ISTH guidelines for antithrombotic treatment in COVID-19: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the ISTH guidelines for antithrombotic treatment in COVID-19. This evidence-based guideline serves as a useful decision aid for Nordic anaesthesiologists caring for patients with COVID-19.

Effects of 12 mg vs. 6 mg dexamethasone on thromboembolism and bleeding in patients with critical COVID-19 - a post hoc analysis of the randomized, blinded COVID STEROID 2 trial.

BACKGROUND: Thromboembolism is more common in patients with critical COVID-19 than in other critically ill patients, and inflammation has been proposed as a possible mechanism. The aim of this study was to investigate if 12 mg vs. 6 mg dexamethasone daily reduced the composite outcome of death or thromboembolism in patients with critical COVID-19. METHODS: Using additional data on thromboembolism and bleeding we did a post hoc analysis of Swedish and Danish intensive care unit patients enrolled in the blinded randomized COVID STEROID 2 trial comparing 12 mg vs. 6 mg dexamethasone daily for up to 10 days. The primary outcome was a composite outcome of death or thromboembolism during intensive care. Secondary outcomes were thromboembolism, major bleeding, and any bleeding during intensive care. RESULTS: We included 357 patients. Whilst in intensive care, 53 patients (29%) in the 12 mg group and 53 patients (30%) in the 6 mg group met the primary outcome with an unadjusted absolute risk difference of - 0.5% (95% CI - 10 to 9.5%, p = 1.00) and an adjusted OR of 0.93 (CI 95% 0.58 to 1.49, p = 0.77). We found no firm evidence of differences in any of the secondary outcomes. CONCLUSIONS: Among patients with critical COVID-19, 12 mg vs. 6 mg dexamethasone daily did not result in a statistically significant difference in the composite outcome of death or thromboembolism. However, uncertainty remains due to the limited number of patients.

Factors related to COVID-19 mortality among three Swedish intensive care units-A retrospective study.

BACKGROUND: Mortality due to acute hypoxemic respiratory failure (AHRF) in patients with coronavirus disease-19 (COVID-19) differs across units, regions, and countries. These variations may be attributed to several factors, including comorbidities, acute physiological derangement, disease severity, treatment, ethnicity, healthcare system strain, and socioeconomic status. This study aimed to explore the features of patient characteristics, clinical management, and staffing that may be related to mortality among three intensive care units (ICUs) within the same hospital system in South Sweden. METHODS: We retrospectively analyzed ICU patients with COVID-19 and AHRF in Region Jönköping County, Sweden. The primary outcome was the 90-day mortality rate. We used univariate and multivariable logistic regression analyses to investigate the relationship of predictors with outcomes. RESULTS: Between March 15, 2020, and May 31, 2021, 331 patients with AHRF and COVID-19 were admitted to the three ICUs. There were differences in disease severity, treatments, process-related factors, and socioeconomic factors between the units. These factors were related to 90-day mortality. After multivariable adjustment, age, severity of acute respiratory distress syndrome, and the number of nurses per ICU-bed independently predicted 90-day mortality. CONCLUSION: Age, disease severity, and nurse staffing, but not treatment or socioeconomic status, were independently associated with 90-day mortality among critically ill patients with AHRF due to COVID-19. We also identified variations in care related processes, which may be a modifiable risk factor and warrants future investigation.

Awake proning in patients with COVID-19-related hypoxemic acute respiratory failure: A rapid practice guideline.

This rapid practice guideline provides evidence-based recommendations for the use of awake proning in adult patients with acute hypoxemic respiratory failure due to COVID-19. The panel included 20 experts from 12 countries, including one patient representative, and used a strict conflict of interest policy for potential financial and intellectual conflicts of interest. Methodological support was provided by the guidelines in intensive care, development, and evaluation (GUIDE) group. Based on an updated systematic review, and the grading of recommendations, assessment, development, and evaluation (GRADE) method we evaluated the certainty of evidence and developed recommendations using the Evidence-to-Decision framework. We conducted an electronic vote, requiring >80% agreement amongst the panel for a recommendation to be adopted. The panel made a strong recommendation for a trial of awake proning in adult patients with COVID-19 related hypoxemic acute respiratory failure who are not invasively ventilated. Awake proning appears to reduce the risk of tracheal intubation, although it may not reduce mortality. The panel judged that most patients would want a trial of awake proning, although this may not be feasible in some patients and some patients may not tolerate it. However, given the high risk of clinical deterioration amongst these patients, awake proning should be conducted in an area where patients can be monitored by staff experienced in rapidly detecting and managing clinical deterioration. This RPG panel recommends a trial of awake prone positioning in patients with acute hypoxemic respiratory failure due to COVID-19.

Incidence of acute myocardial injury and its association with left and right ventricular systolic dysfunction in critically ill COVID-19 patients.

BACKGROUND: Previous studies have found an increase in cardiac troponins (cTns) and echocardiographic abnormalities in patients with COVID-19 and reported their association with poor clinical outcomes. Whether acute injury occurs during the course of critical care and if it is associated with cardiac function is unknown. The purpose of this study was to document the incidence of acute myocardial injury (AMInj) and echocardiographically defined left ventricular (LV) and right ventricular (RV) systolic dysfunction in consecutive patients admitted to an intensive care unit (ICU) for COVID-19. The relationship between AMInj and echocardiographic abnormalities during the first 14 days of ICU admission was studied. Finally, the association between echocardiographic findings, AMInj and clinical outcome was evaluated. METHODS: Seventy-four consecutive patients (≥18 years) admitted to the ICU at Linköping University Hospital between 19 Mar 2020 and 31 Dec 2020 for COVID-19 were included. High-sensitivity troponin-T (hsTnT) was measured daily for up to 14 days. Transthoracic echocardiography was conducted within 72 h of ICU admission. Acute myocardial injury was defined as an increased hsTnT > 14ng/l and a > 20% absolute change with or without ischaemic symptoms. LV and RV systolic dysfunction was defined as at least 2 abnormal indicators of systolic function specified by consensus guidelines. RESULTS: Increased hsTnT was observed in 59% of patients at ICU admission, and 82% developed AMInj with peak levels at 8 (3-13) days after ICU admission. AMInj was not statistically significantly associated with 30-day mortality but was associated with an increased duration of invasive mechanical ventilation (10 (3-13) vs. 5 days (0-9), p=0.001) as well as ICU length of stay (LOS) (19.5 (11-28) vs. 7 days (5-13), p=0.015). After adjustment for SAPS-3 and admission SOFA score, the effect of AMInj was significant only for the duration of mechanical ventilation (p=0.030). The incidence of LV and RV dysfunction was 28% and 22%, respectively. Only indices of LV and RV longitudinal contractility (mitral and tricuspid annular plane systolic excursion) were associated with AMInj. Echocardiographic parameters were not associated with clinical outcome. CONCLUSIONS: Myocardial injury is common in critically ill patients with COVID-19, with AMInj developing in more than 80% after ICU admission. In contrast, LV and RV dysfunction occurred in approximately one-quarter of patients. AMInj was associated with an increased need for mechanical ventilation and ICU LOS but neither AMInj nor ventricular dysfunction was significantly associated with mortality.

Echocardiography findings in COVID-19 patients admitted to intensive care units: a multi-national observational study (the ECHO-COVID study).

PURPOSE: Severely ill patients affected by coronavirus disease 2019 (COVID-19) develop circulatory failure. We aimed to report patterns of left and right ventricular dysfunction in the first echocardiography following admission to intensive care unit (ICU). METHODS: Retrospective, descriptive study that collected echocardiographic and clinical information from severely ill COVID-19 patients admitted to 14 ICUs in 8 countries. Patients admitted to ICU who received at least one echocardiography between 1st February 2020 and 30th June 2021 were included. Clinical and echocardiographic data were uploaded using a secured web-based electronic database (REDCap). RESULTS: Six hundred and seventy-seven patients were included and the first echo was performed 2 [1, 4] days after ICU admission. The median age was 65 [56, 73] years, and 71% were male. Left ventricle (LV) and/or right ventricle (RV) systolic dysfunction were found in 234 (34.5%) patients. 149 (22%) patients had LV systolic dysfunction (with or without RV dysfunction) without LV dilatation and no elevation in filling pressure. 152 (22.5%) had RV systolic dysfunction. In 517 patients with information on both paradoxical septal motion and quantitative RV size, 90 (17.4%) had acute cor pulmonale (ACP). ACP was associated with mechanical ventilation (OR > 4), pulmonary embolism (OR > 5) and increased PaCO2. Exploratory analyses showed that patients with ACP and older age were more likely to die in hospital (including ICU). CONCLUSION: Almost one-third of this cohort of critically ill COVID-19 patients exhibited abnormal LV and/or RV systolic function in their first echocardiography assessment. While LV systolic dysfunction appears similar to septic cardiomyopathy, RV systolic dysfunction was related to pressure overload due to positive pressure ventilation, hypercapnia and pulmonary embolism. ACP and age seemed to be associated with mortality in this cohort.

Therapeutics and COVID-19-A living WHO guideline: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.

The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the Living WHO guideline on therapeutics and COVID-19. This trustworthy continuously updated guideline serves as a highly useful decision aid for Nordic anaesthesiologists caring for patients with COVID-19.

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial.

PURPOSE: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. METHODS: We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. RESULTS: The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI -0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. CONCLUSION: We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial.

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

A descriptive study of the surge response and outcomes of ICU patients with COVID-19 during first wave in Nordic countries.

BACKGROUND: We sought to provide a description of surge response strategies and characteristics, clinical management and outcomes of patients with severe COVID-19 in the intensive care unit (ICU) during the first wave of the pandemic in Denmark, Finland, Iceland, Norway and Sweden. METHODS: Representatives from the national ICU registries for each of the five countries provided clinical data and a description of the strategies to allocate ICU resources and increase the ICU capacity during the pandemic. All adult patients admitted to the ICU for COVID-19 disease during the first wave of COVID-19 were included. The clinical characteristics, ICU management and outcomes of individual countries were described with descriptive statistics. RESULTS: Most countries more than doubled their ICU capacity during the pandemic. For patients positive for SARS-CoV-2, the ratio of requiring ICU admission for COVID-19 varied substantially (1.6%-6.7%). Apart from age (proportion of patients aged 65 years or over between 29% and 62%), baseline characteristics, chronic comorbidity burden and acute presentations of COVID-19 disease were similar among the five countries. While utilization of invasive mechanical ventilation was high (59%-85%) in all countries, the proportion of patients receiving renal replacement therapy (7%-26%) and various experimental therapies for COVID-19 disease varied substantially (e.g. use of hydroxychloroquine 0%-85%). Crude ICU mortality ranged from 11% to 33%. CONCLUSION: There was substantial variability in the critical care response in Nordic ICUs to the first wave of COVID-19 pandemic, including usage of experimental medications. While ICU mortality was low in all countries, the observed variability warrants further attention.

Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

National outcomes and characteristics of patients admitted to Swedish intensive care units for COVID-19: A registry-based cohort study.

BACKGROUND: Mortality among patients admitted to intensive care units (ICUs) with COVID-19 is unclear due to variable follow-up periods. Few nationwide data are available to compare risk factors, treatment and outcomes of COVID-19 patients after ICU admission. OBJECTIVE: To evaluate baseline characteristics, treatments and 30-day outcomes of patients admitted to Swedish ICUs with COVID-19. DESIGN: Registry-based cohort study with prospective data collection. SETTING: Admissions to Swedish ICUs from 6 March to 6 May 2020 with laboratory confirmed COVID-19 disease. PARTICIPANTS: Adult patients admitted to Swedish ICUs. EXPOSURES: Baseline characteristics, intensive care treatments and organ failures. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. A multivariable model was used to determine the independent association between potential predictor variables and death. RESULTS: We identified 1563 patients with complete 30-day follow-up. The 30-day all-cause mortality was 26.7%. Median age was 61 [52 to 69], Simplified Acute Physiology Score III (SAPS III) was 53 [46 to 59] and 62.5% had at least one comorbidity. Median PaO2/FiO2 on admission was 97.5 [75.0 to 140.6] mmHg, 74.7% suffered from moderate-to-severe acute respiratory failure. Age, male sex [adjusted odds ratio (aOR) 1.5 (1.1 to 2.2)], SAPS III score [aOR 1.3 (1.2 to 1.4)], severe respiratory failure [aOR 3.0 (2.0 to 4.7)], specific COVID-19 pharmacotherapy [aOR 1.4 (1.0 to 1.9)] and continuous renal replacement therapy [aOR 2.1 (1.5 to 3.0)] were associated with increased mortality. Except for chronic lung disease, the presence of comorbidities was not independently associated with mortality. CONCLUSIONS: Thirty-day mortality rate in COVID-19 patients admitted to Swedish ICUs is generally lower than previously reported despite a severe degree of hypoxaemia on admission. Mortality was driven by age, baseline disease severity, the presence and degree of organ failure, rather than pre-existing comorbidities. TRIAL REGISTRATION NO: NCT04462393.

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. METHODS: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. DISCUSSION: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.