Research priorities for therapeutic plasma exchange in critically ill patients.

Therapeutic plasma exchange (TPE) is a therapeutic intervention that separates plasma from blood cells to remove pathological factors or to replenish deficient factors. The use of TPE is increasing over the last decades. However, despite a good theoretical rationale and biological plausibility for TPE as a therapy for numerous diseases or syndromes associated with critical illness, TPE in the intensive care unit (ICU) setting has not been studied extensively. A group of eighteen experts around the globe from different clinical backgrounds used a modified Delphi method to phrase key research questions related to "TPE in the critically ill patient". These questions focused on: (1) the pathophysiological role of the removal and replacement process, (2) optimal timing of treatment, (3) dosing and treatment regimes, (4) risk-benefit assumptions and (5) novel indications in need of exploration. For all five topics, the current understanding as well as gaps in knowledge and future directions were assessed. The content should stimulate future research in the field and novel clinical applications.

ICU without borders.

Critical illness is a continuum, but patient care is often fragmented. Value-based critical care focuses on the overall health of the patient, not on an episode of care. The "ICU without borders" model incorporates a concept where members of the critical care team are involved in the management of patients from the onset of critical illness until recovery and beyond. In this paper, we summarise the potential benefits and challenges to patients, families, staff and the wider healthcare system and list some essential requirements, including a tight governance framework, advanced technologies, investment and trust. We also argue that "ICU without borders" should be viewed as a bi-directional model, allowing extended visiting hours, giving patients and families direct access to experienced critical care staff and offering mutual aid when needed.

Relationship between D-dimers and dead-space on disease severity and mortality in COVID-19 acute respiratory distress syndrome: A retrospective observational cohort study

Background Despite its diagnostic and prognostic importance, physiologic dead space fraction is not included in the current ARDS definition or severity classification. ARDS caused by COVID-19 (C-ARDS) is characterized by increased physiologic dead space fraction and hypoxemia. Our aim was to investigate the relationship between dead space indices, markers of inflammation, immunothrombosis, severity and intensive care unit (ICU) mortality. Results Retrospective data including demographics, gas exchange, ventilatory parameters, and respiratory mechanics in the first 24 h of invasive ventilation. Plasma concentrations of D-dimers and ferritin were not significantly different across C-ARDS severity categories. Weak relationships were found between D-dimers and VR (r = 0.07, p = 0.13), PETCO2/PaCO2 (r = −0.1, p = 0.02), or estimated dead space fraction (r = 0.019, p = 0.68). Age, PaO2/FiO2, pH, PETCO2/PaCO2 and ferritin, were independently associated with ICU mortality. We found no association between D-dimers or ferritin and any dead-space indices adjusting for PaO2/FiO2, days of ventilation, tidal volume, and respiratory system compliance. Conclusions We report no association between dead space and inflammatory markers in mechanically ventilated patients with C-ARDS. Our results support theories suggesting that multiple mechanisms, in addition to immunothrombosis, play a role in the pathophysiology of respiratory failure and degree of dead space in C-ARDS.

The Role of Cell Cycle Arrest Biomarkers for Predicting Acute Kidney Injury in Critically Ill COVID-19 Patients: A Multicenter, Observational Study.

OBJECTIVES: Patients with COVID-19-associated acute respiratory distress syndrome (ARDS) have a high risk for developing acute kidney injury (AKI) which is associated with an increased risk of death and persistent renal failure. Early prediction of AKI is crucial in order to implement preventive strategies. The purpose of this study was to investigate the predictive performance of tissue inhibitor of metalloproteinases 2 and insulin like growth factor binding protein 7 (TIMP-2) × (IGFBP7) in critically ill patients with COVID-19-associated ARDS. DESIGN: Multicenter, prospective, observational study. SETTING: Twelve centers across Europe and United Kingdom. PATIENTS: Patients with moderate or severe COVID-19-associated ARDS were included and serial measurements of (TIMP-2) × (IGFBP7) were performed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the development of moderate or severe AKI according to the Kidney Disease: Improving Global Outcomes definition. Three hundred patients were available for the primary analysis, and 39 met the primary endpoint. At enrollment, urinary (TIMP-2) × (IGFBP7) had high predictive value for the primary endpoint with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.84-0.93). (TIMP-2) × (IGFBP7) was significantly higher in endpoint-positive patients at enrollment and at 12 hours. CONCLUSIONS: Urinary (TIMP-2) × (IGFBP7) predicts the occurrence of AKI in critically ill patients with COVID-19-associated ARDS.

Study protocol of a randomised, double-blind, placebo-controlled, two-arm parallel-group, multi-centre phase 3 pivotal trial to investigate the efficacy and safety of recombinant human alkaline phosphatase for treatment of patients with sepsis-associated acute kidney injury.

INTRODUCTION: Sepsis, the leading cause of acute kidney injury (AKI), is associated with a high morbidity and mortality. Alkaline phosphatase (ALP) is an endogenous detoxifying enzyme. A recombinant human ALP compound, ilofotase alfa, showed no safety or tolerability concerns in a phase 2 trial. Renal function improvement over 28 days was significantly greater in the ilofotase alfa group. Moreover, a significant relative reduction in 28-day all-cause mortality of >40% was observed. A follow-up trial has been designed to confirm these findings. METHODS AND ANALYSIS: This is a phase 3, global, multi-centre, randomised, double-blind, placebo-controlled, sequential design trial in which patients are randomly assigned to either placebo or 1.6 mg/kg ilofotase alfa. Randomisation is stratified by baseline modified Sequential Organ Failure Assessment (mSOFA) score and trial site. The primary objective is to confirm the survival benefit with ilofotase alfa by demonstrating a reduction in 28-day all-cause mortality in patients with sepsis-associated AKI requiring vasopressors. A maximum of 1400 patients will be enrolled at ∼120 sites in Europe, North America, Japan, Australia and New Zealand. Up to four interim analyses will take place. Based on predefined decision rules, the trial may be stopped early for futility or for effectiveness. In addition, patients with COVID-19 disease and patients with 'moderate to severe' chronic kidney disease are analysed as 2 separate cohorts of 100 patients each. An independent Data Monitoring Committee evaluates safety data at prespecified intervals throughout the trial. ETHICS AND DISSEMINATION: The trial is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, guidelines of Good Clinical Practice, Code of Federal Regulations and all other applicable regulations. Results of this study will determine the potential of ilofotase alfa to reduce mortality in critically ill patients with sepsis-associated AKI and will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: EudraCT CT Number 2019-0046265-24. US IND Number 117 605 Pre-results. CLINICALTRIALS: gov number: NCT04411472.

Changing epidemiology of acute kidney injury in critically ill patients with COVID-19: a prospective cohort.

BACKGROUND: Acute kidney injury (AKI) is common in critically ill patients with coronavirus disease-19 (COVID-19). We aimed to explore the changes in AKI epidemiology between the first and the second COVID wave in the United Kingdom (UK). METHODS: This was an observational study of critically ill adult patients with COVID-19 in an expanded tertiary care intensive care unit (ICU) in London, UK. Baseline characteristics, organ support, COVID-19 treatments, and patient and kidney outcomes up to 90 days after discharge from hospital were compared. RESULTS: A total of 772 patients were included in the final analysis (68% male, mean age 56 ± 13.6). Compared with wave 1, patients in wave 2 were older, had higher body mass index and clinical frailty score, but lower baseline serum creatinine and C-reactive protein (CRP). The proportion of patients receiving invasive mechanical ventilation (MV) on ICU admission was lower in wave 2 (61% vs 80%; p < 0.001). AKI incidence within 14 days of ICU admission was 76% in wave 1 and 51% in wave 2 (p < 0.001); in wave 1, 32% received KRT compared with 13% in wave 2 (p < 0.001). Patients in wave 2 had significantly lower daily cumulative fluid balance (FB) than in wave 1. Fewer patients were dialysis dependent at 90 days in wave 2 (1% vs. 4%; p < 0.001). CONCLUSIONS: In critically ill adult patients admitted to ICU with COVID-19, the risk of AKI and receipt of KRT significantly declined in the second wave. The trend was associated with less MV, lower PEEP and lower cumulative FB. TRIAL REGISTRATION: NCT04445259.

Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave: the global UNITE-COVID study.

PURPOSE: To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. METHODS: Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. RESULTS: 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%-50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. CONCLUSIONS: ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality.

Review of Anti-inflammatory and Antiviral Therapeutics for Hospitalized Patients Infected with Severe Acute Respiratory Syndrome Coronavirus 2.

Severe acute respiratory syndrome coronavirus 2 infection leads to dysregulation of immune pathways. Therapies focusing on suppressing cytokine activity have some success. Current evidence supports the use of dexamethasone in hospitalized patients requiring oxygen to decrease mortality. Interleukin-6 inhibitors, like tocilizumab and sarilumab, are also beneficial in hypoxemic patients, if used early. Janus kinase inhibition in combination with glucocorticoids is emerging as a potential therapeutic option for patients with moderate to severe symptoms. Data on the role of anakinra, hyperimmune immunoglobulin/convalescent plasma, or plasma purification are limited.

Variation in communication and family visiting policies in intensive care within and between countries during the Covid-19 pandemic: The COVISIT international survey.

BACKGROUND: During the COVID-19 pandemic, intensive care units (ICU) introduced restrictions to in-person family visiting to safeguard patients, healthcare personnel, and visitors. METHODS: We conducted a web-based survey (March-July 2021) investigating ICU visiting practices before the pandemic, at peak COVID-19 ICU admissions, and at the time of survey response. We sought data on visiting policies and communication modes including use of virtual visiting (videoconferencing). RESULTS: We obtained 667 valid responses representing ICUs in all continents. Before the pandemic, 20% (106/525) had unrestricted visiting hours; 6% (30/525) did not allow in-person visiting. At peak, 84% (558/667) did not allow in-person visiting for patients with COVID-19; 66% for patients without COVID-19. This proportion had decreased to 55% (369/667) at time of survey reporting. A government mandate to restrict hospital visiting was reported by 53% (354/646). Most ICUs (55%, 353/615) used regular telephone updates; 50% (306/667) used telephone for formal meetings and discussions regarding prognosis or end-of-life. Virtual visiting was available in 63% (418/667) at time of survey. CONCLUSIONS: Highly restrictive visiting policies were introduced at the initial pandemic peaks, were subsequently liberalized, but without returning to pre-pandemic practices. Telephone became the primary communication mode in most ICUs, supplemented with virtual visits.

Angiotensin II infusion in COVID-19: An international, multicenter, registry-based study.

To expand our understanding of the role of angiotensin II (ANGII) in coronavirus infectious disease 2019 (COVID-19), we conducted an international, multicenter registry study to assess the use of ANGII in patients with COVID-19 compared to patients not receiving ANGII. Critically ill adult patients who were diagnosed with COVID-19 and received ANGII were matched with COVID-19 patients not receiving ANGII according to age, respiratory support, history of hypertension, use of angiotensin-converting enzyme inhibitors and/or ANGII receptor blocker, and date of admission. All outcomes were exploratory in nature and included improvement in oxygenation, duration of organ support, and mortality. In one year, 132 patients were included (65 in the ANGII group and 67 in the control group), and patients were comparable in baseline characteristics. During the first 12 h of infusion, patients in the ANGII had a faster decrease in FiO2  and maintained similar mean arterial pressure levels. Hospital mortality was not statistically significantly different between the groups (53.8% vs. 40.3%; p = 0.226). Within the limitations of such a study design, our findings confirm previous observations of a potentially positive effect of ANGII on blood pressure and FiO2 but no effect on patient-centered outcomes.

Review of Anti-inflammatory and Anti-viral therapeutics for hospitalized patients infected with SARS-CoV-2

Synopsis: SARS-CoV-2 infection leads to dysregulation of immune pathways. Therapies focusing on suppressing cytokine activity have some success. Current evidence supports the use of dexamethasone in hospitalized patients requiring oxygen to decrease mortality. IL-6 inhibitors like tocilizumab and sarilumab are also beneficial in hypoxemic patients, if used early. JAK inhibition in combination with glucocorticoids is emerging as a potential therapeutic option for patients with moderate to severe symptoms. Data on the role of anakinra, hyperimmune immunoglobulin/convalescent plasma, or plasma purification is limited.

Do ventilatory parameters influence outcome in patients with severe acute respiratory infection? Secondary analysis of an international, multicentre14-day inception cohort study.

PURPOSE: To investigate the possible association between ventilatory settings on the first day of invasive mechanical ventilation (IMV) and mortality in patients admitted to the intensive care unit (ICU) with severe acute respiratory infection (SARI). MATERIALS AND METHODS: In this pre-planned sub-study of a prospective, multicentre observational study, 441 patients with SARI who received controlled IMV during the ICU stay were included in the analysis. RESULTS: ICU and hospital mortality rates were 23.1 and 28.1%, respectively. In multivariable analysis, tidal volume and respiratory rate on the first day of IMV were not associated with an increased risk of death; however, higher driving pressure (DP: odds ratio (OR) 1.05; 95% confidence interval (CI): 1.01-1.1, p = 0.011), plateau pressure (Pplat) (OR 1.08; 95% CI: 1.04-1.13, p < 0.001) and positive end-expiratory pressure (PEEP) (OR 1.13; 95% CI: 1.03-1.24, p = 0.006) were independently associated with in-hospital mortality. In subgroup analysis, in hypoxemic patients and in patients with acute respiratory distress syndrome (ARDS), higher DP, Pplat, and PEEP were associated with increased risk of in-hospital death. CONCLUSIONS: In patients with SARI receiving IMV, higher DP, Pplat and PEEP, and not tidal volume, were associated with a higher risk of in-hospital death, especially in those with hypoxemia or ARDS.

Acute kidney injury prevalence, progression and long-term outcomes in critically ill patients with COVID-19: a cohort study.

BACKGROUND: There are limited data on acute kidney injury (AKI) progression and long-term outcomes in critically ill patients with coronavirus disease-19 (COVID-19). We aimed to describe the prevalence and risk factors for development of AKI, its subsequent clinical course and AKI progression, as well as renal recovery or dialysis dependence and survival in this group of patients. METHODS: This was a retrospective observational study in an expanded tertiary care intensive care unit in London, United Kingdom. Critically ill patients admitted to ICU between 1st March 2020 and 31st July 2020 with confirmed SARS-COV2 infection were included. Analysis of baseline characteristics, organ support, COVID-19 associated therapies and their association with mortality and outcomes at 90 days was performed. RESULTS: Of 313 patients (70% male, mean age 54.5 ± 13.9 years), 240 (76.7%) developed AKI within 14 days after ICU admission: 63 (20.1%) stage 1, 41 (13.1%) stage 2, 136 (43.5%) stage 3. 113 (36.1%) patients presented with AKI on ICU admission. Progression to AKI stage 2/3 occurred in 36%. Risk factors for AKI progression were mechanical ventilation [HR (hazard ratio) 4.11; 95% confidence interval (CI) 1.61-10.49] and positive fluid balance [HR 1.21 (95% CI 1.11-1.31)], while steroid therapy was associated with a reduction in AKI progression (HR 0.73 [95% CI 0.55-0.97]). Kidney replacement therapy (KRT) was initiated in 31.9%. AKI patients had a higher 90-day mortality than non-AKI patients (34% vs. 14%; p < 0.001). Dialysis dependence was 5% at hospital discharge and 4% at 90 days. Renal recovery was identified in 81.6% of survivors at discharge and in 90.9% at 90 days. At 3 months, 16% of all AKI survivors had chronic kidney disease (CKD); among those without renal recovery, the CKD incidence was 44%. CONCLUSIONS: During the first COVID-19 wave, AKI was highly prevalent among severely ill COVID-19 patients with a third progressing to severe AKI requiring KRT. The risk of developing CKD was high. This study identifies factors modifying AKI progression, including a potentially protective effect of steroid therapy. Recognition of risk factors and monitoring of renal function post-discharge might help guide future practice and follow-up management strategies. Trial registration NCT04445259.

Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU: First Update.

BACKGROUND: The coronavirus disease 2019 pandemic continues to affect millions worldwide. Given the rapidly growing evidence base, we implemented a living guideline model to provide guidance on the management of patients with severe or critical coronavirus disease 2019 in the ICU. METHODS: The Surviving Sepsis Campaign Coronavirus Disease 2019 panel has expanded to include 43 experts from 14 countries; all panel members completed an electronic conflict-of-interest disclosure form. In this update, the panel addressed nine questions relevant to managing severe or critical coronavirus disease 2019 in the ICU. We used the World Health Organization's definition of severe and critical coronavirus disease 2019. The systematic reviews team searched the literature for relevant evidence, aiming to identify systematic reviews and clinical trials. When appropriate, we performed a random-effects meta-analysis to summarize treatment effects. We assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach, then used the evidence-to-decision framework to generate recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. RESULTS: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued nine statements (three new and six updated) related to ICU patients with severe or critical coronavirus disease 2019. For severe or critical coronavirus disease 2019, the panel strongly recommends using systemic corticosteroids and venous thromboprophylaxis but strongly recommends against using hydroxychloroquine. In addition, the panel suggests using dexamethasone (compared with other corticosteroids) and suggests against using convalescent plasma and therapeutic anticoagulation outside clinical trials. The Surviving Sepsis Campaign Coronavirus Diease 2019 panel suggests using remdesivir in nonventilated patients with severe coronavirus disease 2019 and suggests against starting remdesivir in patients with critical coronavirus disease 2019 outside clinical trials. Because of insufficient evidence, the panel did not issue a recommendation on the use of awake prone positioning. CONCLUSION: The Surviving Sepsis Campaign Coronavirus Diease 2019 panel issued several recommendations to guide healthcare professionals caring for adults with critical or severe coronavirus disease 2019 in the ICU. Based on a living guideline model the recommendations will be updated as new evidence becomes available.