BACKGROUND: Dexamethasone 6 mg in patients with severe COVID-19 has been shown to decrease mortality and morbidity. The effects of higher doses of corticosteroid, that would further increase anti-inflammatory effects, are uncertain. The objective of our study was to assess the effect of 20 mg dexamethasone vs. 6 mg dexamethasone intravenously in patients with moderate-to-severe acute respiratory distress syndrome (ARDS) and COVID-19. METHODS: In a multicenter, open-label, randomized trial conducted in nine hospitals in the Czech Republic, we randomized adult patients with ARDS and COVID-19 requiring high-flow oxygen, noninvasive or invasive mechanical ventilation to receive either intravenous high-dose dexamethasone (20 mg/day on days 1-5, 10 mg/day on days 6-10) or standard-dose dexamethasone (6 mg/d, days 1-10). The primary outcome was 28-day ventilator-free days. The five secondary outcomes were 60-day mortality, C-reactive protein dynamics, 14-day WHO (World Health Organization) Clinical Progression Scale score, adverse events and 90-day Barthel index. The long-term outcomes were 180- and 360-day mortality and the Barthel index. The planned sample size was 300, with interim analysis after enrollment of 150 patients. RESULTS: The trial was stopped due to a lack of recruitment, and the follow-up was completed in February 2023. Among 234 randomized patients of 300 planned patients, the primary outcome was available for 224 patients (110 high-dose and 114 standard-dose dexamethasone; median [interquartile range (IQR)] age, 59.0 [48.5-66.0] years; 130 [58.0%] were receiving noninvasive or invasive mechanical ventilation at baseline). The mean number of 28-day ventilator-free days was 8.9 (± 11.5) days for high-dose dexamethasone and 8.0 (± 10.7) days for standard-dose dexamethasone, with an absolute difference of + 0.81 days (95% CI - 2.12-3.73 days). None of the prespecified secondary outcomes, including adverse events, differed between the groups. CONCLUSIONS: Despite not reaching its prespecified enrollment, there was no signal to either benefit or harm high-dose dexamethasone over standard-dose dexamethasone in patients with COVID-19 and moderate-to-severe ARDS. Trial registration Trial registration: ClinicalTrials.gov Identifier: NCT04663555. Registered 10 December 2020, https://clinicaltrials.gov/study/NCT04663555?term=NCT04663555&rank=1 and EudraCT: 2020-005887-70.
- Klíčová slova
- ARDS, COVID-19, Dexamethasone, Long-term outcomes, Randomized clinical trial, Ventilator-free days,
- MeSH
- COVID-19 * mortalita komplikace MeSH
- dexamethason * aplikace a dávkování terapeutické užití MeSH
- farmakoterapie COVID-19 * MeSH
- lidé středního věku MeSH
- lidé MeSH
- SARS-CoV-2 MeSH
- senioři MeSH
- syndrom dechové tísně * farmakoterapie mortalita MeSH
- umělé dýchání * MeSH
- výsledek terapie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Česká republika epidemiologie MeSH
- Názvy látek
- dexamethason * MeSH
BACKGROUND: The optimal dose of dexamethasone for severe/critical COVID-19 is uncertain. We compared higher versus standard doses of dexamethasone in adults with COVID-19 and hypoxia. METHODS: We searched PubMed and trial registers until 23 June 2023 for randomised clinical trials comparing higher (>6 mg) versus standard doses (6 mg) of dexamethasone in adults with COVID-19 and hypoxia. The primary outcome was mortality at 1 month. Secondary outcomes were mortality closest to 90 days; days alive without life support; and the occurrence of serious adverse events/reactions (SAEs/SARs) closest to 1 month. We assessed the risk of bias using the Cochrane RoB2 tool, risk of random errors using trial sequential analysis, and certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included eight trials (2478 participants), of which four (1293 participants) had low risk of bias. Higher doses of dexamethasone probably resulted in little to no difference in mortality at 1 month (relative risk [RR] 0.97, 95% CI: 0.79-1.19), mortality closest to Day 90 (RR 1.01, 95% CI: 0.86-1.20), and SAEs/SARs (RR 1.00, 95% CI: 0.97-1.02). Higher doses of dexamethasone probably increased the number of days alive without invasive mechanical ventilation and circulatory support but had no effect on days alive without renal replacement therapy. CONCLUSIONS: Based on low to moderate certainty evidence, higher versus standard doses of dexamethasone probably result in little to no difference in mortality, SAEs/SARs, and days alive without renal replacement therapy, but probably increase the number of days alive without invasive mechanical ventilation and circulatory support.
- Klíčová slova
- COVID-19, corticosteroids, dexamethasone, hypoxia, meta-analysis,
- MeSH
- COVID-19 * MeSH
- dexamethason škodlivé účinky MeSH
- dospělí MeSH
- farmakoterapie COVID-19 MeSH
- hypoxie MeSH
- lidé MeSH
- pacienti MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
- systematický přehled MeSH
- Názvy látek
- dexamethason MeSH
Beta-lactam antibiotics remain one of the most preferred groups of antibiotics in critical care due to their excellent safety profiles and their activity against a wide spectrum of pathogens. The cornerstone of appropriate therapy with beta-lactams is to achieve an adequate plasmatic concentration of a given antibiotic, which is derived primarily from the minimum inhibitory concentration (MIC) of the specific pathogen. In a critically ill patient, the plasmatic levels of drugs could be affected by many significant changes in the patient's physiology, such as hypoalbuminemia, endothelial dysfunction with the leakage of intravascular fluid into interstitial space and acute kidney injury. Predicting antibiotic concentration from models based on non-critically ill populations may be misleading. Therapeutic drug monitoring (TDM) has been shown to be effective in achieving adequate concentrations of many drugs, including beta-lactam antibiotics. Reliable methods, such as high-performance liquid chromatography, provide the accurate testing of a wide range of beta-lactam antibiotics. Long turnaround times remain the main drawback limiting their widespread use, although progress has been made recently in the implementation of different novel methods of antibiotic testing. However, whether the TDM approach can effectively improve clinically relevant patient outcomes must be proved in future clinical trials.
Cryptococcal superinfection is a rare but potentially fatal complication, especially if its detection and subsequent treatment are delayed. Histopathological findings of pulmonary parenchyma from a deceased patient with these complications were acquired. Quite interestingly, only a minimal inflammatory reaction could be seen in an individual with no previously known immune suppression, indicating a disturbance of the immune system. This finding was well in concordance with the described changes in cellular immunity in COVID-19. We report the case of a 60 year old male with critical coronavirus disease 2019 (COVID-19) complicated by cryptococcal pneumonia and multiorgan failure. Both X-ray and CT scans revealed lung infiltrates corresponding with COVID-19 infection early after the onset of symptoms. Despite receiving standard treatment, the patient progressed into multiple organ failure, requiring mechanical ventilation, circulatory support, and haemodialysis. Cryptococcus neoformans was detected by subsequent BAL, and specific antifungal treatment was instituted. His clinical status deteriorated despite all treatment, and he died of refractory circulatory failure after 21 days from hospital admission. Histopathological findings confirmed severe diffuse alveolar damage (DAD) caused by COVID-19 and cryptococcal pneumonia. Timely diagnosis of cryptococcal superinfection may be challenging; therefore, PCR panels detecting even uncommon pathogens should be implemented while taking care of critical COVID-19 patients.
- Klíčová slova
- COVID-19, Cryptococcus, SARS-CoV-2, fungal superinfection,
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Providing palliative care at the end of life (EOL) in intensive care units (ICUs) seems to be modified during the COVID-19 pandemic with potential burden of moral distress to health care providers (HCPs). We seek to assess the practice of EOL care during the COVID-19 pandemic in ICUs in the Czech Republic focusing on the level of moral distress and its possible modifiable factors. METHODS: Between 16 June 2021 and 16 September 2021, a national, cross-sectional study in intensive care units (ICUs) in Czech Republic was performed. All physicians and nurses working in ICUs during the COVID-19 pandemic were included in the study. For questionnaire development ACADEMY and CHERRIES guide and checklist were used. A multivariate logistic regression model was used to analyse possible modifiable factors of moral distress. RESULTS: In total, 313 HCPs (14.5% out of all HCPs who opened the questionnaire) fully completed the survey. Results showed that 51.8% (n = 162) of respondents were exposed to moral distress during the COVID-19 pandemic. 63.1% (n = 113) of nurses and 71.6% of (n = 96) physicians had experience with the perception of inappropriate care. If inappropriate care was perceived, a higher chance for the occurrence of moral distress for HCPs (OR, 1.854; CI, 1.057-3.252; p = 0.0312) was found. When patients died with dignity, the chance for moral distress was lower (OR, 0.235; CI, 0.128-0.430; p < 0.001). The three most often reported differences in palliative care practice during pandemic were health system congestion, personnel factors, and characteristics of COVID-19 infection. CONCLUSIONS: HCPs working at ICUs experienced significant moral distress during the COVID-19 pandemic in the Czech Republic. The major sources were perceiving inappropriate care and dying of patients without dignity. Improvement of the decision-making process and communication at the end of life could lead to a better ethical and safety climate. TRIAL REGISTRATION: NCT04910243 .
- Klíčová slova
- COVID-19, Ethical climate, Inappropriate care, Moral distress, Palliative care, Pandemic, Survey,
- MeSH
- COVID-19 * epidemiologie MeSH
- jednotky intenzivní péče MeSH
- lidé MeSH
- mravy MeSH
- paliativní péče * MeSH
- pandemie MeSH
- postoj zdravotnického personálu MeSH
- průřezové studie MeSH
- průzkumy a dotazníky MeSH
- psychický stres MeSH
- smrt MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinická studie MeSH
- Geografické názvy
- Česká republika epidemiologie MeSH
BACKGROUND: Since December 2019, SARS-CoV-2 virus has infected millions of people worldwide. In patients with COVID-19 pneumonia in need of oxygen therapy or mechanical ventilation, dexamethasone 6 mg per day is currently recommended. However, the dose of 6 mg of dexamethasone is currently being reappraised and may miss important therapeutic potential or may prevent potential deleterious effects of higher doses of corticosteroids. METHODS: REMED is a prospective, open-label, randomised controlled trial testing the superiority of dexamethasone 20 mg (dexamethasone 20 mg on days 1-5, followed by dexamethasone 10 mg on days 6-10) vs 6 mg administered once daily intravenously for 10 days in adult patients with moderate or severe ARDS due to confirmed COVID-19. Three hundred participants will be enrolled and followed up for 360 days after randomization. Patients will be randomised in a 1:1 ratio into one of the two treatment arms. The following stratification factors will be applied: age, Charlson Comorbidity Index, CRP levels and trial centre. The primary endpoint is the number of ventilator-free days (VFDs) at 28 days after randomisation. The secondary endpoints are mortality from any cause at 60 days after randomisation; dynamics of the inflammatory marker, change in WHO Clinical Progression Scale at day 14; and adverse events related to corticosteroids and independence at 90 days after randomisation assessed by the Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days. The study will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. DISCUSSION: We aim to compare two different doses of dexamethasone in patients with moderate to severe ARDS undergoing mechanical ventilation regarding efficacy and safety. TRIAL REGISTRATION: EudraCT No. 2020-005887-70. ClinicalTrials.gov NCT04663555. Registered on December 11, 2020.
- Klíčová slova
- ARDS, COVID-19, Dexamethasone, Protocol, Randomised controlled trial, Ventilator-free days,
- MeSH
- dexamethason škodlivé účinky MeSH
- dospělí MeSH
- farmakoterapie COVID-19 * MeSH
- kvalita života MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- prospektivní studie MeSH
- randomizované kontrolované studie jako téma MeSH
- SARS-CoV-2 MeSH
- syndrom dechové tísně * diagnóza farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- protokol klinické studie MeSH
- Názvy látek
- dexamethason MeSH
OBJECTIVES: The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. TRIAL DESIGN: REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO2/FiO2 100-200 mmHg; • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. INTERVENTION AND COMPARATOR: Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. MAIN OUTCOMES: Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. RANDOMISATION: Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. BLINDING (MASKING): This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. TRIAL STATUS: This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. TRIAL REGISTRATION: The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. FULL PROTOCOL: The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
- Klíčová slova
- ARDS, COVID-19, Dexamethasone, Protocol, Randomised controlled trial, Ventilator-free days,
- MeSH
- COVID-19 komplikace terapie MeSH
- délka pobytu MeSH
- dexamethason aplikace a dávkování MeSH
- glukokortikoidy aplikace a dávkování MeSH
- hodnocení ekvivalence jako téma MeSH
- klinické zkoušky, fáze II jako téma MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- progrese nemoci MeSH
- randomizované kontrolované studie jako téma MeSH
- SARS-CoV-2 MeSH
- syndrom dechové tísně etiologie terapie MeSH
- umělé dýchání * MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- protokol klinické studie MeSH
- Názvy látek
- dexamethason MeSH
- glukokortikoidy MeSH
BACKGROUND: Hospital-acquired pneumonia (HAP) is associated with high mortality. In Central Europe, there is a dearth of information on the prevalence and treatment of HAP. This project was aimed at collecting multicenter epidemiological data on patients with HAP in the Czech Republic and comparing them with supraregional data. METHODS: This prospective, multicenter, observational study processed data from a database supported by a Czech Ministry of Health grant project. Included were all consecutive patients aged 18 and over who were admitted to participating intensive care units (ICUs) between 1 May 2013 and 31 December 2014 and met the inclusion criterion of having HAP. The primary endpoint was to analyze the relationships between 30-day mortality (during the stay in or after discharge from ICUs) and the microbiological etiological agent and adequacy of initial empirical antibiotic therapy in HAP patients. RESULTS: The group dataset contained data on 330 enrolled patients. The final validated dataset involved 214 patients, 168 males (78.5%) and 46 females (21.5%), from whom 278 valid lower airway samples were obtained. The mean patient age was 59.9 years. The mean APACHE II score at admission was 21. Community-acquired pneumonia was identified in 13 patients and HAP in 201 patients, of whom 26 (12.1%) had early-onset and 175 (81.8%) had late-onset HAP. Twenty-two bacterial species were identified as etiologic agents but only six of them exceeded a frequency of detection of 5% (Klebsiella pneumoniae 20.4%, Pseudomonas aeruginosa 20.0%, Escherichia coli 10.8%, Enterobacter spp. 8.1%, Staphylococcus aureus 6.2% and Burkholderia cepacia complex 5.8%). Patients infected with Staphylococcus aureus had significantly higher rates of early-onset HAP than those with other etiologic agents. The overall 30-day mortality rate for HAP was 29.9%, with 19.2% mortality for early-onset HAP and 31.4% mortality for late-onset HAP. Patients with late-onset HAP receiving adequate initial empirical antibiotic therapy had statistically significantly lower 30-day mortality than those receiving inadequate initial antibiotic therapy (23.8% vs 42.9%). Patients with ventilator-associated pneumonia (VAP) had significantly higher mortality than those who developed HAP with no association with mechanical ventilation (34.6% vs 12.7%). Patients having VAP treated with adequate initial antibiotic therapy had lower 30-day mortality than those receiving inadequate therapy (27.2% vs 44.8%). CONCLUSIONS: The present study was the first to collect multicenter data on the epidemiology of HAP in the Central European Region, with respect to the incidence of etiologic agents causing HAP. It was concerned with relationships between 30-day patient mortality and the type of HAP, etiologic agent and adequacy of initial empirical antibiotic therapy.
- Klíčová slova
- HAP, VAP, antibiotic therapy, hospital-acquired pneumonia, mortality,
- MeSH
- antibakteriální látky terapeutické užití MeSH
- bakteriální pneumonie epidemiologie MeSH
- infekce spojené se zdravotní péčí epidemiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- prevalence MeSH
- prospektivní studie MeSH
- ventilátorová pneumonie epidemiologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika epidemiologie MeSH
- Názvy látek
- antibakteriální látky MeSH
