Drug interventions for prevention of COVID-19 progression to severe disease in outpatients: a systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients. SETTING: Outpatient treatment. PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities. INTERVENTIONS: Drug interventions authorised by EMA or FDA. PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events. RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups. CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression. PROSPERO REGISTRATION NUMBER: CRD42020178787.

Blood volume in patients likely to be preload responsive: a post hoc analysis of a randomized controlled trial.

BACKGROUND: Preload responsive postoperative patients with signs of inadequate organ perfusion are commonly assumed to be hypovolemic and therefore treated with fluids to increase preload. However, preload is influenced not only by blood volume, but also by venous vascular tone and the contribution of these factors to preload responsiveness in this setting is unknown. Based on this, the objective of this study was to investigate blood volume status in preload-responsive postoperative patients. METHODS: Data from a clinical trial including postoperative patients after major abdominal surgery were analyzed. Patients with signs of inadequate organ perfusion and with data from a passive leg raising test (PLR) were included. An increase in pulse pressure by ≥ 9% was used to identify patients likely to be preload responsive. Blood volume was calculated from plasma volume measured using radiolabelled albumin and hematocrit. Patients with a blood volume of at least 10% above or below estimated normal volume were considered hyper- and hypovolemic, respectively. RESULTS: A total of 63 patients were included in the study. Median (IQR) blood volume in the total was 57 (50-65) ml/kg, and change in pulse pressure after PLR was 14 (7-24)%. A total of 43 patients were preload responsive. Of these patients, 44% were hypovolemic, 28% euvolemic and 28% hypervolemic. CONCLUSIONS: A large fraction of postoperative patients with signs of hypoperfusion that are likely to be preload responsive, are hypervolemic. In these patients, treatments other than fluid administration may be a more rational approach to increase cardiac output. Trial registration EudraCT 2013-004446-42.

Protocolised reduction of non-resuscitation fluids versus usual care in patients with septic shock (REDUSE): a protocol for a multicentre feasibility trial.

INTRODUCTION: Administration of large volumes of fluids is associated with poor outcome in septic shock. Recent data suggest that non-resuscitation fluids are the major source of fluids in the intensive care unit (ICU) patients suffering from septic shock. The present trial is designed to test the hypothesis that a protocol targeting this source of fluids can reduce fluid administration compared with usual care. METHODS AND ANALYSIS: The design will be a multicentre, randomised, feasibility trial. Adult patients admitted to ICUs with septic shock will be randomised within 12 hours of admission to receive non-resuscitation fluids either according to a restrictive protocol or to receive usual care. The healthcare providers involved in the care of participants will not be blinded. The participants, outcome assessors at the 6-month follow-up and statisticians will be blinded. Primary outcome will be litres of fluids administered within 3 days of randomisation. Secondary outcomes will be proportion of randomised participants with outcome data on all-cause mortality; days alive and free of mechanical ventilation within 90 days of inclusion; any acute kidney injury and ischaemic events in the ICU (cerebral, cardiac, intestinal or limb ischaemia); proportion of surviving randomised patients who were assessed by European Quality of Life 5-Dimensions 5-Level questionnaire and Montreal Cognitive Assessment; proportion of all eligible patients who were randomised and proportion of participants experiencing at least one protocol violation. ETHICS AND DISSEMINATION: Ethics approval has been obtained in Sweden. Results of the primary and secondary outcomes will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05249088.

Mechanical complications after central venous catheterisation in the ultrasound-guided era: a prospective multicentre cohort study.

BACKGROUND: Limited data are available on the incidence of mechanical complications after ultrasound-guided central venous catheterisation. We aimed to determine the incidence of mechanical complications in hospitals where real-time ultrasound guidance is clinical practice for central venous access and to identify variables associated with mechanical complications. METHODS: All central venous catheter insertions in patients ≥16 yr at four emergency care hospitals in Sweden from March 2, 2019 to December 31, 2020 were eligible for inclusion. Every insertion was monitored for complete documentation and occurrence of mechanical complications within 24 h after catheterisation. Multivariable logistic regression analyses were used to determine associations between predefined variables and mechanical complications. RESULTS: In total, 12 667 catheter insertions in 8586 patients were included. The incidence (95% confidence interval [CI]) of mechanical complications was 7.7% (7.3-8.2%), of which 0.4% (0.3-0.5%) were major complications. The multivariable analyses showed that patient BMI <20 kg m-2 (odds ratio 2.69 [95% CI: 1.17-5.62]), male operator gender (3.33 [1.60-7.38]), limited operator experience (3.11 [1.64-5.77]), and increasing number of skin punctures (2.18 [1.59-2.88]) were associated with major mechanical complication. Subclavian vein catheterisation was associated with pneumothorax (5.91 [2.13-17.26]). CONCLUSIONS: The incidence of major mechanical complications is low in hospitals where real-time ultrasound guidance is the standard of care for central venous access. Several variables independently associated with mechanical complications can be used for risk stratification before catheterisation procedures, which might further reduce complication rates. CLINICAL TRIAL REGISTRATION: NCT03782324.

Cystatin C and derived measures of renal function as risk factors for mortality and acute kidney injury in sepsis - A post-hoc analysis of the FINNAKI cohort.

PURPOSE: To assess the association between cystatin C-derived estimates of kidney function and mortality and acute kidney injury (AKI) in sepsis. MATERIALS AND METHODS: Post-hoc analysis of sepsis patients in the FINNAKI-cohort (n = 802). Primary outcome was 90-day mortality. We measured plasma cystatin C and creatinine at intensive care unit (ICU) admission and estimated glomerular filtration rates (eGFRcys, eGFRcrea) and shrunken pore syndrome (SPS; defined as eGFRcys/eGFRcrea ratio < 0.7). Associations were assessed using Cox- or logistic regression. RESULTS: Increased cystatin C and decreased eGFRcys were associated with mortality in unadjusted analyses and in analyses adjusted for illness severity and creatinine. Hazard ratios (HRs) in unadjusted analyses were 3.30 (95% CI; 2.12-5.13, p < 0.001) and 3.26 (95% CI; 2.12-5.02, p < 0.001) respectively. SPS was associated with mortality in an unadjusted- (HR 1.78, 95% CI; 1.33-2.37, p < 0.001) and in an adjusted analysis (HR 1.54, 95% CI; 1.07-2.22, p = 0.021). All cystatin C-derived measures were associated with mortality also after adjustment for AKI development. Cystatin C was associated with AKI in unadjusted analyses but not in analyses adjusted for creatinine. CONCLUSION: Cystatin C and derived measures of kidney function at ICU admission are associated with an increased 90-day mortality. Increased AKI incidence does not fully explain this association.

Environmental impact of single-use, reusable, and mixed trocar systems used for laparoscopic cholecystectomies.

INTRODUCTION: Climate change is one of the 21st century's biggest public health issues and health care contributes up to 10% of the emissions of greenhouse gases in developed countries. About 15 million laparoscopic procedures are performed annually worldwide and single-use medical equipment is increasingly used during these procedures. Little is known about costs and environmental footprint of this change in practice. METHODS: We employed Life Cycle Assessment method to evaluate and compare the environmental impacts of single-use, reusable, and mixed trocar systems used for laparoscopic cholecystectomies at three hospitals in southern Sweden. The environmental impacts were calculated using the IMPACT 2002+ method and a functional unit of 500 procedures. Monte Carlo simulations were used to estimate differences between trocar systems. Data are presented as medians and 2.5th to 97.5th percentiles. Financial costs were calculated using Life Cycle Costing. RESULTS: The single-use system had a 182% higher impact on resources than the reusable system [difference: 5160 MJ primary (4400-5770)]. The single-use system had a 379% higher impact on climate change than the reusable system [difference: 446 kg CO2eq (413-483)]. The single-use system had an 83% higher impact than the reusable system on ecosystem quality [difference: 79 PDF*m2*yr (24-112)] and a 240% higher impact on human health [difference: 2.4x10-4 DALY/person/yr (2.2x10-4-2.6x10-4)]. The mixed and single-use systems had a similar environmental impact. Differences between single-use and reusable trocars with regard to resource use and ecosystem quality were found to be sensitive to lower filling of machines in the sterilization process. For ecosystem quality the difference between the two were further sensitive to a 50% decrease in number of reuses, and to using a fossil fuel intensive electricity mix. Differences regarding effects on climate change and human health were robust in the sensitivity analyses. The reusable and mixed trocar systems were approximately half as expensive as the single-use systems (17360 € and 18560 € versus 37600 €, respectively). CONCLUSION: In the Swedish healthcare system the reusable trocar system offers a robust opportunity to reduce both the environmental impact and financial costs for laparoscopic surgery.

The Dynamics of Circulating Heparin-Binding Protein: Implications for Its Use as a Biomarker.

Heparin-binding protein (HBP) is a promising biomarker for the development and severity of sepsis. To guide its use, it is important to understand the factors that could lead to false-positive or negative results, such as inappropriate release and inadequate clearance of HBP. HBP is presumably released only by neutrophils, and the organs responsible for its elimination are unknown. In this study, we aimed to determine whether non-neutrophil cells can be a source of circulating HBP and which organs are responsible for its removal. We found that in two cohorts of neutropenic patients, 12% and 19% of patients in each cohort, respectively, had detectable plasma HBP levels. In vitro, three leukemia-derived monocytic cell lines and healthy CD14+ monocytes constitutively released detectable levels of HBP. When HBP was injected intravenously in rats, we found that plasma levels of HBP decreased rapidly, with a distribution half-life below 10 min and an elimination half-life of 1-2 h. We measured HBP levels in the liver, spleen, kidneys, lungs, and urine using both ELISA and immunofluorescence quantitation, and found that the majority of HBP was present in the liver, and a small amount was present in the spleen. Immunofluorescence imaging indicated that HBP is associated mainly with hepatocytes in the liver and monocytes/macrophages in the spleen. The impact of hematologic malignancies and liver diseases on plasma HBP levels should be explored further in clinical studies.

Non-corticosteroid adjuvant therapies for acute bacterial meningitis.

BACKGROUND: Acute bacterial meningitis is a bacterial infection of the membranes that surround and protect the brain, known as the meninges. The primary therapy for bacterial meningitis is antibiotics and corticosteroids. Although these therapies significantly improve outcomes, bacterial meningitis still has a high risk of death and a high risk of neurological sequelae in survivors. New adjuvant therapies are needed to further reduce the risk of death and neurological sequelae in bacterial meningitis. OBJECTIVES: To assess the effects of non-corticosteroid adjuvant pharmacological therapies for mortality, hearing loss, and other neurological sequelae in people with acute bacterial meningitis. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and LILACS databases and ClinicalTrials.gov and WHO ICTRP trials registers up to 30 September 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any pharmacological adjuvant therapy for acute bacterial meningitis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed and extracted data on methods, participants, interventions, and outcomes. We assessed risk of bias of studies with the Cochrane risk of bias tool and the certainty of the evidence using the GRADE approach. We presented results using risk ratios (RR) and 95% confidence intervals (CI) when meta-analysis was possible. All other results are presented in a narrative synthesis. MAIN RESULTS: We found that five different adjuvant therapies have been tested in RCTs for bacterial meningitis. These include paracetamol (3 studies, 1274 participants who were children); immunoglobulins (2 studies, 49 participants; one study included children, and the other adults); heparin (1 study, 15 participants who were adults); pentoxifylline (1 study, 57 participants who were children); and a mixture of succinic acid, inosine, nicotinamide, and riboflavin mononucleotide (1 study, 30 participants who were children). Paracetamol may make little or no difference to mortality (paracetamol 35.2% versus placebo 37.4%, 95% CI 30.3% to 40.8%; RR 0.94, 95% CI 0.81 to 1.09; 3 studies, 1274 participants; I² = 0%; low certainty evidence); hearing loss (RR 1.04, 95% CI 0.80 to 1.34; 2 studies, 901 participants; I² = 0%; low certainty evidence); neurological sequelae other than hearing loss (RR 1.56, 95% CI 0.98 to 2.50; 3 studies, 1274 participants; I² = 60%; low certainty evidence); and severe hearing loss (RR 0.96, 95% CI 0.67 to 1.36; 2 studies, 901 participants; I² = 0%; low certainty evidence). Paracetamol may lead to slightly more short-term neurological sequelae other than hearing loss (RR 1.99, 95% CI 1.40 to 2.81; 2 studies, 1096 participants; I² = 0%; low certainty evidence) and slightly more long-term neurological sequelae other than hearing loss (RR 2.32, 95% CI 1.34 to 4.04; 2 studies, 901 participants; I² = 0%; low certainty evidence). No adverse events were reported in either group in any of the paracetamol studies (very low certainty evidence). Two paracetamol studies had a low risk of bias in most domains, and one had low or unclear risk of bias in all domains. We judged the certainty of evidence to be low for mortality due to limitations in study design (unclear risk of bias in at least one domain and imprecision (high level of uncertainty in absolute effects), and low for all other outcomes due to limitations in study design (unclear risk of bias in at least one domain), and imprecision (low sample size and few events) or inconsistency in effect estimates (heterogeneity). We were not able to perform meta-analysis for any of the other adjuvant therapies due to the limited number of included studies. It is uncertain whether immunoglobulins, heparin, or pentoxifylline improves mortality outcomes due to the very low certainty of the evidence. Zero adverse events were reported for immunoglobulins (very low certainty evidence), and allergic reactions occurred at a rate of 3.3% in participants receiving a mixture of succinic acid, inosine, nicotinamide, and riboflavin mononucleotide (intervention group) (very low certainty evidence). None of our other outcomes (hearing loss, neurological sequelae other than hearing loss, severe hearing loss, and short-term or long-term neurological sequelae other than hearing loss) were reported in these studies, and all of these studies were judged to have a high risk of bias. All reported outcomes for all included adjuvant therapies, other than paracetamol, were graded as very low certainty of evidence due to limitations in study design (unclear or high risk of bias in at least four domains) and imprecision (extremely low sample size and few events). AUTHORS' CONCLUSIONS: Few adjuvant therapies for bacterial meningitis have been tested in RCTs. Paracetamol may make little or no difference to mortality, with a high level of uncertainty in the absolute effects (low certainty evidence). Paracetamol may make little or no difference to hearing loss, neurological sequelae other than hearing loss, and severe hearing loss (all low certainty evidence). Paracetamol may lead to slightly more short-term and long-term neurological sequelae other than hearing loss (both outcomes low certainty evidence). There is insufficient evidence to determine whether any of the adjuvant therapies included in this review (paracetamol, immunoglobulins, heparin, pentoxifylline, or a mixture of succinic acid, inosine, nicotinamide, and riboflavin mononucleotide) are beneficial or detrimental in acute bacterial meningitis.

DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis.

OBJECTIVE: Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt cerebrospinal fluid (CSF) transport by the glymphatic system and contribute to edema formation in S pneumoniae meningitis. METHODS: We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S pneumoniae meningitis. RESULTS: Our analysis showed that CSF influx into the brain parenchyma, as well as CSF drainage to the cervical lymph nodes, was significantly reduced in the rat model of S pneumoniae meningitis. Degrading NETs by DNase treatment restored glymphatic transport and eliminated the increase in brain weight in the rats. In contrast, first-line antibiotic treatment had no such effect on restoring fluid dynamics. INTERPRETATION: This study suggests that CSF accumulation is responsible for cerebral edema formation and identifies the glymphatic system and NETs as possible new treatment targets in S pneumoniae meningitis. ANN NEUROL 2021;90:653-669.

Efficacy of an implementation package on documentation of central venous catheter insertions: an observational study.

BACKGROUND: Proper documentation of central venous catheter (CVC) insertions in electronic healthcare records is the basis for good follow-up and quality assurance. We have noted serious deficiencies in the documentation of CVC insertions and introduced an implementation package with the purpose of increasing the completeness of this documentation. The aim of the present study was to estimate the effect of the implementation package by assessing the proportion of missing data before and after the introduction of the implementation package. METHODS: In this single centre observational study, data from CVC insertion templates in a common electronic health record were extracted and analysed after introducing the implementation package. The package included adoption of new local CVC-directions, a new updated CVC-insertion template in the regional common electronic health record and a review of all CVC-insertion templates with a reminder to the inserting physician to supplement missing data. The proportion of terms with missing data was reviewed and also compared with the proportion of missing data in a study prior to the introduction of the package. RESULTS: In total, 7126 CVC-insertion templates were included. Of these 5539 (78%) were without missing data for any of the 13 predefined variables. Completed insertion templates for three common terms increased from 38% prior to the introduction of the implementation package to 93%, which represents an absolute reduction for missing data of 55% (95% CI 53% to 56%, p<0.0001). CONCLUSION: The implementation package was highly effective in increasing the proportion of fully documented CVC insertions.

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

BACKGROUND: COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. METHODS AND FINDINGS: We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. CONCLUSIONS: No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178787.

Markers of renal function at admission and mortality in hip fracture patients - a single center prospective observational study.

Plasma cystatin C and shrunken pore syndrome (SPS) are associated with increased mortality in older adults. The objective was to assess the association between these markers of kidney function at admission and mortality in hip fracture patients. Hip fracture patients presenting at Lund University Hospital were eligible for inclusion. Cox regression was used to assess association between plasma cystatin C, creatinine, cystatin C- or creatinine-based estimations of glomerular filtration rate (eGFRCYS and eGFRCREA), or SPS (defined as eGFRCYS/eGFRCREA < 0.7) and mortality during one year follow up. Improvement in discrimination relative to the Nottingham Hip fracture score was assessed by Receiver Operational Characteristics (ROC) analysis and calculation of Net Reclassification Index (NRI). 996 patients were included in the study. Cystatin C, creatinine, eGFRCYS and eGFRCREA were associated with one-year mortality in both unadjusted and adjusted analyses. The association with mortality was stronger for cystatin C and for eGFRCYS than for creatinine and eGFRCREA. Patients with SPS had doubled mortality compared with patients without SPS (43.7 and 20.2%, respectively, p < .001). Hazard ratio for SPS in the adjusted analysis was 1.66 (95%CI; 1.16-2.39, p = .006). None of the markers improved discrimination compared to the Nottingham Hip Fracture Score using ROC analysis whereas eGFRCYS and eGFRCREA improved NRI. Our conclusion is that plasma concentrations of creatinine or cystatin C, eGFRCYS or eGFRCREA or SPS at admission in hip fracture patients are associated with mortality when known risk factors are accounted for. Identification of high risk patients may be improved by eGFRCYS or eGFRCREA.

Effects of different mean arterial pressure targets on plasma volume, ANP and glycocalyx-A randomized trial.

BACKGROUND: Arterial haematocrit (Hct) has been shown to decrease after anaesthesia induction, most probably because of an increased plasma volume (PV). The primary objective was to quantify change in PV if mean arterial pressure (MAP) was kept at baseline level or allowed to decrease to 60 mm Hg. Our secondary objective was to evaluate underlying mechanisms of this response. METHODS: Twenty-four coronary artery bypass patients were randomized to a higher (90 mm Hg, intervention group) or lower (60 mm Hg, control group) MAP by titration of norepinephrine. During the experimental procedure, no fluids were administered. Baseline PV was measured by 125 I-albumin and the change in PV was calculated from the change in Hct. Changes in MAP, plasma 125 I-albumin, colloid osmotic pressure, albumin, Mid Regional-pro Atrial Natriuretic Peptide (MR-proANP) and endothelial glycocalyx components were measured from baseline to 50 minutes after anaesthesia induction. RESULTS: The MAP during the trial was 93 ± 9 mm Hg in the intervention group and 62 ± 5 mm Hg in the control group. PV increased with up to 420 ± 180 mL in the control group and 45 ± 130 mL in the intervention group (P < .001). Albumin and colloid osmotic pressure decreased significantly more in the control group. MR-proANP increased in the control group but no shedding of the glycocalyx layer was detected in either of the groups. CONCLUSION: Allowing mean arterial pressure to fall to 60 mm Hg during anaesthesia induction, increases the plasma volume due to reabsorption of interstitial water, with no ANP-induced degradation of the endothelial glycocalyx.

Effects of red blood cell transfusions given to non-septic critically ill patients: a propensity score matched study.

INTRODUCTION: Previous studies have demonstrated that low-grade red blood cell transfusions (RBC) given to septic patients are harmful. The objectives of the present study were to compare mortality and morbidity in non-septic critically ill patients who were given low-grade RBC transfusions at haemoglobin level > 70 γ L-1 with patients without RBC-transfusions any of the first 5 days in intensive care. MATERIAL AND METHODS: Adult patients admitted to a general intensive care unit between 2007 and 2018 at a university hospital were eligible for inclusion. Patients who received > 2 units RBC transfusion per day during the first 5 days after admisasion, with pre-transfusion haemoglobin level < 70 γ L-1 or with severe sepsis or septic shock, were excluded. RESULTS: In total, 9491 admissions were recorded during the study period. Propensity score matching resulted in 2 well matched groups with 674 unique patients in each. Median pre-transfusion haemoglobin was 98 γ L-1 (interquartile range 91-107 γ L-1). Mortality was higher in the RBC group with an absolute risk increase for death at 180 days of 5.9% (95% CI: 3.6-8.3; P < 0.001). Low-grade RBC-transfusion was also associated with renal, circulatory, and respiratory failure as well as a higher SOFA-max score. Sensitivity analyses suggested that disease trajectories during the exposure time did not significantly differ between the groups. CONCLUSIONS: Low-grade RBC-transfusions given to non-septic critically ill patients without significant anaemia were associated with increased mortality, increased kidney, circulatory, and respiratory failure, as well as higher SOFA-max score.

Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. METHODS AND FINDINGS: This is the first edition of a living systematic review of randomized clinical trials comparing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Cochrane guidelines, and our 8-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and nonserious adverse events. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until August 7, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 33 randomized clinical trials enrolling a total of 13,312 participants. All trials were at overall high risk of bias. We identified one trial randomizing 6,425 participants to dexamethasone versus standard care. This trial showed evidence of a beneficial effect of dexamethasone on all-cause mortality (rate ratio 0.83; 95% confidence interval [CI] 0.75-0.93; p < 0.001; low certainty) and on mechanical ventilation (risk ratio [RR] 0.77; 95% CI 0.62-0.95; p = 0.021; low certainty). It was possible to perform meta-analysis of 10 comparisons. Meta-analysis showed no evidence of a difference between remdesivir versus placebo on all-cause mortality (RR 0.74; 95% CI 0.40-1.37; p = 0.34, I2 = 58%; 2 trials; very low certainty) or nonserious adverse events (RR 0.94; 95% CI 0.80-1.11; p = 0.48, I2 = 29%; 2 trials; low certainty). Meta-analysis showed evidence of a beneficial effect of remdesivir versus placebo on serious adverse events (RR 0.77; 95% CI 0.63-0.94; p = 0.009, I2 = 0%; 2 trials; very low certainty) mainly driven by respiratory failure in one trial. Meta-analyses and trial sequential analyses showed that we could exclude the possibility that hydroxychloroquine versus standard care reduced the risk of all-cause mortality (RR 1.07; 95% CI 0.97-1.19; p = 0.17; I2 = 0%; 7 trials; low certainty) and serious adverse events (RR 1.07; 95% CI 0.96-1.18; p = 0.21; I2 = 0%; 7 trials; low certainty) by 20% or more, and meta-analysis showed evidence of a harmful effect on nonserious adverse events (RR 2.40; 95% CI 2.01-2.87; p < 0.00001; I2 = 90%; 6 trials; very low certainty). Meta-analysis showed no evidence of a difference between lopinavir-ritonavir versus standard care on serious adverse events (RR 0.64; 95% CI 0.39-1.04; p = 0.07, I2 = 0%; 2 trials; very low certainty) or nonserious adverse events (RR 1.14; 95% CI 0.85-1.53; p = 0.38, I2 = 75%; 2 trials; very low certainty). Meta-analysis showed no evidence of a difference between convalescent plasma versus standard care on all-cause mortality (RR 0.60; 95% CI 0.33-1.10; p = 0.10, I2 = 0%; 2 trials; very low certainty). Five single trials showed statistically significant results but were underpowered to confirm or reject realistic intervention effects. None of the remaining trials showed evidence of a difference on our predefined outcomes. Because of the lack of relevant data, it was not possible to perform other meta-analyses, network meta-analysis, or individual patient data meta-analyses. The main limitation of this living review is the paucity of data currently available. Furthermore, the included trials were all at risks of systematic errors and random errors. CONCLUSIONS: Our results show that dexamethasone and remdesivir might be beneficial for COVID-19 patients, but the certainty of the evidence was low to very low, so more trials are needed. We can exclude the possibility of hydroxychloroquine versus standard care reducing the risk of death and serious adverse events by 20% or more. Otherwise, no evidence-based treatment for COVID-19 currently exists. This review will continuously inform best practice in treatment and clinical research of COVID-19.

Mortality and morbidity of low-grade red blood cell transfusions in septic patients: a propensity score-matched observational study of a liberal transfusion strategy.

BACKGROUND: Red blood cell (RBC) transfusions are associated with risks including immunological reactions and volume overload. Current guidelines suggest a restrictive transfusion strategy in most patients with sepsis but based on previous randomized controlled trials and observational studies, there are still uncertainties about the safety in giving low-grade RBC transfusions to patients with sepsis. METHODS: Critically ill patients with severe sepsis or septic shock admitted to a university hospital intensive care unit between 2007 and 2018 that received less or equal to 2 units of RBCs during the first 5 days of admission were propensity score matched to controls. Outcomes were 90- and 180-day mortality, highest acute kidney injury network (AKIN) score the first 10 days, days alive and free of organ support the first 28 days after admission to the intensive care unit and highest sequential organ failure assessment score (SOFA-max). RESULTS: Of 9490 admissions, 1347 were diagnosed with severe sepsis or septic shock. Propensity-score matching resulted in two well-matched groups with 237 patients in each. The annual inclusion rate in both groups was similar. The median hemoglobin level before RBC transfusion was 95 g/L (interquartile range 88-104) and the majority of the patients were transfused in first 2 days of admission. Low-grade RBC transfusion was associated with increased 90- and 180-day mortality with an absolute risk increase for death 9.3% (95% confidence interval: 0.6-18%, P = 0.032) and 11% (95% confidence interval: 1.7-19%, P = 0.018), respectively. Low-grade RBC transfusion also correlated with increased kidney, circulatory and respiratory failure and higher SOFA-max score. CONCLUSIONS: Low-grade RBC transfusion during the first 5 days of admission was associated with increased mortality and morbidity in a liberal transfusion setting. The results support the current practice of a restrictive transfusion strategy in septic critically ill patients.

A functional observational battery for evaluation of neurological outcomes in a rat model of acute bacterial meningitis.

BACKGROUND: Acute bacterial meningitis is a disease with a high mortality and a high incidence of neurological sequelae in survivors. There is an acute need to develop new adjuvant therapies. To ensure that new therapies evaluated in animal models are translatable to humans, studies must evaluate clinically relevant and patient-important outcomes, including neurological symptoms and sequelae. METHODS: We developed and tested a functional observational battery to quantify the severity of a variety of relevant neurological and clinical symptoms in a rat model of bacterial meningitis. The functional observational battery included symptoms relating to general clinical signs, gait and posture abnormalities, involuntary motor movements, focal neurological signs, and neuromotor abnormalities which were scored according to severity and summed to obtain a combined clinical and neurological score. To test the functional observational battery, adult Sprague-Dawley rats were infected by intracisternal injection of a clinical isolate of Streptococcus pneumoniae. Rats were evaluated for 6 days following the infection. RESULTS: Pneumococcal meningitis was not lethal in this model; however, it induced severe neurological symptoms. Most common symptoms were hearing loss (75% of infected vs 0% of control rats; p = 0.0003), involuntary motor movements (75% of infected vs 0% of control rats; p = 0.0003), and gait and posture abnormality (67% of infected vs 0% of control rats; p = 0.0013). Infected rats had a higher combined score when determined by the functional observational battery than control rats at all time points (24 h 12.7 ± 4.0 vs 4.0 ± 2.0; 48 h 17.3 ± 7.1 vs 3.4 ± 1.8; 6 days 17.8 ± 7.4 vs 1.7 ± 2.4; p < 0.0001 for all). CONCLUSIONS: The functional observational battery described here detects clinically relevant neurological sequelae of bacterial meningitis and could be a useful tool when testing new therapeutics in rat models of meningitis.