Uromodulin in sepsis and severe pneumonia: a two-sample Mendelian randomization study.

The outcome for patients with sepsis-associated acute kidney injury in the intensive care unit (ICU) remains poor. Low serum uromodulin (sUMOD) protein levels have been proposed as a causal mediator of this effect. We investigated the effect of different levels of sUMOD on the risk of sepsis and severe pneumonia and outcomes in these conditions. A two-sample Mendelian randomization (MR) study was performed. Single-nucleotide polymorphisms (SNPs) associated with increased levels of sUMOD were identified and used as instrumental variables for association with outcomes. Data from different cohorts were combined based on disease severity and meta-analyzed. Five SNPs associated with increased sUMOD levels were identified and tested in six datasets from two biobanks. There was no protective effect of increased levels of sUMOD on the risk of sepsis [two cohorts, odds ratio (OR) 0.99 (95% confidence interval 0.95-1.03), P = 0.698, and OR 0.95 (0.91-1.00), P = 0.060, respectively], risk of sepsis requiring ICU admission [OR 1.04 (0.93-1.16), P = 0.467], ICU mortality in sepsis [OR 1.00 (0.74-1.37), P = 0.987], risk of pneumonia requiring ICU admission [OR 1.05 (0.98-1.14), P = 0.181], or ICU mortality in pneumonia [OR 1.17 (0.98-1.39), P = 0.079]. Meta-analysis of hospital-admitted and ICU-admitted patients separately yielded similar results [OR 0.98 (0.95-1.01), P = 0.23, and OR 1.05 (0.99-1.12), P = 0.86, respectively]. Among patients with sepsis and severe pneumonia, there was no protective effect of different levels of sUMOD. Results were consistent regardless of geographic origins and not modified by disease severity. NEW & NOTEWORTHY The presence of acute kidney injury in severe infections increases the likelihood of poor outcome severalfold. A decrease in serum uromodulin (sUMOD), synthetized in the kidney, has been proposed as a mediator of this effect. Using the Mendelian randomization technique, we tested the hypothesis that increased sUMOD is protective in severe infections. Analyses, however, showed no evidence of a protective effect of higher levels of sUMOD in sepsis or severe pneumonia.

Metabolomic pattern associated with physical sequelae in patients presenting with respiratory symptoms validates the aestivation concept in dehydrated patients.

Hypertonic dehydration is associated with muscle wasting and synthesis of organic osmolytes. We recently showed a metabolic shift to amino acid production and urea cycle activation in coronavirus-2019 (COVID-19), consistent with the aestivation response. The aim of the present investigation was to validate the metabolic shift and development of long-term physical outcomes in the non-COVID cohort of the Biobanque Québécoise de la COVID-19 (BQC19). We included 824 patients from BQC19, where 571 patients had data of dehydration in the form of estimated osmolality (eOSM = 2Na + 2K + glucose + urea), and 284 patients had metabolome data and long-term follow-up. We correlated the degree of dehydration to mortality, invasive mechanical ventilation, acute kidney injury, and long-term symptoms. As found in the COVID cohort, higher eOSM correlated with a higher proportion of urea and glucose of total eOSM, and an enrichment of amino acids compared with other metabolites. Sex-stratified analysis indicated that women may show a weaker aestivation response. More severe dehydration was associated with mortality, invasive mechanical ventilation, and acute kidney injury during the acute illness. Importantly, more severe dehydration was associated with physical long-term symptoms but not mental long-term symptoms after adjustment for age, sex, and disease severity. Patients with water deficit in the form of increased eOSM tend to have more severe disease and experience more physical symptoms after an acute episode of care. This is associated with amino acid and urea production, indicating dehydration-induced muscle wasting.NEW & NOTEWORTHY We have previously shown that humans exhibit an aestivation-like response where dehydration leads to a metabolic shift to urea synthesis, which is associated with long-term weakness indicating muscle wasting. In the present study, we validate this response in a new cohort and present a deeper metabolomic analysis and pathway analysis. Finally, we present a sex-stratified analysis suggesting weaker aestivation in women. However, women show less dehydration, so the association warrants further study.

Physical activity is associated with a lower risk of contracting and dying in infection and sepsis: a Swedish population-based cohort study.

BACKGROUND: Sepsis is a condition where the immune response to infection becomes dysregulated and life-threatening. It is not known whether lifestyle factors influence the risk of sepsis. The aim of the present study is to investigate the association between physical activity and the risk of acquiring and dying in infection or sepsis. METHODS: The population-based Swedish Mammography Cohort and Cohort of Swedish Men sent participants lifestyle questionnaires in 1997 and have subsequently followed participants in national Swedish registers, including the National Patient Register, the Swedish Intensive Care Registry and the Cause of Death Register. The risk of contracting infection and sepsis, the risk of intensive care unit admission and the risk of death were estimated using multivariable Cox regression. RESULTS: Among 64,850 cohort participants, 26,124 individuals suffered at least one episode of infection or sepsis and 4708 individuals died of infection or sepsis during the study period. In adjusted analyses, compared to exercising less than one hour per week, stated exercise one hour per week was associated with lower risk of contracting infection or sepsis, hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.90-0.97), and lower risk of dying in infection or sepsis, HR 0.87 (95% CI 0.80-0.96). Further exercise was associated with even lower risk, and similar patterns were observed for walking. The population-attributable risks of contracting and dying in infection or sepsis for not exercising were 2.6% and 4.5%, respectively. CONCLUSIONS: Exercise and walking demonstrate inverse dose-response associations with both the risk of contracting and dying in infection and sepsis, presenting possible preventative interventions for this critical condition.

Audio podcast and procedural video use in anaesthesiology and intensive care: A nationwide survey of Swedish anaesthetists.

BACKGROUND: Digital modalities which enable asynchronous learning, such as audio podcasts and videos demonstrating procedures, may benefit acquisition and retention of knowledge and clinical skills. The main objective of this nationwide cross-sectional survey study was to evaluate key aspects and factors related to usage of audio podcasts and procedural videos in anaesthesiology and intensive care. METHODS: A 20-item multiple-choice-question online survey was created through a consensus process including pilot testing among residents and consultants. Data were collected over a 3-month period, September-November 2023. RESULTS: The survey was completed by 466 anaesthetists. More than a third reported using procedural videos ≥1 time per week, whereas fewer than one in four participants used audio podcasts at least once per week. Multivariable logistic regression analysis showed that working at a university hospital, male sex, and younger age were independently associated with podcast use ≥1 time per week, with the highest odds ratio (OR) for younger age (<40 years vs. ≥40 years old; OR 5.86 (95% confidence interval 3.55-9.67), p < .001). Younger age was also significantly associated with higher frequency of video use (OR 1.71 (1.13-2.58), p = .011), while working predominantly in intensive care was associated with a lower frequency of video use. Podcasts were often used during commuting (42.3%), household work (30.7%), and exercise (24.9%), indicating a role in multi-tasking. Approximately half of respondents expressed that audio podcast-based learning has a moderate to very large positive impact on acquisition of theoretical knowledge, as well as practical skills. A vast majority, 85.2%, reported that procedural videos have a moderate to very large impact on development of clinical skills. CONCLUSION: Audio podcasts and procedural videos are appreciated tools with potential to supplement more traditional didactic techniques in anaesthesiology and intensive care. Procedural video use is common, with perceived large effects on development of clinical skills. Further data are needed to fully understand learning outcomes, quality of peer-review processes, and potential sex-differences.

Swedish multicentre study of target attainments with ß-lactams in the ICU: which MIC parameter should be used?

BACKGROUND: Therapeutic drug monitoring (TDM) has been suggested to optimize antimicrobial target attainment, typically using 100%T>MIC, in ß-lactam treatment in the ICU. The MIC parameter used in this equation is mostly the worst case scenario MIC (MICWCS)-the highest MIC the empirical treatment should cover. However, the impact of the MIC parameter used in pharmacokinetic/pharmacodynamic calculations has been poorly investigated. OBJECTIVES: To assess the influence of target attainment rates for two different MIC parameters using actual MICs of the causative pathogens as the primary reference. METHODS: In a Swedish multicentre study of target attainment for 138 ICU patients treated with ß-lactams, the causative pathogen was isolated and subjected to reference MIC testing. Whenever the strain belonged to the WT distribution, we assigned it to the category MICECOFF (epidemiological cut-off value). In the calculations we compared the MICECOFF and the MICWCS. RESULTS: The proportion of patients with target attainment failure for all antibiotics using 100%T>MIC was 45% (95% CI, 37%-53%) for MICWCS and 23% (95% CI, 16%-31%) for MICECOFF. When the target 50%T>4×MIC was used, corresponding attainment failures were 57% (95% CI, 49%-66%) and 25% (95% CI, 17%-32%) for MICWCS and MICECOFF, respectively. CONCLUSIONS: MICWCS can overestimate target attainment failure. The use of MICWCS could be one reason for the difficulties in establishing a relationship between target failure and mortality in other studies. Based on findings herein, the MICECOFF, which is based on the MIC of the causative pathogen, should be considered a more suitable alternative. When no pathogen is detected, the MICECOFF of likely pathogens according to infection type should be used.

Predicting cytokine kinetics during sepsis; a modelling framework from a porcine sepsis model with live Escherichia coli.

BACKGROUND: Describing the kinetics of cytokines involved as biomarkers of sepsis progression could help to optimise interventions in septic patients. This work aimed to quantitively characterise the cytokine kinetics upon exposure to live E. coli by developing an in silico model, and to explore predicted cytokine kinetics at different bacterial exposure scenarios. METHODS: Data from published in vivo studies using a porcine sepsis model were analysed. A model describing the time courses of bacterial dynamics, endotoxin (ETX) release, and the kinetics of TNF and IL-6 was developed. The model structure was extended from a published model that quantifies the ETX-cytokines relationship. An external model evaluation was conducted by applying the model to literature data. Model simulations were performed to explore the sensitivity of the host response towards differences in the input rate of bacteria, while keeping the total bacterial burden constant. RESULTS: The analysis included 645 observations from 30 animals. The blood bacterial count was well described by a one-compartment model with linear elimination. A scaling factor was estimated to quantify the ETX release by bacteria. The model successfully described the profiles of TNF, and IL-6 without a need to modify the ETX-cytokines model structure. The kinetics of TNF, and IL-6 in the external datasets were well predicted. According to the simulations, the ETX tolerance development results in that low initial input rates of bacteria trigger the lowest cytokine release. CONCLUSION: The model quantitively described and predicted the cytokine kinetics triggered by E. coli exposure. The host response was found to be sensitive to the bacterial exposure rate given the same total bacterial burden.

Risk of malignant disease in 1-year sepsis survivors, a registry-based nationwide follow-up study.

BACKGROUND: Cancer and sepsis share risk factors, and sepsis patients may have impaired immune response and increased morbidity long after intensive care. This study aimed to assess whether sepsis survivors are at increased risk for cancer. Our objective was to assess the incidence of new cancer in 1-year sepsis survivors and test the hypothesis that it is higher than that of the general population. METHODS: We obtained data on ICU admissions of adult patients from Swedish Intensive care registry (SICR) from 2005 to 2017. We included patients with an explicit ICD-10 code for sepsis for the primary ICU admission. We obtained data on cancer diagnoses (2001-2018), death (2005-2018) and emigration (2005-2018) from Cancer and Cause of death and National Patient Registry databases of the National Board of Health and Welfare; age and sex-specific cancer incidence rates in Sweden from NORDCAN registry from 2006 to 2018. One-year survivors formed the final cohort, that was followed for new cancer diagnoses until death, emigration, or end of 2018, whichever came first. The main outcome measure was standardized incidence rate ratio (SIR) to compare the incidence of cancer in 1-year sepsis survivors to that in the general population (NORDCAN). We also performed several sensitivity analyses. RESULTS: In a cohort of 18,550 1-year survivors, 75,427 person years accumulated during a median follow-up (FU) of 3.36 years (IQR 1.72-5.86), 6366 (34.3%) patients died, and 1625 (8.8%) patients were diagnosed with a new cancer after a median FU of 2.51 (IQR 1.09-4.48) years. The incidence ratio of any new cancer over the whole FU was 1.31 (95% CI 1.23-1.40) for men and 1.74 (95% CI 1.61-1.88) for women. The difference in incidence rates persisted in several sensitivity analyses. The SIRs were highest in cancers of gastrointestinal tract, genital organs, and skin. CONCLUSION AND RELEVANCE: Compared to general population, incidence of cancer is increased in 1-year sepsis survivors. Variation in the findings depending on follow-up time suggests that factors other than sepsis alone are involved. Surveillance for malignant disease may be warranted in sepsis survivors.

Point of Care Analysis of Hematology in the Operating Theater - a Prospective Observational Study of Accuracy and Feasibility.

BACKGROUND: Major surgery entails the risk of severe hemorrhage, and an optimized substitution with red blood cell (RBC) and platelet (PLT) transfusions necessitate rapid test results for RBCs/hemoglobin (HGB)/hematocrit (HCT), and PLTs. The HemoScreen (PixCell Medical, Yokneam Ilit, Israel) is an automated point-of-care hematology analyzer employing image analysis and single-use cuvettes. This study aimed to investigate the correspondence between the HemoScreen and standard laboratory testing (SLT) using the Sysmex XN-9000 in patients undergoing major surgery and to evaluate the feasibility in the operating theater. METHODS: A total of 145 blood samples from 91 adult patients were sampled during abdominal and orthopedic surgery and analyzed on both cell counters. Coefficient of variation (CV) was calculated, Passing-Bablok regression analysis was performed, and Bland-Altman plots were constructed. User experience was assessed through a questionnaire. RESULTS: The HemoScreen showed imprecision with a CV below 5%. Passing-Bablok regression showed positive proportional and negative constant errors for HGB and HCT, a positive proportional error for PLTs, but no dif-ference for RBCs. Bias in the Bland-Altman plots with limits of agreement: RBCs 0.09 x 1012/L (+/- 0.20 x 1012/L), HGB 1.1 g/L (+/- 8.4 g/L), HCT 0.4 % (+/- 2.6%), and PLTs 28.8 x 109/L (+/- 33 x 109/L). The analyzer was scored easy to use with shorter turnaround times compared to SLT. CONCLUSIONS: The HemoScreen is feasible and provides rapid test results with acceptable accuracy for the evaluated application but the two methods cannot be regarded as interchangeable based on the results in this study.

Estimated glomerular filtration rates are higher when creatinine-based equations are compared with a cystatin C-based equation in coronavirus disease 2019.

OBJECTIVES: Estimations of glomerular filtration rate (eGFR) are based on analyses of creatinine and cystatin C, respectively. Coronavirus disease 2019 (COVID-19) patients in the intensive care unit (ICU) often have acute kidney injury (AKI) and are at increased risk of drug-induced kidney injury. The aim of this study was to compare creatinine-based eGFR equations to cystatin C-based eGFR in ICU patients with COVID-19. METHODS: After informed consent, we included 370 adult ICU patients with COVID-19. Creatinine and cystatin C were analyzed at admission to the ICU as part of the routine care. Creatinine-based eGFR (ml/min) was calculated using the following equations, developed in chronological order; the Cockcroft-Gault (C-G), Modified Diet in Renal Disease (MDRD)1999, MDRD 2006, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Lund-Malmö revised (LMR) equations, which were compared with eGFR calculated using the cystatin C-based Caucasian Asian Pediatric Adult (CAPA) equation. RESULTS: The median eGFR when determined by C-G was 99 ml/min and interquartile range (IQR: 67 ml/min). Corresponding estimations for MDRD1999 were 90 ml/min (IQR: 54); MDRD2006: 85 ml/min (IQR: 51); CKD-EPI: 91 ml/min (IQR: 47); and for LMR 83 ml/min (IQR: 41). eGFR was calculated using cystatin C and the CAPA equation value was 70 ml/min (IQR: 38). All differences between creatinine-based eGFR versus cystatin C-based eGFR were significant (p < .00001). CONCLUSIONS: Estimation of GFR based on various analyses of creatinine are higher when compared with a cystatin C-based equation. The C-G equation had the worst performance and should not be used in combination with modern creatinine analysis methods for determination of drug dosage in COVID-19 patients.

Strain on the ICU resources and patient outcomes in the COVID-19 pandemic: A Swedish national registry cohort study.

BACKGROUND: The Coronavirus 2019 (COVID-19) pandemic has led to an unprecedented strain on the ICU resources. It is not known how the ICU resources employed in treating COVID-19 patients are related to inpatient characteristics, use of organ support or mortality. OBJECTIVES: To investigate how the use of ICU resources relate to use of organ support and mortality in COVID-19 patients. DESIGN: A national register-based cohort study. SETTING: All Swedish ICUs from March 2020 to November 2021. PATIENTS: All patients admitted to Swedish ICUs with a primary diagnosis of COVID-19 reported to the national Swedish Intensive Care Register (SIR). MAIN OUTCOME MEASURES: Organ support (mechanical ventilation, noninvasive ventilation, high-flow oxygen therapy, prone positioning, surgical and percutaneous tracheostomy, central venous catheterisation, continuous renal replacement therapy and intermittent haemodialysis), discharge at night, re-admission, transfer and ICU and 30-day mortality. RESULTS: Seven thousand nine hundred and sixty-nine patients had a median age of 63 years, and 70% were men. Median daily census was 167% of habitual census, daily new admissions were 20% of habitual census and the median occupancy was 82%. Census and new admissions were associated with mechanical ventilation, OR 1.37 (95% CI 1.28 to 1.48) and OR 1.44 (95% CI 1.13 to 1.84), respectively, but negatively associated with noninvasive ventilation, OR 0.83 (95% CI 0.77 to 0.89) and OR 0.40 (95% CI 0.30 to 52) and high-flow oxygen therapy, OR 0.72 (95% CI 0.67 to 0.77) and OR 0.77 (95% CI 0.61 to 0.97). Occupancy above 90% of available beds was not associated with mechanical ventilation or noninvasive ventilation, but with high-flow oxygen therapy, OR 1.36 (95% CI 1.21 to 1.53). All measures of pressure on resources were associated with transfer to other hospitals, but none were associated with discharge at night, ICU mortality or 30-day mortality. CONCLUSIONS: Pressure on ICU resources was associated with more invasive respiratory support, indicating that during these times, ICU resources were reserved for sicker patients.

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity.

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

Soluble TNF receptors predict acute kidney injury and mortality in critically ill COVID-19 patients: A prospective observational study.

BACKGROUND: Although pneumonia is the hallmark of coronavirus disease 2019 (COVID-19), multiple organ failure may develop in severe disease. TNFα receptors in their soluble form (sTNFR) are involved in the immune cascade in other systemic inflammatory processes such as septic shock, and could mediate the inflammatory activation of distant organs. The aim of this study is to analyse plasma levels of sTNFR 1 and 2 in association with organ failure and outcome in critically ill patients with COVID-19. METHODS: After informed consent, we included 122 adult patients with PCR-confirmed COVID-19 at ICU admission. Demographic data, illness severity scores, organ failure and survival at 30 days were collected. Plasma sTNFR 1 and 2 levels were quantified during the first days after ICU admission. Twenty-five healthy blood donors were used as control group. RESULTS: Levels of sTNFR were higher in severe COVID-19 patients compared to controls (p < 0.001). Plasma levels of sTNFR were associated to illness severity scores (SAPS 3 and SOFA), inflammation biomarkers such as IL-6, ferritin and PCT as well as development of AKI during ICU stay. sTNFR 1 higher than 2.29 ng/mL and? sTNFR 2 higher than 11.7 ng/mL were identified as optimal cut-offs to discriminate survivors and non-survivors 30 days after ICU admission and had an area under the curve in receiver operating characteristic curve of 0.75 and 0.67 respectively. CONCLUSION: Plasma levels of sTNFR 1 and 2 were higher in COVID-19 patients compared to controls and were strongly associated with other inflammatory biomarkers, severity of illness and acute kidney injury development during ICU stay. In addition, sTNFR 1 was an independent predictor of 30-day mortality after adjustment for age and respiratory failure.

Optimized diagnosis-based comorbidity measures for all-cause mortality prediction in a national population-based ICU population.

BACKGROUND: We aimed to optimize prediction of long-term all-cause mortality of intensive care unit (ICU) patients, using quantitative register-based comorbidity information assessed from hospital discharge diagnoses prior to intensive care treatment. MATERIAL AND METHODS: Adult ICU admissions during 2006 to 2012 in the Swedish intensive care register were followed for at least 4 years. The performance of quantitative comorbidity measures based on the 5-year history of number of hospital admissions, length of stay, and time since latest admission in 36 comorbidity categories was compared in time-to-event analyses with the Charlson comorbidity index (CCI) and the Simplified Acute Physiology Score (SAPS3). RESULTS: During a 7-year period, there were 230,056 ICU admissions and 62,225 deaths among 188,965 unique individuals. The time interval from the most recent hospital stays and total length of stay within each comorbidity category optimized mortality prediction and provided clear separation of risk categories also within strata of age and CCI, with hazard ratios (HRs) comparing lowest to highest quartile ranging from 1.17 (95% CI: 0.52-2.64) to 6.41 (95% CI: 5.19-7.92). Risk separation was also observed within SAPS deciles with HR ranging from 1.07 (95% CI: 0.83-1.38) to 3.58 (95% CI: 2.12-6.03). CONCLUSION: Baseline comorbidity measures that included the time interval from the most recent hospital stay in 36 different comorbidity categories substantially improved long-term mortality prediction after ICU admission compared to the Charlson index and the SAPS score. Trial registration ClinicalTrials.gov ID NCT04109001, date of registration 2019-09-26 retrospectively.

Limitations of the ARDS criteria during high-flow oxygen or non-invasive ventilation: evidence from critically ill COVID-19 patients.

BACKGROUND: The ratio of partial pressure of arterial oxygen to inspired oxygen fraction (PaO2/FIO2) during invasive mechanical ventilation (MV) is used as criteria to grade the severity of respiratory failure in acute respiratory distress syndrome (ARDS). During the SARS-CoV2 pandemic, the use of PaO2/FIO2 ratio has been increasingly used in non-invasive respiratory support such as high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV). The grading of hypoxemia in non-invasively ventilated patients is uncertain. The main hypothesis, investigated in this study, was that the PaO2/FIO2 ratio does not change when switching between MV, NIV and HFNC. METHODS: We investigated respiratory function in critically ill patients with COVID-19 included in a single-center prospective observational study of patients admitted to the intensive care unit (ICU) at Uppsala University Hospital in Sweden. In a steady state condition, the PaO2/FIO2 ratio was recorded before and after any change between two of the studied respiratory support techniques (i.e., HFNC, NIV and MV). RESULTS: A total of 148 patients were included in the present analysis. We find that any change in respiratory support from or to HFNC caused a significant change in PaO2/FIO2 ratio. Changes in respiratory support between NIV and MV did not show consistent change in PaO2/FIO2 ratio. In patients classified as mild to moderate ARDS during MV, the change from HFNC to MV showed a variable increase in PaO2/FIO2 ratio ranging between 52 and 140 mmHg (median of 127 mmHg). This made prediction of ARDS severity during MV from the apparent ARDS grade during HFNC impossible. CONCLUSIONS: HFNC is associated with lower PaO2/FIO2 ratio than either NIV or MV in the same patient, while NIV and MV provided similar PaO2/FIO2 and thus ARDS grade by Berlin definition. The large variation of PaO2/FIO2 ratio indicates that great caution should be used when estimating ARDS grade as a measure of pulmonary damage during HFNC.

Chest dual-energy CT to assess the effects of steroids on lung function in severe COVID-19 patients.

BACKGROUND: Steroids have been shown to reduce inflammation, hypoxic pulmonary vasoconstriction (HPV) and lung edema. Based on evidence from clinical trials, steroids are widely used in severe COVID-19. However, the effects of steroids on pulmonary gas volume and blood volume in this group of patients are unexplored. OBJECTIVE: Profiting by dual-energy computed tomography (DECT), we investigated the relationship between the use of steroids in COVID-19 and distribution of blood volume as an index of impaired HPV. We also investigated whether the use of steroids influences lung weight, as index of lung edema, and how it affects gas distribution. METHODS: Severe COVID-19 patients included in a single-center prospective observational study at the intensive care unit at Uppsala University Hospital who had undergone DECT were enrolled in the current study. Patients' cohort was divided into two groups depending on the administration of steroids. From each patient's DECT, 20 gas volume maps and the corresponding 20 blood volume maps, evenly distributed along the cranial-caudal axis, were analyzed. As a proxy for HPV, pulmonary blood volume distribution was analyzed in both the whole lung and the hypoinflated areas. Total lung weight, index of lung edema, was estimated. RESULTS: Sixty patients were analyzed, whereof 43 received steroids. Patients not exposed to steroids showed a more extensive non-perfused area (19% vs 13%, p < 0.01) and less homogeneous pulmonary blood volume of hypoinflated areas (kurtosis: 1.91 vs 2.69, p < 0.01), suggesting a preserved HPV compared to patients treated with steroids. Moreover, patients exposed to steroids showed a significantly lower lung weight (953 gr vs 1140 gr, p = 0.01). A reduction in alveolar-arterial difference of oxygen followed the treatment with steroids (322 ± 106 mmHg at admission vs 267 ± 99 mmHg at DECT, p = 0.04). CONCLUSIONS: The use of steroids might cause impaired HPV and might reduce lung edema in severe COVID-19. This is consistent with previous findings in other diseases. Moreover, a reduced lung weight, as index of decreased lung edema, and a more homogeneous distribution of gas within the lung were shown in patients treated with steroids. TRIAL REGISTRATION: Clinical Trials ID: NCT04316884, Registered March 13, 2020.

Decreased renal perfusion during acute kidney injury in critical COVID-19 assessed by magnetic resonance imaging: a prospective case control study.

BACKGROUND: Renal hypoperfusion has been suggested to contribute to the development of acute kidney injury (AKI) in critical COVID-19. However, limited data exist to support this. We aim to investigate the differences in renal perfusion, oxygenation and water diffusion using multiparametric magnetic resonance imaging in critically ill COVID-19 patients with and without AKI. METHODS: A prospective case-control study where patients without prior kidney disease treated in intensive care for respiratory failure due to COVID-19 were examined. Kidney Disease: Improving Global Outcomes Creatinine criteria were used for group allocation. Main comparisons were tested using Mann-Whitney U test. RESULTS: Nineteen patients were examined, ten with AKI and nine without AKI. Patients with AKI were examined in median 1 [0-2] day after criteria fulfillment. Age and baseline Plasma-Creatinine were similar in both groups. Total renal blood flow was lower in patients with AKI compared with patients without (median 645 quartile range [423-753] vs. 859 [746-920] ml/min, p = 0.037). Regional perfusion was reduced in both cortex (76 [51-112] vs. 146 [123-169] ml/100 g/min, p = 0.015) and medulla (28 [18-47] vs. 47 [38-73] ml/100 g/min, p = 0.03). Renal venous saturation was similar in both groups (72% [64-75] vs. 72% [63-84], ns.), as was regional oxygenation (R2*) in cortex (17 [16-19] vs. 17 [16-18] 1/s, ns.) and medulla (29 [24-39] vs. 27 [23-29] 1/s, ns.). CONCLUSIONS: In critically ill COVID-19 patients with AKI, the total, cortical and medullary renal blood flows were reduced compared with similar patients without AKI, whereas no differences in renal oxygenation were demonstrable in this setting. Trial registration ClinicalTrials ID: NCT02765191 , registered May 6 2014 and updated May 7 2020.

Dehydration is associated with production of organic osmolytes and predicts physical long-term symptoms after COVID-19: a multicenter cohort study.

BACKGROUND: We have previously shown that iatrogenic dehydration is associated with a shift to organic osmolyte production in the general ICU population. The aim of the present investigation was to determine the validity of the physiological response to dehydration known as aestivation and its relevance for long-term disease outcome in COVID-19. METHODS: The study includes 374 COVID-19 patients from the Pronmed cohort admitted to the ICU at Uppsala University Hospital. Dehydration data was available for 165 of these patients and used for the primary analysis. Validation was performed in Biobanque Québécoise de la COVID-19 (BQC19) using 1052 patients with dehydration data. Dehydration was assessed through estimated osmolality (eOSM = 2Na + 2 K + glucose + urea), and correlated to important endpoints including death, invasive mechanical ventilation, acute kidney injury, and long COVID-19 symptom score grouped by physical or mental. RESULTS: Increasing eOSM was correlated with increasing role of organic osmolytes for eOSM, while the proportion of sodium and potassium of eOSM were inversely correlated to eOSM. Acute outcomes were associated with pronounced dehydration, and physical long-COVID was more strongly associated with dehydration than mental long-COVID after adjustment for age, sex, and disease severity. Metabolomic analysis showed enrichment of amino acids among metabolites that showed an aestivating pattern. CONCLUSIONS: Dehydration during acute COVID-19 infection causes an aestivation response that is associated with protein degradation and physical long-COVID. TRIAL REGISTRATION: The study was registered à priori (clinicaltrials.gov: NCT04316884 registered on 2020-03-13 and NCT04474249 registered on 2020-06-29).

Population pharmacokinetics of cefotaxime in intensive care patients.

PURPOSE: To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates. METHODS: This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000-3000 mg given 2-6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis. RESULTS: A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%. CONCLUSION: A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

Intensive care-treated COVID-19 patients' perception of their illness and remaining symptoms.

BACKGROUND: The remaining symptoms in patients with coronavirus disease 2019 (COVID-19) treated in intensive care unit are limited described. Therefore, we assessed patient's perception of their COVID-19 disease, stay in intensive care, and remaining symptoms three to six months after intensive care. METHODS: Prospective cohort study was performed in one intensive care unit of a university hospital in Sweden during the first wave. A questionnaire with open-ended questions and closed-ended questions was used. Data were analyzed using qualitative and quantitative content analysis and descriptive statistics. RESULTS: Out of 123 patients treated for COVID-19, 64 answered the questionnaire 3-6 months after discharge from intensive care. Memories from illness and hospital stay revealed in three categories; awareness of the illness, losing anchor to reality and being cared for in a dynamic environment. Information was perceived as spare by 48% and they wanted the information to be more personal. The diary was perceived as personal and was received by 33% patients. The relationship with family was affected among 39% and 13% of the patients indicated that they had not resumed their daily life. A large amount, 84%, indicated that they had remaining symptoms from COVID-19. The dominated symptoms were impaired strength and energy both physically and mentally. CONCLUSION: Patients reported a variety of physical and mental symptoms, and revealed memories from the ICU, and specific awareness of other patients' health. It illustrates the need for screening patients for remaining symptoms after COVID-19 disease and ICU care and may affect resuming patients' daily life.