Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19.

BACKGROUND: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. METHODS: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. RESULTS: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P = 0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. CONCLUSIONS: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.).

Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial.

Importance: Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. ß-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. Objectives: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. Design, Setting, and Participants: An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 µg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. Intervention: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. Main Outcomes and Measures: The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. Results: The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, -0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, -4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, -1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event. Conclusion and Relevance: Among patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock. Trial Registration: EU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919.

Bayesian analysis of a systematic review of early versus late tracheostomy in ICU patients.

BACKGROUND: A recent systematic review and meta-analysis of RCTs of early vs late tracheostomy in mechanically ventilated patients suggest that early tracheostomy reduces the duration of ICU stay and mechanical ventilation, but does not reduce short-term mortality or ventilator-associated pneumonia (VAP). Meta-analysis of randomised trials is typically performed using a frequentist approach, and although reporting confidence intervals, interpretation is usually based on statistical significance. To provide a robust basis for clinical decision-making, we completed the search used from the previous review and analysed the data using Bayesian methods to estimate posterior probabilities of the effect of early tracheostomy on clinical outcomes. METHODS: The search was completed for RCTS comparing early vs late tracheostomy in the databases PubMed, EMBASE, and Cochrane library in June 2022. Effect estimates and 95% confidence intervals were calculated for the outcomes short-term mortality, VAP, duration of ICU stay, and mechanical ventilation. A Bayesian meta-analysis was performed with uninformative priors. Risk ratios (RRs) and standardised mean differences (SMDs) with 95% credible intervals were reported alongside posterior probabilities for any benefit (RR<1; SMD<0), a small benefit (number needed to treat, 200; SMD<-0.5), or modest benefit (number needed to treat, 100; SMD<-1). RESULTS: Nineteen RCTs with 3508 patients were included. Comparing patients with early vs late tracheostomy, the posterior probabilities for any benefit, small benefit, and modest benefit, respectively, were: 99%, 99%, and 99% for short-term mortality; 94%, 78%, and 51% for VAP; 97%, 43%, and 1% for duration of mechanical ventilation; and 97%, 75%, and 27% and for length of ICU stay. CONCLUSIONS: Bayesian meta-analysis suggests a high probability that early tracheostomy compared with delayed tracheostomy has at least some benefit across all clinical outcomes considered.

Association Between Hospital Volume and Mortality in Status Epilepticus: A National Cohort Study.

OBJECTIVES: In various medical and surgical conditions, research has found that centers with higher patient volumes have better outcomes. This relationship has not previously been explored for status epilepticus. This study sought to examine whether centers that see higher volumes of patients with status epilepticus have lower in-hospital mortality than low-volume centers. DESIGN: Cohort study, using 2010-2015 data from the nationwide Case Mix Programme database of the U.K.'s Intensive Care National Audit and Research Centre. SETTING: Greater than 90% of ICUs in United Kingdom, Wales, and Northern Ireland. PATIENTS: Twenty-thousand nine-hundred twenty-two adult critical care admissions with a primary or secondary diagnosis of status epilepticus or prolonged seizure. INTERVENTIONS: Annual hospital status epilepticus admission volume. MEASUREMENTS AND MAIN RESULTS: We used multiple logistic regression to evaluate the association between hospital annual status epilepticus admission volume and in-hospital mortality. Hospital volume was modeled as a nonlinear variable using restricted cubic splines, and generalized estimating equations with robust SEs were used to account for clustering by institution. There were 2,462 in-hospital deaths (11.8%). There was no significant association between treatment volume and in-hospital mortality for status epilepticus (p = 0.54). This conclusion was unchanged across a number of subgroup and sensitivity analyses, although we lacked data on seizure duration and medication use. Secondary analyses suggest that many high-risk patients were already transferred from low- to high-volume centers. CONCLUSIONS: We find no evidence that higher volume centers are associated with lower mortality in status epilepticus overall. It is likely that national guidelines and local pathways in the United Kingdom allow efficient patient transfer from smaller centers like district general hospitals to provide satisfactory patient care in status epilepticus. Future research using more granular data should explore this association for the subgroup of patients with refractory and superrefractory status epilepticus.

Landiolol for managing atrial fibrillation in intensive care.

Landiolol is an injectable ultrashort acting beta-blocker with high beta1 selectivity indicated for heart rate control of atrial fibrillation in the emergency and critical care setting. Accordingly, landiolol is associated with a significantly reduced risk of arterial hypotension and negative inotropic effects. Based on this particular profile along with the clinical experience in Japan for more than a decade landiolol represents a promising agent for the management of elevated heart rate and atrial fibrillation in intensive care patients even with catecholamine requirements. This article provides a review and perspective of landiolol for heart rate control in intensive care patients based on the current literature.

The Association Between Visiting Intensivists and ICU Outcomes.

OBJECTIVES: We hypothesized that intensivists unfamiliar with an ICU team and the context of that ICU would affect patient outcomes. We examined differences in mortality when ICU patients were admitted under intensivists routinely working in that ICU and compared with those admitted by intensivists familiar with an ICU elsewhere in the same hospital. DESIGN, SETTINGS, AND PATIENTS: A 5-year natural experimental crossover study involving patients admitted to four ICUs in a large U.K. teaching hospital. INTERVENTIONS: During a period of service reconfiguration, intensivists routinely rostered to work in one ICU worked in another of the hospital's four ICUs. "Home" intensivists were those who continued to work in their usual ICU; "visitor" intensivists were those who delivered care in an unfamiliar ICU. Patient data were obtained from electronic patient records to provide analysis on sex, age, admission Sequential Organ Failure Assessment score, date and time of admission, and admission type (elective, transfer, or unplanned). MEASUREMENTS AND MAIN RESULTS: We analyzed 9,981 admissions to four separate ICUs over a 5-year period. In total, 34.5% of patients were admitted by intensivists working in nonfamiliar surroundings. Visitor intensivists admitted patients with similar age and gender distributions but with greater physiologic derangement (mean Sequential Organ Failure Assessment score, 4.1 ± 2.8 vs 3.9 ± 2.8; p < 0.001) than home intensivists. Overall ICU mortality rates were higher in visitor intensivists, albeit not significantly so (11.5% vs 10.2%; p = 0.052). However, when the ICUs were analyzed separately, visitor mortality rates were found to be significantly higher than for home intensivists in two of the four ICUs (p = 0.017, 0.006). A multivariable analysis adjusting for confounding factors and the clustering of consultants revealed that the overall mortality rate was significantly higher for visitors (odds ratio, 1.18; 95% CI, 1.02-1.37; p = 0.024). A significant interaction between the ICU and visitor status was also detected (p = 0.046), with the visitor effect remaining significant in the two ICUs identified previously (both p = 0.009). CONCLUSIONS: Visitor intensivists in some ICUs were associated with higher mortality. The reasons are unknown but could relate to intensivists' practices, unfamiliarity with the patients, or the interaction with the interprofessional team.

A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure.

BACKGROUND & AIMS: Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown. In a prospective randomized controlled trial we investigated if maintenance of MH prevented development of ICH in ALF patients at high risk of the complication. METHODS: Patients with ALF, high-grade encephalopathy and intracranial pressure (ICP) monitoring in specialist intensive care units were randomized by sealed envelope to targeted temperature management (TTM) groups of 34°C (MH) or 36°C (control) for a period of 72h. Investigators were not blinded to group assignment. The primary outcome was a sustained elevation in ICP >25mmHg, with secondary outcomes the occurrence of predefined serious adverse effects, magnitude of ICP elevations and cerebral and all-cause hospital mortality (with or without transplantation). RESULTS: Forty-six patients were randomized, of whom forty-three were studied. There was no significant difference between the TTM groups in the primary outcome during the study period (35% vs. 27%, p=0.56), for the MH (n=17) or control (n=26) groups respectively, relative risk 1.31 (95% CI 0.53-3.2). Groups had similar incidence of adverse events and overall mortality (41% vs. 46%, p=0.75). CONCLUSIONS: In patients with ALF at high risk of ICH, MH at 33-34°C did not confer a benefit above management at 36°C in prevention of ICH or in overall survival. This study did not confirm advantage of its prophylactic use. (ISRCTN registration number 74268282; no funding.) LAY SUMMARY: Studies in animals with acute liver failure (ALF) have suggested that cooling (hypothermia) could prevent or limit the development of brain swelling, a dangerous complication of the condition. There is limited data on its effects in humans. In a randomized controlled trial in severely ill patients with ALF we compared the effects of different temperatures and found no benefit on improving survival or preventing brain swelling by controlling temperature at 33-34°C against 36°C.

The ageing population is neglected in research studies of traumatic brain injury.

INTRODUCTION: The UK population is ageing with increasing number of elderly patients suffering traumatic brain injury (TBI). The purpose of this study was to identify national TBI admission demographics, analyse the temporal evolution of TBI mortality in a single centre and conduct a systematic review of the literature to identify whether there is an age bias amongst researchers studying TBI. METHODS: National demographics for TBI were obtained from Health Episode Statistics. TBI patients admitted from 2000 to 2011 to Cambridge University Hospitals Neurocritical Care Unit (NCCU) were divided into age groups (<60, 60-74, ≥75 years). Temporal evolution of mortality was analysed using a logistic regression method. A systematic literature review was conducted to identify primary TBI research studies. Patient's ages were extracted and an average mean age was calculated and compared over time. RESULTS: From 1998, national TBI admissions have increased with the greatest rise in >60-year age group (p < 0.0001). In a tertiary referral critical care unit (n = 1145), the 60-74 year age group (compared to <60) had a significantly lower improvement in mortality over time (OR: 1.15, 95% CI: 1.02-1.31). A literature review revealed a mean age of 32.73 years (SD ± 12.85) for patients recruited to primary TBI studies. CONCLUSION: Despite increased admissions of elderly patients following TBI and static mortality (single centre, 60-74 year age group) there is little or no evidence of a corresponding increase in the age of patients recruited for TBI studies. In addition to the difficulties this presents in forming evidence-based decisions for the patient with TBI, it may also represent a wider problem for ICU research in an ever-ageing critical care population. More research needs to be conducted to establish the treatment end points for an ageing population.

Tracheostomy in special groups of critically ill patients: Who, when, and where?

Tracheostomy is one of the most common procedures undertaken in critically ill patients. It offers many theoretical advantages over translaryngeal intubation. Recent evidence in a heterogeneous group of critically ill patients, however, has not demonstrated a benefit for tracheostomy, in terms of mortality, length of stay in Intensive Care Unit (ICU), or incidence of ventilator-associated pneumonia. It may be a beneficial intervention in articular subsets of ICU patients. In this article, we will focus on the evidence for the timing of tracheostomy and its effect on various subgroups of patients in critical care.

Systematic review of statins in sepsis: There is no evidence of dose response.

OBJECTIVES: Sepsis is a common cause of morbidity and mortality and is associated with significant costs to the healthcare organizations. We performed a systematic review and meta-analysis to assess whether high or low-dose statin therapy improved mortality in patients with sepsis. METHODS: The trials analyzed in this study were multicenter or single center randomized control studies using statins for sepsis in a hospital setting. The patients included were adults with suspected or confirmed infection. INTERVENTIONS: This study found eight randomized controlled trials where participants were given either a statin or placebo daily for 14-28 days, the duration of their illness, or until their death or discharge, which ever occurred first. PRIMARY AND SECONDARY OUTCOMES MEASURED: This meta-analysis measured the effect of statin therapy on in hospital and 28 days mortality. RESULTS: In unselected patients, there was no demonstrable difference in the 28 days mortality (relative risk [RR] 0.88 95% confidence interval [CI], 0.70-1.12 and P = 0.16). There was also no significant difference between statin versus placebo for in-hospital mortality (RR 0.98 95% CI, 0.85-1.14 P = 0.36). When the studies where divided into low-dose and high-dose groups, there were no statistically significant differences for in-hospital mortality between low-dose statin versus placebo for (RR 0.81 CI 0.44-1.49 P = 0.27) or high-dose statin versus placebo (RR 0.99 95% CI 0.85-1.16, P = 0.28). There was no significant difference in adverse effects between the high- and low-dose groups. CONCLUSIONS: In this meta-analysis, we found that the use of statins did not significantly improve either in-hospital mortality or 28-day mortality in patients with sepsis. In the low-dose group, there were fewer quality multicenter studies; hence, conclusions based on the results of this subgroup are limited.

Vancomycin-associated nephrotoxicity in the critically ill: a retrospective multivariate regression analysis*.

OBJECTIVES: To evaluate the influence of vancomycin dose, serum trough concentration, and dosing strategy on the evolution of acute kidney injury in critically ill patients. DESIGN: Retrospective, single-center, observational study. SETTING: University Hospital ICU, Birmingham, UK. PATIENTS: All critically ill patients receiving vancomycin from December 1, 2004, to August 31, 2009. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The prevalence of new onset nephrotoxicity was reported using Risk, Injury, Failure, Loss, End-stage renal disease criteria, and independent factors predictive of nephrotoxicity were identified using logistic regression analysis. Complete data were available for 1,430 patients. Concomitant vasoactive therapy (odds ratio = 1.633; p < 0.001), median serum vancomycin (odds ratio = 1.112; p < 0.001), and duration of therapy (odds ratio = 1.041; p ≤ 0.001) were significant positive predictors of nephrotoxicity. Intermittent infusion was associated with a significantly greater risk of nephrotoxicity than continuous infusion (odds ratio = 8.204; p ≤ 0.001). CONCLUSIONS: In a large dataset, higher serum vancomycin concentrations and greater duration of therapy are independently associated with increased odds of nephrotoxicity. Furthermore, continuous infusion is associated with a decreased likelihood of nephrotoxicity compared with intermittent infusion. This large dataset supports the use of continuous infusion of vancomycin in critically ill patients.

Diagnosis and management of subarachnoid haemorrhage.

Aneurysmal subarachnoid haemorrhage (aSAH) presents a challenge to clinicians because of its multisystem effects. Advancements in computed tomography (CT), endovascular treatments, and neurocritical care have contributed to declining mortality rates. The critical care of aSAH prioritises cerebral perfusion, early aneurysm securement, and the prevention of secondary brain injury and systemic complications. Early interventions to mitigate cardiopulmonary complications, dyselectrolytemia and treatment of culprit aneurysm require a multidisciplinary approach. Standardised neurological assessments, transcranial doppler (TCD), and advanced imaging, along with hypertensive and invasive therapies, are vital in reducing delayed cerebral ischemia and poor outcomes. Health care disparities, particularly in the resource allocation for SAH treatment, affect outcomes significantly, with telemedicine and novel technologies proposed to address this health inequalities. This article underscores the necessity for comprehensive multidisciplinary care and the urgent need for large-scale studies to validate standardised treatment protocols for improved SAH outcomes.

The 'analysis of gene expression and biomarkers for point-of-care decision support in Sepsis' study; temporal clinical parameter analysis and validation of early diagnostic biomarker signatures for severe inflammation andsepsis-SIRS discrimination.

Introduction: Early diagnosis of sepsis and discrimination from SIRS is crucial for clinicians to provide appropriate care, management and treatment to critically ill patients. We describe identification of mRNA biomarkers from peripheral blood leukocytes, able to identify severe, systemic inflammation (irrespective of origin) and differentiate Sepsis from SIRS, in adult patients within a multi-center clinical study. Methods: Participants were recruited in Intensive Care Units (ICUs) from multiple UK hospitals, including fifty-nine patients with abdominal sepsis, eighty-four patients with pulmonary sepsis, forty-two SIRS patients with Out-of-Hospital Cardiac Arrest (OOHCA), sampled at four time points, in addition to thirty healthy control donors. Multiple clinical parameters were measured, including SOFA score, with many differences observed between SIRS and sepsis groups. Differential gene expression analyses were performed using microarray hybridization and data analyzed using a combination of parametric and non-parametric statistical tools. Results: Nineteen high-performance, differentially expressed mRNA biomarkers were identified between control and combined SIRS/Sepsis groups (FC>20.0, p<0.05), termed 'indicators of inflammation' (I°I), including CD177, FAM20A and OLAH. Best-performing minimal signatures e.g. FAM20A/OLAH showed good accuracy for determination of severe, systemic inflammation (AUC>0.99). Twenty entities, termed 'SIRS or Sepsis' (S°S) biomarkers, were differentially expressed between sepsis and SIRS (FC>2·0, p-value<0.05). Discussion: The best performing signature for discriminating sepsis from SIRS was CMTM5/CETP/PLA2G7/MIA/MPP3 (AUC=0.9758). The I°I and S°S signatures performed variably in other independent gene expression datasets, this may be due to technical variation in the study/assay platform.

High generation of reactive oxygen species from neutrophils in patients with severe COVID-19.

Neutrophilia and an elevated neutrophil:lymphocyte ratio are both characteristic features of severe COVID-19 infection. However, functional neutrophil responses have been poorly investigated in this setting. We utilised a novel PMA-based stimulation assay to determine neutrophil-derived reactive oxygen species (ROS) generation in patients with severe COVID-19 infection, non-COVID related sepsis and healthy study participants. ROS production was markedly elevated in COVID-19 patients with median values ninefold higher than in healthy controls and was particularly high in patients on mechanical ventilation. ROS generation correlated strongly with neutrophil count and elevated levels were also seen in patients with non-COVID related sepsis. Relative values, adjusted for neutrophil count, were high in both groups but extreme low or high values were seen in two patients who died shortly after testing, potentially indicating a predictive value for neutrophil function. Our results show that the high levels of neutrophils observed in patients with COVID-19 and sepsis exhibit functional capacity for ROS generation. This may contribute to the clinical features of acute disease and represents a potential novel target for therapeutic intervention.

Presymptomatic diagnosis of postoperative infection and sepsis using gene expression signatures.

PURPOSE: Early accurate diagnosis of infection ± organ dysfunction (sepsis) remains a major challenge in clinical practice. Utilizing effective biomarkers to identify infection and impending organ dysfunction before the onset of clinical signs and symptoms would enable earlier investigation and intervention. To our knowledge, no prior study has specifically examined the possibility of pre-symptomatic detection of sepsis. METHODS: Blood samples and clinical/laboratory data were collected daily from 4385 patients undergoing elective surgery. An adjudication panel identified 154 patients with definite postoperative infection, of whom 98 developed sepsis. Transcriptomic profiling and subsequent RT-qPCR were undertaken on sequential blood samples taken postoperatively from these patients in the three days prior to the onset of symptoms. Comparison was made against postoperative day-, age-, sex- and procedure- matched patients who had an uncomplicated recovery (n =151) or postoperative inflammation without infection (n =148). RESULTS: Specific gene signatures optimized to predict infection or sepsis in the three days prior to clinical presentation were identified in initial discovery cohorts. Subsequent classification using machine learning with cross-validation with separate patient cohorts and their matched controls gave high Area Under the Receiver Operator Curve (AUC) values. These allowed discrimination of infection from uncomplicated recovery (AUC 0.871), infectious from non-infectious systemic inflammation (0.897), sepsis from other postoperative presentations (0.843), and sepsis from uncomplicated infection (0.703). CONCLUSION: Host biomarker signatures may be able to identify postoperative infection or sepsis up to three days in advance of clinical recognition. If validated in future studies, these signatures offer potential diagnostic utility for postoperative management of deteriorating or high-risk surgical patients and, potentially, other patient populations.

Namilumab or infliximab compared with standard of care in hospitalised patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label, adaptive, phase 2, proof-of-concept trial.

BACKGROUND: Dysregulated inflammation is associated with poor outcomes in COVID-19. We aimed to assess the efficacy of namilumab (a granulocyte-macrophage colony stimulating factor inhibitor) and infliximab (a tumour necrosis factor inhibitor) in hospitalised patients with COVID-19, to prioritise agents for phase 3 trials. METHODS: In this randomised, multicentre, multi-arm, multistage, parallel-group, open-label, adaptive, phase 2, proof-of-concept trial (CATALYST), we recruited patients (aged ≥16 years) admitted to hospital with COVID-19 pneumonia and C-reactive protein (CRP) concentrations of 40 mg/L or greater, at nine hospitals in the UK. Participants were randomly assigned with equal probability to usual care or usual care plus a single intravenous dose of namilumab (150 mg) or infliximab (5 mg/kg). Randomisation was stratified by care location within the hospital (ward vs intensive care unit [ICU]). Patients and investigators were not masked to treatment allocation. The primary endpoint was improvement in inflammation, measured by CRP concentration over time, analysed using Bayesian multilevel models. This trial is now complete and is registered with ISRCTN, 40580903. FINDINGS: Between June 15, 2020, and Feb 18, 2021, we screened 299 patients and 146 were enrolled and randomly assigned to usual care (n=54), namilumab (n=57), or infliximab (n=35). For the primary outcome, 45 patients in the usual care group were compared with 52 in the namilumab group, and 29 in the usual care group were compared with 28 in the infliximab group. The probabilities that the interventions were superior to usual care alone in reducing CRP concentration over time were 97% for namilumab and 15% for infliximab; the point estimates for treatment-time interactions were -0·09 (95% CI -0·19 to 0·00) for namilumab and 0·06 (-0·05 to 0·17) for infliximab. 134 adverse events occurred in 30 (55%) of 55 patients in the namilumab group compared with 145 in 29 (54%) of 54 in the usual care group. 102 adverse events occurred in 20 (69%) of 29 patients in the infliximab group compared with 112 in 17 (50%) of 34 in the usual care group. Death occurred in six (11%) patients in the namilumab group compared with ten (19%) in the usual care group, and in four (14%) in the infliximab group compared with five (15%) in the usual care group. INTERPRETATION: Namilumab, but not infliximab, showed proof-of-concept evidence for reduction in inflammation-as measured by CRP concentration-in hospitalised patients with COVID-19 pneumonia. Namilumab should be prioritised for further investigation in COVID-19. FUNDING: Medical Research Council.

Rehabilitation Levels in Patients with COVID-19 Admitted to Intensive Care Requiring Invasive Ventilation. An Observational Study.

Rationale: Patients with severe coronavirus disease (COVID-19) have complex organ support needs that necessitate prolonged stays in the intensive care unit (ICU), likely to result in a high incidence of neuromuscular weakness and loss of well-being. Early and structured rehabilitation has been associated with improved outcomes for patients requiring prolonged periods of mechanical ventilation, but at present no data are available to describe similar interventions or outcomes in COVID-19 populations.Objectives: To describe the demographics, clinical status, level of rehabilitation, and mobility status at ICU discharge of patients with COVID-19.Methods: Adults admitted to the ICU with a confirmed diagnosis of COVID-19 and mechanically ventilated for >24 hours were included. Rehabilitation status was measured daily using the Manchester Mobility Score to identify the time taken to first mobilize (defined as sitting on the edge of the bed or higher) and highest level of mobility achieved at ICU discharge.Results: A total of n = 177 patients were identified, of whom n = 110 survived to ICU discharge and were included in the subsequent analysis. While on ICU, patients required prolonged periods of mechanical ventilation (mean 19 ± 10 d), most received neuromuscular blockade (90%) and 67% were placed in the prone position on at least one occasion. The mean ± standard deviation time to first mobilize was 14 ± 7 days, with a median Manchester Mobility Score at ICU discharge of 5 (interquartile range: 4-6), which represents participants able to stand and step around to a chair with or without assistance. Time to mobilize was significantly longer in those with higher body mass index (P < 0.001), and older patients (P = 0.012) and those with more comorbidities (P = 0.017) were more likely to require further rehabilitation after discharge.Conclusions: The early experience of the COVID-19 pandemic in the United Kingdom resembles the experience in other countries, with high acuity of illness and prolonged period of mechanical ventilation required for those patients admitted to the ICU. Although the time to commence rehabilitation was delayed owing to this severity of illness, rehabilitation was possible within the ICU and led to increased levels of mobility from waking before ICU discharge.Clinical trial registered with ClinicalTrials.gov (NCT04396197).

Stability of OCT and OCTA in the Intensive Therapy Unit Setting.

To assess the stability of retinal structure and blood flow measures over time and in different clinical settings using portable optical coherence tomography angiography (OCTA) as a potential biomarker of central perfusion in critical illness, 18 oesophagectomy patients completed retinal structure and blood flow measurements by portable OCT and OCTA in the eye clinic and intensive therapy unit (ITU) across three timepoints: (1) pre-operation in a clinic setting; (2) 24-48 h post-operation during ITU admission; and (3) seven days post-operation, if the patient was still admitted. Blood flow and macular structural measures were stable between the examination settings, with no consistent variation between pre- and post-operation scans, while retinal nerve fibre layer thickness increased in the post-operative scans (+2.31 µm, p = 0.001). Foveal avascular zone (FAZ) measurements were the most stable, with an intraclass correlation coefficient of up to 0.92 for right eye FAZ area. Blood flow and structural measures were lower in left eyes than right eyes. Retinal blood flow assessed in patients before and during an ITU stay using portable OCTA showed no systematic differences between the clinical settings. The stability of retinal blood flow measures suggests the potential for portable OCTA to provide clinically useful measures in ITU patients.

Study into the reversal of septic shock with landiolol (beta blockade): STRESS-L Study protocol for a randomised trial.

INTRODUCTION: In 2013, a single-centre study reported the safe use of esmolol in patients with septic shock and tachycardia who required vasopressor therapy for more than 24 hours. Although not powered to detect a change in mortality, marked improvements were seen in survival (adjusted HR, 0.39; 95% CI, 0.26 to 0.59; p<0.001). Beta blockers are one of the most studied groups of drugs but their effect in septic shock is poorly understood; proposed mechanisms include not only the modulation of cardiac function but also immunomodulation. METHODS AND ANALYSIS: STRESS-L is a randomised, open-label, non-blinded clinical trial which is enrolling a total of 340 patients with septic shock as defined by Sepsis-3 consensus definition and a tachycardia (heart rate ≥95 beats per minute (bpm)) after vasopressor treatment of at least 24 hours. Standard randomisation (1:1 ratio) allocates patients to receive usual care (according to international standards) versus usual care and a continuous landiolol infusion to reduce the heart rate between 80 and 94 bpm. The primary endpoint is the mean Sequential Organ Failure Assessment score over 14 days from entry into the trial and while in intensive care unit. Results will inform current clinical practice guidelines. ETHICS AND DISSEMINATION: This trial has clinical trial authorisation from the UK competent authority, the Medicines and Healthcare products Regulatory Agency, and has been approved by the East of England-Essex Research Ethics Committee (reference: 17/EE/0368).The results of the trial will be reported first to trial collaborators. The main report will be drafted by the trial coordinating team, and the final version will be agreed by the Trial Steering Committee before submission for publication, on behalf of the collaboration. REGISTRATION: The trial is funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) (Project Number: EME-14/150/85) and registered ISRCTN12600919 and EudraCT: 2017-001785-14.