Ulinastatin Add-on to Standard of Care in Critically Ill COVID-19 Patients: A Multicenter, Retrospective Study.

AIM: To assess the impact on 30-day mortality with ulinastatin (ULI) used as add-on to standard of care (SOC) compared to SOC alone in coronavirus disease (COVID-19) patients requiring admission to the intensive care unit (ICU). MATERIALS AND METHODS: In this multicentric, retrospective study, we collected data on clinical, laboratory, and outcome parameters in patients with COVID-19. Thirty-day mortality outcome was compared among patients treated with SOC alone and ULI used as add-on to SOC. Odds ratio (OR) and 95% confidence intervals (CI) were determined to identify the predictors of 30-day mortality. RESULTS: Ninety-four patients were identified and enrolled in both groups with comparable baseline parameters. On univariate analysis, 30-day mortality was significantly lower in ULI plus SOC group than SOC alone group (36.2 vs 51.1%, OR 0.54, 95% CI 0.30-0.97, p = 0.040). The effect on mortality was more pronounced in patients who did not require intubation (10.9 vs 34.0%, OR 0.24, 95% CI 0.09-0.66, p = 0.006) and with early administration (within 72 hours of admission) of ULI (30.7 vs 57.9%, OR 0.32, 95% CI 0.11-0.91, p = 0.032). On multivariate analysis, only intubation predicted mortality (adjusted OR 10.13, 95% CI 3.77-27.25, p<0.0001) and the effect of ULI on survival was not significant (adjusted OR 0.58, 95% CI 0.22-1.52, p = 0.270). CONCLUSION: Given the limited options for COVID-19 patients treated in ICU, early administration of ULI may be helpful, especially in patients not requiring intubation to improve the outcomes. Further, a large, randomized study is warranted to confirm these findings.

The Lifeboat at World's End: Moving Beyond Crisis Standards of Care.

It may be too late to avoid the climate crisis, likely to be humanity's most expensive, widespread, and enduring catastrophe. This is a qualitatively different kind of catastrophe, in which increased costs, decreased revenue, and no possibility of bailout force communities to harshly cut budgets, especially in health care. Little is known about making such brutal cuts fair or efficient, nor how to help the public accept them. The crisis presents an opportunity for bioethicists to play a crucial role, but one for which traditional approaches are inherently inadequate. Although often dismissed as heartless, Garrett Hardin's "lifeboat ethics" started a conversation about making ethical choices in global disasters-where all options are painful and unacceptable-and may provide guidance. Bioethics during the climate crisis must focus on communities rather than individuals and help survivors grieve the terrible consequences. Because today's choices will affect many generations, with the burdens falling most heavily on poor communities, we have to construct a radical bioethics to help tomorrow's health care become green, efficient, and fair.

Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19: A Randomized Phase 2/3 Clinical Trial.

Importance: COVID-19 pneumonia is often associated with hyperinflammation. The efficacy and safety of anakinra in treating patients with severe COVID-19 pneumonia and hyperinflammation are still unclear. Objective: To assess the efficacy and safety of anakinra vs standard of care alone for patients with severe COVID-19 pneumonia and hyperinflammation. Design, Setting, and Participants: The Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to COVID-19 (ANA-COVID-GEAS) was a multicenter, randomized, open-label, 2-group, phase 2/3 clinical trial conducted at 12 hospitals in Spain between May 8, 2020, and March 1, 2021, with a follow-up of 1 month. Participants were adult patients with severe COVID-19 pneumonia and hyperinflammation. Hyperinflammation was defined as interleukin-6 greater than 40 pg/mL, ferritin greater than 500 ng/mL, C-reactive protein greater than 3 mg/dL (rationale, ≥5 upper normal limit), and/or lactate dehydrogenase greater than 300 U/L. Severe pneumonia was considered if at least 1 of the following conditions was met: ambient air oxygen saturation 94% or less measured with a pulse oximeter, ratio of partial pressure O2 to fraction of inspired O2 of 300 or less, and/or a ratio of O2 saturation measured with pulse oximeter to fraction of inspired O2 of 350 or less. Data analysis was performed from April to October 2021. Interventions: Usual standard of care plus anakinra (anakinra group) or usual standard of care alone (SoC group). Anakinra was given at a dose of 100 mg 4 times a day intravenously. Main Outcomes and Measures: The primary outcome was the proportion of patients not requiring mechanical ventilation up to 15 days after treatment initiation, assessed on an intention-to-treat basis. Results: A total of 179 patients (123 men [69.9%]; mean [SD] age, 60.5 [11.5] years) were randomly assigned to the anakinra group (92 patients) or to the SoC group (87 patients). The proportion of patients not requiring mechanical ventilation up to day 15 was not significantly different between groups (64 of 83 patients [77.1%] in the anakinra group vs 67 of 78 patients [85.9%] in the SoC group; risk ratio [RR], 0.90; 95% CI, 0.77-1.04; P = .16). Anakinra did not result in any difference in time to mechanical ventilation (hazard ratio, 1.72; 95% CI, 0.82-3.62; P = .14). There was no significant difference between groups in the proportion of patients not requiring invasive mechanical ventilation up to day 15 (RR, 0.99; 95% CI, 0.88-1.11; P > .99). Conclusions and Relevance: In this randomized clinical trial, anakinra did not prevent the need for mechanical ventilation or reduce mortality risk compared with standard of care alone among hospitalized patients with severe COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov Identifier: NCT04443881.

Efficacy and safety of Ixekizumab vs. low-dose IL-2 vs. Colchicine vs. standard of care in the treatment of patients hospitalized with moderate-to-critical COVID-19: A pilot randomized clinical trial (STRUCK: Survival Trial Using Cytokine Inhibitors).

BACKGROUND: Cases of coronavirus disease 2019 (COVID-19) requiring hospitalization continue to appear in vulnerable populations, highlighting the importance of novel treatments. The hyperinflammatory response underlies the severity of the disease, and targeting this pathway may be useful. Herein, we tested whether immunomodulation focusing on interleukin (IL)-6, IL-17, and IL-2, could improve the clinical outcomes of patients admitted with COVID-19. METHODS: This multicenter, open-label, prospective, randomized controlled trial was conducted in Brazil. Sixty hospitalized patients with moderate-to-critical COVID-19 received in addition to standard of care (SOC): IL-17 inhibitor (ixekizumab 80 mg SC/week) 1 dose every 4 weeks; low-dose IL-2 (1.5 million IU per day) for 7 days or until discharge; or indirect IL-6 inhibitor (colchicine) orally (0.5 mg) every 8 hours for 3 days, followed by 4 weeks at 0.5 mg 2x/day; or SOC alone. The primary outcome was accessed in the "per protocol" population as the proportion of patients with clinical improvement, defined as a decrease greater or equal to two points on the World Health Organization's (WHO) seven-category ordinal scale by day 28. RESULTS: All treatments were safe, and the efficacy outcomes did not differ significantly from those of SOC. Interestingly, in the colchicine group, all participants had an improvement of greater or equal to two points on the WHO seven-category ordinal scale and no deaths or patient deterioration were observed. CONCLUSIONS: Ixekizumab, colchicine, and IL-2 were demonstrated to be safe but ineffective for COVID-19 treatment. These results must be interpreted cautiously because of the limited sample size.

Crisis standards of care within the first wave of the COVID-19 pandemic.

The ability of the healthcare infrastructure to overcome overwhelming needs during a crisis or disaster with equitable care stems from the implementation of crisis standards of care (CSC). CSC provides a framework for the discussion and planning of how to adapt care to meet these needs, while focusing on the greatest good for the greatest number. The COVID-19 pandemic has challenged healthcare infrastructure, but no formal CSC declaration or disclosure to the public within the first wave of the COVID-19 pandemic leads to the need for further inquiry surrounding the planning and implementation for CSC. This research evaluates data and inferential indicators related to CSC implementations from public documents in Brazil, India, Italy, and New York State during the first wave of the COVID-19 pandemic. Were there mitigation methods that could be implemented prior to the need for CSC? Are there policy and decision-making implications to CSC? Lastly, how does CSC relate to changes in mortality during a pandemic, especially with the phenomena surrounding excess mortality? While CSC were not openly implemented by any nation or state in the first wave of the COVID-19 pandemic, CSC principle use of expanding capacity to non-clinical areas, need for healthcare workers, critical supply lacking, and excess mortality, along with healthcare collapse for India and Brazil can be gleaned from the data. Acknowledging a strain on healthcare infrastructure and the need for CSC implementation allows for the community to respond as a whole to better ensure that care remains equitable.

Efficacy and Safety of Garadacimab in Combination with Standard of Care Treatment in Patients with Severe COVID-19.

BACKGROUND: Garadacimab, a fully human IgG4 monoclonal antibody, inhibits the kallikrein-kinin pathway at a key initiator, activated coagulation factor XII (FXIIa), and may play a protective role in preventing the progression of COVID-19. This phase 2 study evaluated the efficacy and safety of garadacimab plus standard of care (SOC) versus placebo plus SOC in patients with severe COVID-19. METHODS: Patients hospitalised with COVID-19 were randomised (1:1) to a single intravenous dose of garadacimab (700 mg) plus SOC or placebo plus SOC. Co-primary endpoint was incidence of endotracheal intubation or death between randomisation and Day 28. All-cause mortality, safety and pharmacokinetic/pharmacodynamic parameters were assessed. RESULTS: No difference in incidence of tracheal intubation or death (p = 0.274) or all-cause mortality was observed (p = 0.382). Garadacimab was associated with a lower incidence of treatment-emergent adverse events (60.3% vs 67.8%) and fewer serious adverse events (34 vs 45 events) versus placebo. No garadacimab-related deaths or bleeding events were reported, including in the 45.9% (n = 28/61) of patients who received concomitant heparin. Prolonged activated partial thromboplastin time (aPTT), and increased coagulation factor XII (FXII) levels were observed with garadacimab versus placebo to Day 14, whilst FXIIa-mediated kallikrein activity (FXIIa-mKA) was suppressed to Day 28. CONCLUSION: In patients with severe COVID-19, garadacimab did not confer a clinical benefit over placebo. Transient aPTT prolongation and suppressed FXIIa-mKA showed target engagement of garadacimab that was not associated with bleeding events even with concomitant anticoagulant use. The safety profile of garadacimab was consistent with previous studies in patients with hereditary angioedema. GOV IDENTIFIER: NCT04409509. Date of registration: 28 May, 2020.

Co-administration of AYUSH 64 as an adjunct to standard of care in mild and moderate COVID-19: A randomized, controlled, multicentric clinical trial.

OBJECTIVE: Evaluate the efficacy of AYUSH 64, a standard polyherbal Ayurvedic drug in COVID-19. METHODS: During the first pandemic wave, 140 consenting and eligible hospitalized adult participants with mild-moderate symptomatic disease (specific standard RT-PCR assay positive) were selected as per a convenience sample, and randomized (1:1 ratio) to an open-label (assessor blind) two-arm multicentric drug trial; standard of care (SOC as per Indian guidelines) versus AYUSH 64 combined with SOC (AYUSH plus). Participants were assessed daily and discharged once clinical recovery (CR, primary efficacy) was achieved which was based on a predetermined set of criteria (resolution of symptoms, normal peripheral oximetry, and negative specific RT-PCR assay). Each participant was followed using an indigenous software program(mobile phone) and completed a 12-week study period. The dose of AYUSH 64 was 2 tablets oral, 500 mg each, bid for 12 weeks (AYUSH plus only). Significant P was <0.05 (two-sided). On randomization, the groups were found well matched. RESULTS: The mean interval time from randomization to CR was significantly superior in the AYUSH plus group [mean 6.45 days versus 8.26 days, 95% Confidence Interval of the difference -3.02 to -0.59 (P = 0.003, Student's 't test] as per-protocol analysis (134 participants); significant (P = 0.002) on an intention to treat analysis. 70% of the participants in AYUSH plus recovered during the first week (P = 0.046, Chi-square) and showed a significantly better change in physical health, fatigue, and quality of life measures. 48 adverse events, mostly mild and gut related, were reported by each group. There were 20 patient withdrawals (8 in AYUSH plus) but none due to an AE. There were no deaths. Daily assessment (hospitalization) and supervised drug intake ensured robust efficacy data. The open-label design was a concern (study outcome). CONCLUSIONS: AYUSH 64 in combination with SOC hastened recovery, reduced hospitalization, and improved health in COVID-19. It was considered safe and well-tolerated. Further clinical validation (Phase III) is required. TRIAL REGISTRATION: CTRI/2020/06/025557.

Lessons From COVID-19 for the Next War: Crisis Standards of Care in the Role 3 Intensive Care Unit.

The rationing of medical resources became a common practice during the SARS-CoV-2 (COVID-19) pandemic. To cope with overwhelming patient numbers, hospitals were forced to adopt "crisis standards of care" (CSC) guidelines, which allow physicians to navigate the task of rationing health care resources in both an effective and ethically sound manner. The Military Health System currently has clinical guidelines for mass casualty incident (MCI) triage but lacks deployed Role 3 intensive care unit (ICU) CSC guidelines. In future peer and near-peer conflicts, this gap may prove detrimental when thousands of casualties following a single battle create a continuous and prolonged mass casualty event. The challenges of providing critical care in a battlefield hospital during a large conflict are unique and numerous, but lessons from COVID-19 ICUs such as transitioning to a utilitarian ethic, clear definitions, decision points, and decision authorities, as well as the establishment of clinical practice guidelines formulated from evidence-based protocols, can better prepare the U.S. expeditionary medical force for future conflicts. A battlefield CSC will allow military critical care physicians and nurses to manage overwhelmed ICUs and make better triage decisions, allowing them to provide a higher quality of care to the collective. In this commentary, we explore the need for Wartime CSC in the battlefield Role 3 ICU and the tools and methods used by civilian and military institutions to create and enact CSCs throughout the COVID-19 pandemic.

Is Telehealth Here To Stay.

The telehealth explosion was facilitated by the onset of the coronavirus disease 2019 (COVID-19) pandemic, but what happens when the crisis is over? Will there be lasting changes to the practice of medicine and delivery of care, or will providers and patients alike be eager to go back to the "old way" of doing things? Jeremy Gabrysch, MD, a physician and CEO of Remedy, an on-demand urgent care service that delivers doctors right to your front door, discusses what the future of telehealth may hold.

Outpatient parenteral antimicrobial therapy (OPAT) from an emergency model applied during the COVID-19 pandemic to standard of care: Preliminary lessons from our experience.

OBJECTIVES: We wish to report on our experience of OPAT during the first two years of the COVID19 outbreak. PATIENTS AND METHODS: We recorded data on all patients treated in the OPAT regimen in 2020 and 2021 and compared overall trends, use of carbapenems and saved days of hospitalization. RESULTS: The OPAT model enabled us to ensure the administration of first choice antibiotic therapy to 239 patients with an increase of 21.3% from 2020 to 2021 (108 vs 131). Applying this model, we also recorded a reduction in the use of carbapenems from 33% in 2020 to 26% in 2021 and a total of 3041 recovery days saved in 2021.The clinical cure rate reached 94%. Few adverse events occurred (35/239; 14.6%), and they did not require hospitalization. CONCLUSION: OPAT is a safe, efficacious, and cost-effective model that functioned effectively during the COVID-19 crisis and could become the standard of care for the treatment of selected patients.

4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes-2023.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Convalescent or standard plasma versus standard of care in the treatment of COVID-19 patients with respiratory impairment: short and long-term effects. A three-arm randomized controlled clinical trial.

BACKGROUND: The efficacy of early treatment with convalescent plasma in patients with COVID-19 is debated. Nothing is known about the potential effect of other plasma components other than anti-SARS-CoV-2 antibodies. METHODS: To determine whether convalescent or standard plasma would improve outcomes for adults in early phase of Covid19 respiratory impairment we designed this randomized, three-arms, clinical trial (PLACO COVID) blinded on interventional arms that was conducted from June 2020 to August 2021. It was a multicentric trial at 19 Italian hospitals. We enrolled 180 hospitalized adult patients with COVID-19 pneumonia within 5 days from the onset of respiratory distress. Patients were randomly assigned in a 1:1:1 ratio to standard of care (n = 60) or standard of care + three units of standard plasma (n = 60) or standard of care + three units of high-titre convalescent plasma (n = 60) administered on days 1, 3, 5 after randomization. Primary outcome was 30-days mortality. Secondary outcomes were: incidence of mechanical ventilation or death at day 30, 6-month mortality, proportion of days with mechanical ventilation on total length of hospital stay, IgG anti-SARS-CoV-2 seroconversion, viral clearance from plasma and respiratory tract samples, and variations in Sequential Organ Failure Assessment score. The trial was analysed according to the intention-to-treat principle. RESULTS: 180 patients (133/180 [73.9%] males, mean age 66.6 years [IQR 57-73]) were enrolled a median of 8 days from onset of symptoms. At enrollment, 88.9% of patients showed moderate/severe respiratory failure. 30-days mortality was 20% in Control arm, 23% in Convalescent (risk ratio [RR] 1.13; 95% confidence interval [CI], 0.61-2.13, P = 0.694) and 25% in Standard plasma (RR 1.23; 95%CI, 0.63-2.37, P = 0.544). Time to viral clearance from respiratory tract was 21 days for Convalescent, 28 for Standard plasma and 23 in Control arm but differences were not statistically significant. No differences for other secondary endpoints were seen in the three arms. Serious adverse events were reported in 1.7%, 3.3% and 5% of patients in Control, Standard and Convalescent plasma arms respectively. CONCLUSIONS: Neither high-titer Convalescent nor Standard plasma improve outcomes of COVID-19 patients with acute respiratory failure. Trial Registration Clinicaltrials.gov Identifier: NCT04428021. First posted: 11/06/2020.

Protocols of Standard of Care for Adult Patients with Primary Antibody Deficiencies Will Improve Timing of Diagnosis, Survival, and Quality of Life.

The majority of primary immunodeficiencies (PIDs) are antibody deficiencies (PADs), and not all of them are rare diseases; As an example, Caucasian individuals suffer from selective IgA deficiency at a frequency of 1:500. In addition to infections, symptomatic patients with PAD are more likely to develop neoplastic, autoimmune, and allergic diseases. In the event that PAD is neglected or delayed for more than ten years, complications develop, eventually resulting in death. No studies have been conducted to devise and report detailed ready-to-use protocols for managing PAD to date. This study aimed to propose protocols and guidelines for the adult PAD patients' standard care. Preparing the protocol, we considered the frequency and type of laboratory tests, imaging, endoscopic examinations, specialist consultations, and standardized recommendations for further care in the place of residence.  As a result of the proposed monitoring scheme, patients can be provided with complete care in terms of their underlying conditions and comorbidities, as well as early detection of complications. This protocol will serve as a guide for physicians dealing with these patients and enable comparisons of patient groups across a variety of treatment centers, even far away from each other. A national consultant in the field of clinical immunology verified the protocol mainly developed by Polish experts from reference immunology centres for adults.

Afebrile chemotherapy-induced neutropenia: an international survey spots oncologists' routine clinical practice versus the standard of care and the impact of COVID-19.

INTRODUCTION: Afebrile chemotherapy-induced neutropenia represents a frequent clinical situation where chemotherapy protocol, patient's comorbidities, and disease status determine the risk of infection hence the management plan. Internationally distributed, this questionnaire aims to evaluate the routine practice and the impact of the COVID-19 pandemic on afebrile chemotherapy-induced neutropenia management. MATERIAL AND METHODS: Coordinators from Egypt, Morocco, Azerbaijan, and Russia developed a 12-item questionnaire using Google forms to explore how oncologists deal with afebrile chemotherapy-induced neutropenia. The link to the survey was available internationally through social media and to their local societies over the period from July to September 2021. RESULTS: We received 151 responses from 4 world regions: 58.9, 9.9, 11.3, and 15.2% from the Mena area, Russia, Europe, and Asia. The responses deviated from the guideline-driven practice as G-CSF was the most chosen option for intermediate risk that was statistically different based on the academic background of the treating physician. Half of the responders ignored patients and disease risk factors in the intermediate-risk cases that trend was statistically different based on the geographical distribution. The steroid was a valid option for intermediate and low-risk as per oncologists practicing in Russia. COVID-19 pandemic positively affected the rate of prescription of G-CSF as expected. CONCLUSION: The disparities in the routine practice of oncologists based on their geographical and academic backgrounds highlight the need to analyze the underlying obstacles that hinder guideline-based practice like workload or lack of the proper knowledge.

Fluid balance neutralization secured by hemodynamic monitoring versus protocolized standard of care in critically ill patients requiring continuous renal replacement therapy: study protocol of the GO NEUTRAL randomized controlled trial.

BACKGROUND: Fluid overload is associated with worse outcome in critically ill patients requiring continuous renal replacement therapy (CRRT). Net ultrafiltration (UFNET) allows precise control of the fluid removal but is frequently ceased due to hemodynamic instability episodes. However, approximately 50% of the hemodynamic instability episodes in ICU patients treated with CRRT are not associated with preload dependence (i.e., are not related to a decrease in cardiac preload), suggesting that volume removal is not responsible for these episodes of hemodynamic impairment. The use of advanced hemodynamic monitoring, comprising continuous cardiac output monitoring to repeatedly assess preload dependency, could allow securing UFNET to allow fluid balance control and prevent fluid overload. METHODS: The GO NEUTRAL trial is a multicenter, open-labeled, randomized, controlled, superiority trial with parallel groups and balanced randomization with a 1:1 ratio. The trial will enroll adult patients with acute circulatory failure treated with vasopressors and severe acute kidney injury requiring CRRT who already have been equipped with a continuous cardiac output monitoring device. After informed consent, patients will be randomized into two groups. The control group will receive protocolized fluid removal with an UFNET rate set to 0-25 ml h-1 between inclusion and H72 of inclusion. The intervention group will be treated with an UFNET rate set on the CRRT of at least 100 ml h-1 between inclusion and H72 of inclusion if hemodynamically tolerated based on a protocolized hemodynamic protocol aiming to adjust UFNET based on cardiac output, arterial lactate concentration, and preload dependence assessment by postural maneuvers, performed regularly during nursing rounds, and in case of a hemodynamic instability episode. The primary outcome of the study will be the cumulative fluid balance between inclusion and H72 of inclusion. Randomization will be generated using random block sizes and stratified based on fluid overload status at inclusion. The main outcome will be analyzed in the modified intention-to-treat population, defined as all alive patients at H72 of inclusion, based on their initial allocation group. DISCUSSION: We present in the present protocol all study procedures in regard to the achievement of the GO NEUTRAL trial, to prevent biased analysis of trial outcomes and improve the transparency of the trial result report. Enrollment of patients in the GO NEUTRAL trial has started on June 31, 2021, and is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04801784. Registered on March 12, 2021, before the start of inclusion.