tracheal oxygen and conventional O2 therapy. CONCLUSIONS: The main physiological effect of HFTO as compared to conventional O2 therapy in tracheostomized subjects weaning from mechanical ventilation was improved oxygenation that is probably flow-dependent. Respiratory effort, lung aeration, neuroventilatory drive, and ventilation were similar for HFTO and conventional O2 therapy. Future studies on HFTO should be performed early in the weaning process and should evaluate its effect on sputum clearance and patient-centered outcomes like dyspnea.

The Value of Ischemic Cardiac Biomarkers to Predict Spontaneous Breathing Trial or Extubation Failure: A Systematic Review.

Background: It is unclear whether other cardiac biomarkers than NT-proBNP can be useful in the risk stratification of patients weaning from mechanical ventilation. The aim of this study is to summarize the role of ischemic cardiac biomarkers in predicting spontaneous breathing trial (SBT) or extubation failure. Methods: We systematically searched Embase, MEDLINE, Web of Science, and Cochrane Central for studies published before January 2024 that reported the association between ischemic cardiac biomarkers and SBT or extubation failure. Data were extracted using a standardized form and methodological assessment was performed using the QUIPS tool. Results: Seven observational studies investigating four ischemic cardiac biomarkers (Troponin-T, Troponin-I, CK-MB, Myoglobin) were included. One study reported a higher peak Troponin-I in patients with extubation failure compared to extubation success (50 ng/L [IQR, 20-215] versus 30 ng/L [IQR, 10-86], p = 0.01). A second study found that Troponin-I measured before the SBT was higher in patients with SBT failure in comparison to patients with SBT success (100 ± 80 ng/L versus 70 ± 130 ng/L, p = 0.03). A third study reported a higher CK-MB measured at the end of the SBT in patients with weaning failure (SBT or extubation failure) in comparison to weaning success (8.77 ± 20.5 ng/mL versus 1.52 ± 1.42 ng/mL, p = 0.047). Troponin-T and Myoglobin as well as Troponin-I and CK-MB measured at other time points were not found to be related to SBT or extubation failure. However, most studies were underpowered and with high risk of bias. Conclusions: The association with SBT or extubation failure is limited for Troponin-I and CK-MB and appears absent for Troponin-T and Myoglobin, but available studies are hampered by significant methodological drawbacks. To more definitively determine the role of ischemic cardiac biomarkers, future studies should prioritize larger sample sizes, including patients at risk of cardiac disease, using stringent SBTs and structured timing of laboratory measurements before and after SBT.

Characteristics and outcomes of COVID-19 patients admitted to hospital with and without respiratory symptoms.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83-0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Stem cell factor consistently improves thymopoiesis after experimental transplantation of murine or human hematopoietic stem cells in immunodeficient mice.

Deficient thymopoiesis is a pivotal determinant of impaired immune competence following hematopoietic stem cell transplantation (HSCT). Stem cell factor (SCF) is essentially involved in early thymopoiesis. We evaluated whether SCF administration would improve recovery of thymopoiesis following HSCT in immunodeficient mice receiving: 1) bone marrow (BM) transplantation of congenic mice; or 2) human fetal liver HSCT in the human immune system mouse model. Following murine BM transplantation, SCF significantly enhanced thymopoiesis and peripheral T cell recovery in lymph nodes and spleen. SCF did not affect BM lymphoid progenitor recovery and/or expansion. Median thymic cellularity increased from 0.9 in PBS- to 266 × 10(4)/thymus in SCF-treated mice (p = 0.05). Following human HSCT in human immune system mice, higher thymic cellularity was observed in SCF-treated mice. Double-negative and early double-positive thymocyte subsets increased, but especially late double-positive, CD4 single-positive, and CD8 single-positive thymocyte subsets were significantly enhanced (p < 0.05). These results show that exogenous supply of SCF may significantly improve murine and human posttransplant thymopoiesis, for which the effect is probably exerted by directly promoting T cell development intrathymically rather than by enhanced entry of prethymically expanded lymphoid progenitors.

Diaphragm excursions as proxy for tidal volume during spontaneous breathing in invasively ventilated ICU patients.

There is a need to monitor tidal volume in critically ill patients with acute respiratory failure, given its relation with adverse clinical outcome. However, quantification of tidal volume in non-intubated patients is challenging. In this proof-of-concept study, we evaluated whether ultrasound measurements of diaphragm excursion could be a valid surrogate for tidal volume in patients with respiratory failure. Diaphragm excursions and tidal volumes were simultaneously measured in invasively ventilated patients (N = 21) and healthy volunteers (N = 20). Linear mixed models were used to estimate the ratio between tidal volume and diaphragm excursion. The tidal volume-diaphragm excursion ratio was 201 mL/cm in ICU patients [95% confidence interval (CI) 161-240 mL/cm], and 361 (294-428) mL/cm in healthy volunteers. An excellent association was shown within participants (R2 = 0.96 in ICU patients, R2 = 0.90 in healthy volunteers). However, the differences between observed tidal volume and tidal volume as predicted by the linear mixed models were considerable: the 95% limits of agreement in Bland-Altman plots were ± 91 mL in ICU patients and ± 396 mL in healthy volunteers. Likewise, the variability in tidal volume estimation between participants was large. This study shows that diaphragm excursions measured with ultrasound correlate with tidal volume, yet quantification of absolute tidal volume from diaphragm excursion is unreliable.

Implementation of Recommendations on the Use of Corticosteroids in Severe COVID-19.

Importance: Research diversity and representativeness are paramount in building trust, generating valid biomedical knowledge, and possibly in implementing clinical guidelines. Objectives: To compare variations over time and across World Health Organization (WHO) geographic regions of corticosteroid use for treatment of severe COVID-19; secondary objectives were to evaluate the association between the timing of publication of the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial (June 2020) and the WHO guidelines for corticosteroids (September 2020) and the temporal trends observed in corticosteroid use by region and to describe the geographic distribution of the recruitment in clinical trials that informed the WHO recommendation. Design, Setting, and Participants: This prospective cohort study of 434 851 patients was conducted between January 31, 2020, and September 2, 2022, in 63 countries worldwide. The data were collected under the auspices of the International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC)-WHO Clinical Characterisation Protocol for Severe Emerging Infections. Analyses were restricted to patients hospitalized for severe COVID-19 (a subset of the ISARIC data set). Exposure: Corticosteroid use as reported to the ISARIC-WHO Clinical Characterisation Protocol for Severe Emerging Infections. Main Outcomes and Measures: Number and percentage of patients hospitalized with severe COVID-19 who received corticosteroids by time period and by WHO geographic region. Results: Among 434 851 patients with confirmed severe or critical COVID-19 for whom receipt of corticosteroids could be ascertained (median [IQR] age, 61.0 [48.0-74.0] years; 53.0% male), 174 307 (40.1%) received corticosteroids during the study period. Of the participants in clinical trials that informed the guideline, 91.6% were recruited from the United Kingdom. In all regions, corticosteroid use for severe COVID-19 increased, but this increase corresponded to the timing of the RECOVERY trial (time-interruption coefficient 1.0 [95% CI, 0.9-1.2]) and WHO guideline (time-interruption coefficient 1.9 [95% CI, 1.7-2.0]) publications only in Europe. At the end of the study period, corticosteroid use for treatment of severe COVID-19 was highest in the Americas (5421 of 6095 [88.9%]; 95% CI, 87.7-90.2) and lowest in Africa (31 588 of 185 191 [17.1%]; 95% CI, 16.8-17.3). Conclusions and Relevance: The results of this cohort study showed that implementation of the guidelines for use of corticosteroids in the treatment of severe COVID-19 varied geographically. Uptake of corticosteroid treatment was lower in regions with limited clinical trial involvement. Improving research diversity and representativeness may facilitate timely knowledge uptake and guideline implementation.

Effect of lung ultrasound-guided fluid deresuscitation on duration of ventilation in intensive care unit patients (CONFIDENCE): protocol for a multicentre randomised controlled trial.

BACKGROUND: Fluid therapy is a common intervention in critically ill patients. It is increasingly recognised that deresuscitation is an essential part of fluid therapy and delayed deresuscitation is associated with longer invasive ventilation and length of intensive care unit (ICU) stay. However, optimal timing and rate of deresuscitation remain unclear. Lung ultrasound (LUS) may be used to identify fluid overload. We hypothesise that daily LUS-guided deresuscitation is superior to deresuscitation without LUS in critically ill patients expected to undergo invasive ventilation for more than 24 h in terms of ventilator free-days and being alive at day 28. METHODS: The "effect of lung ultrasound-guided fluid deresuscitation on duration of ventilation in intensive care unit patients" (CONFIDENCE) is a national, multicentre, open-label, randomised controlled trial (RCT) in adult critically ill patients that are expected to be invasively ventilated for at least 24 h. Patients with conditions that preclude a negative fluid balance or LUS examination are excluded. CONFIDENCE will operate in 10 ICUs in the Netherlands and enrol 1000 patients. After hemodynamic stabilisation, patients assigned to the intervention will receive daily LUS with fluid balance recommendations. Subjects in the control arm are deresuscitated at the physician's discretion without the use of LUS. The primary endpoint is the number of ventilator-free days and being alive at day 28. Secondary endpoints include the duration of invasive ventilation; 28-day mortality; 90-day mortality; ICU, in hospital and total length of stay; cumulative fluid balance on days 1-7 after randomisation and on days 1-7 after start of LUS examination; mean serum lactate on days 1-7; the incidence of reintubations, chest drain placement, atrial fibrillation, kidney injury (KDIGO stadium ≥ 2) and hypernatremia; the use of invasive hemodynamic monitoring, and chest-X-ray; and quality of life at day 28. DISCUSSION: The CONFIDENCE trial is the first RCT comparing the effect of LUS-guided deresuscitation to routine care in invasively ventilated ICU patients. If proven effective, LUS-guided deresuscitation could improve outcomes in some of the most vulnerable and resource-intensive patients in a manner that is non-invasive, easy to perform, and well-implementable. TRIAL REGISTRATION: ClinicalTrials.gov NCT05188092. Registered since January 12, 2022.

Keratinocyte growth factor and stem cell factor to improve thymopoiesis after autologous CD34+ cell transplantation in rhesus macaques.

Deficient thymopoiesis and retarded recovery of naive CD4(+) T cells are important determinants of insufficient immune-competence following hematopoietic stem cell transplantation (HSCT). Although keratinocyte growth factor (KGF) may protect the thymic epithelium, stem cell factor (SCF) is involved in early thymopoiesis. We evaluated whether KGF alone or combined with SCF would affect thymopoiesis and hematologic recovery following myeloablative autologous HSCT into rhesus macaques. Purpose-bred adult rhesus macaques received 10(6) autologous CD34(+)-selected mononuclear bone marrow cells (BMC)/kg after 9 Gy myeloablative conditioning. Animals were treated with phosphate-buffered saline (PBS) (n = 2), KGF alone (n = 2), or KGF combined with SCF (n = 2). KGF-treated animals showed accelerated hematologic recovery, improved thymopoiesis, and enhanced naive T-cell recovery following transplantation. Improved T cell recovery was not associated with protection against cytomegalovirus reactivation nor with improved antibody response to tetanus toxoid vaccination. Animals treated with KGF and SCF experienced severe adverse events that precluded evaluation of thymopoiesis and T cell recovery. Collectively, our data confirm that KGF may enhance thymopoiesis.

[High flow nasal oxygen in patients with COVID-19]. / Zuurstoftoediening met hoge nasale flow bij covid-19.

High flow nasal oxygen (HFNO) is proven to be effective in non-COVID-19 hypoxemic respiratory failure. In the beginning of the COVID-19 pandemic, HFNO was quickly introduced into daily clinical practice, although the evidence of its effectiveness in COVID-19 was limited. Randomized controlled trials suggest that HFNO has no effect on survival. However, HFNO may lead to less intubations in comparison with conventional oxygen therapy. The evidence of HFNO use in patients with do-not-intubate orders remains very limited. However, in these patients, improvement in comfort could be an important argument to start treatment with HFNO. Additional research is needed to make an evidence based consideration about the clinical use of HFNO in COVID-19 care.

Effect of intensive care unit-specific virtual reality (ICU-VR) to improve psychological well-being in ICU survivors: study protocol for an international, multicentre, randomised controlled trial-the HORIZON-IC study.

INTRODUCTION: A substantial proportion of intensive care unit (ICU) survivors develop psychological impairments after ICU treatment, part of the postintensive care syndrome, resulting in a decreased quality of life. Recent data suggest that an ICU-specific virtual reality intervention (ICU-VR) for post-ICU patients is feasible and safe, improves satisfaction with ICU aftercare, and might improve psychological sequelae. In the present trial, we firstly aim to determine whether ICU-VR is effective in mitigating post-traumatic stress disorder (PTSD)-related symptoms and secondly to determine the optimal timing for initiation with ICU-VR. METHODS AND ANALYSIS: This international, multicentre, randomised controlled trial will be conducted in 10 hospitals. Between December 2021 and April 2023, we aim to include 300 patients who have been admitted to the ICU ≥72 hours and were mechanically ventilated ≥24 hours. Patients will be followed for 12 consecutive months. Patients will be randomised in a 1:1:1 ratio to the early ICU-VR group, the late ICU-VR group, or the usual care group. All patients will receive usual care, including a mandatory ICU follow-up clinic visit 3 months after ICU discharge. Patients in the early ICU-VR group will receive ICU-VR within 2 weeks after ICU discharge. Patients in the late VR group will receive ICU-VR during the post-ICU follow-up visit. The primary objective is to assess the effect of ICU-VR on PTSD-related symptoms. Secondary objectives are to determine optimal timing for ICU-VR, to assess the effects on anxiety-related and depression-related symptoms and health-related quality of life, and to assess patient satisfaction with ICU aftercare and perspectives on ICU-VR. ETHICS AND DISSEMINATION: The Medical Ethics Committee United, Nieuwegein, the Netherlands, approved this study and local approval was obtained from each participating centre (NL78555.100.21). Our findings will be disseminated by presentation of the results at (inter)national conferences and publication in scientific, peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL9812.

Model-informed precision dosing of beta-lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial.

PURPOSE: Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking. METHODS: This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment. RESULTS: In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes. CONCLUSIONS: We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.