Effectiveness of ivermectin and atazanavir on time to resolution from COVID-19 symptoms: a prospective cohort

Objective: to evaluate the effectiveness of Ivermectin and Atazanavir compared to placebo in the time to resolution of symptoms and duration of illness due to COVID-19. Method: observational, prospective, longitudinal, descriptive and analytical cohort study with symptomatic outpatients, followed for 06 months in two Basic Health Units for COVID-19 care in Teresina-Piaui, Brazil, from November to April 2021 identified by 1:1:1 random sampling. Reverse transcription polymerase chain reaction (RT-PCR) tests were performed for laboratory confirmation of suspected infection with the new coronavirus and sociodemographic and clinical evaluation. Results: of the 87 randomized patients, 62.1% (n=54) were male, with a mean age of 35.1 years, had a partner (53.9%), low income (50.6%), eutrophic (40.7%) and without health comorbidities (78.2%). There was no difference between the median time to resolution of symptoms, which was 21 days (IQR, 8-30) in the atazanavir group, 30 days (IQR, 5-90) in the ivermectin group compared with 14 days (IQR, 9-21) in the control group. At day 180, there was resolution of symptoms in 100% in the placebo group, 93.9% in the atazanavir group, and 95% in the ivermectin group. The median duration of illness was 8 days in all study arms. Conclusion: Treatment with atazanavir (6 days) and ivermectin (3 days) did not reduce the time to symptom resolution or the duration of illness among outpatients with mild COVID-19 compared to the placebo group. The results do not support the use of ivermectin and atazanavir for the treatment of mild to moderate COVID-19.

[Pre-clinical validation of a turbine-based ventilator for invasive ventilation-The ACUTE-19 ventilator]. / Validación preclínica de un respirador de turbina para la ventilación invasiva: el respirador ACUTE-19.

Background: The severe acute respiratory syndrome-coronavirus 2 pandemic pressure on healthcare systems can exhaust ventilator resources, especially where resources are restricted. Our objective was a rapid preclinical evaluation of a newly developed turbine-based ventilator, named the ACUTE-19, for invasive ventilation. Methods: Validation consisted of (a) testing tidal volume delivery in 11 simulated models, with various resistances and compliances; (b) comparison with a commercial ventilator (VIVO-50) adapting the United Kingdom Medicines and Healthcare products Regulatory Agency-recommendations for rapidly manufactured ventilators; and (c) in vivo testing in a sheep before and after inducing acute respiratory distress syndrome by saline lavage. Results: Differences in tidal volume in the simulated models were marginally different (largest difference 33 ml [95% CI 31 to 36]; P < .001). Plateau pressure was not different (-0.3 cmH2O [95% CI -0.9 to 0.3]; P = .409), and positive end-expiratory pressure was marginally different (0.3 cmH2O [95% CI 0.2 to 0.3]; P < .001) between the ACUTE-19 and the commercial ventilator. Bland-Altman analyses showed good agreement (mean bias -0.29 [limits of agreement 0.82 to -1.42], and mean bias 0.56 [limits of agreement 1.94 to -0.81], at a plateau pressure of 15 and 30 cmH2O, respectively). The ACUTE-19 achieved optimal oxygenation and ventilation before and after acute respiratory distress syndrome induction. Conclusions: The ACUTE-19 performed accurately in simulated and animal models yielding a comparable performance with a VIVO-50 commercial device. The ACUTE-19 can provide the basis for the development of a future affordable commercial ventilator.

Validación preclínica de un respirador de turbina para la ventilación invasiva: el respirador ACUTE-19 Pre-clinical validation of a turbine-based ventilator for invasive ventilation–The ACUTE-19 ventilator

Graphical Antecedentes La pandemia producida por el síndrome respiratorio agudo severo por coronavirus 2 puede agotar los recursos sanitarios, especialmente de respiradores, en situaciones de escasez de recursos sanitarios. Nuestro objetivo fue realizar una evaluación preclínica rápida de un prototipo de respirador de turbina para la ventilación invasiva denominado ACUTE-19. Métodos La validación consistió en: a) evaluación de la administración de un volumen corriente en 11 modelos pulmonares simulados, con diversas resistencias y compliancias;b) comparación con un ventilador comercial (VIVO-50) adaptando las recomendaciones de la Agencia Reguladora de Medicamentos y Productos Sanitarios del Reino Unido para ventiladores de fabricación rápida, y c) realización de pruebas in vivo en una oveja antes y después de inducir el síndrome de distrés respiratorio agudo mediante lavado salino. Resultados Las diferencias de volumen corriente en los modelos simulados fueron mínimamente diferentes (la mayor diferencia fue de 33 ml [IC 95%: 31 a 36];p < 0,001). La presión de meseta no fue diferente (−0,3 cmH2O [IC 95%: −0,9 a 0,3];p = 0,409), y la presión positiva al final de la espiración fue levemente diferente (0,3 cmH2O [IC 95%: 0,2 a 0,3];p < 0,001) comparando el ACUTE-19 y el ventilador comercial. El análisis de Bland-Altman mostró una buena concordancia (sesgo medio −0,29 [límites de concordancia 0,82 a −1,42], y sesgo medio 0,56 [límites de concordancia 1,94 a −0,81], a una presión de meseta de 15 y 30 cmH2O, respectivamente). El ACUTE-19 consiguió una oxigenación y ventilación óptimas antes y después de la inducción del síndrome de distrés respiratorio agudo en el modelo animal. Conclusiones El ACUTE-19 se comportó con precisión en los modelos simulados y animales, con un rendimiento comparable al del dispositivo comercial VIVO-50. El ACUTE-19 puede servir de base para el desarrollo de un futuro ventilador comercial asequible.

Pre-clinical validation of a turbine-based ventilator for invasive ventilation-The ACUTE-19 ventilator.

BACKGROUND: The Severe Acute Respiratory Syndrome (SARS)-Coronavirus 2 (CoV-2) pandemic pressure on healthcare systems can exhaust ventilator resources, especially where resources are restricted. Our objective was a rapid preclinical evaluation of a newly developed turbine-based ventilator, named the ACUTE-19, for invasive ventilation. METHODS: Validation consisted of (a) testing tidal volume (V_T) delivery in 11 simulated models, with various resistances and compliances; (b) comparison with a commercial ventilator (VIVO-50) adapting the United Kingdom Medicines and Healthcare products Regulatory Agency-recommendations for rapidly manufactured ventilators; and (c) in vivo testing in a sheep before and after inducing acute respiratory distress syndrome (ARDS) by saline lavage. RESULTS: Differences in V_T in the simulated models were marginally different (largest difference 33ml [95%-confidence interval (CI) 31-36]; P<.001ml). Plateau pressure (P_plat) was not different (-0.3cmH₂O [95%-CI -0.9 to 0.3]; P=.409), and positive end-expiratory pressure (PEEP) was marginally different (0.3 cmH₂O [95%-CI 0.2 to 0.3]; P<.001) between the ACUTE-19 and the commercial ventilator. Bland-Altman analyses showed good agreement (mean bias, -0.29, [limits of agreement, 0.82 to -1.42], and mean bias 0.56 [limits of agreement, 1.94 to -0.81], at a P_plat of 15 and 30cmH₂O, respectively). The ACUTE-19 achieved optimal oxygenation and ventilation before and after ARDS induction. CONCLUSIONS: The ACUTE-19 performed accurately in simulated and animal models yielding a comparable performance with a VIVO-50 commercial device. The acute 19 can provide the basis for the development of a future affordable commercial ventilator.

Hyperoxemia in invasively ventilated COVID-19 patients-Insights from the PRoVENT-COVID study.

OBJECTIVE: We determined the prevalences of hyperoxemia and excessive oxygen use, and the epidemiology, ventilation characteristics and outcomes associated with hyperoxemia in invasively ventilated patients with coronavirus disease 2019 (COVID-19). METHODS: Post hoc analysis of a national, multicentre, observational study in 22 ICUs. Patients were classified in the first two days of invasive ventilation as 'hyperoxemic' or 'normoxemic'. The co-primary endpoints were prevalence of hyperoxemia (PaO2 > 90 mmHg) and prevalence of excessive oxygen use (FiO2 ≥ 60% while PaO2 > 90 mmHg or SpO2 > 92%). Secondary endpoints included ventilator settings and ventilation parameters, duration of ventilation, length of stay (LOS) in ICU and hospital, and mortality in ICU, hospital, and at day 28 and 90. We used propensity matching to control for observed confounding factors that may influence endpoints. RESULTS: Of 851 COVID-19 patients, 225 (26.4%) were classified as hyperoxemic. Excessive oxygen use occurred in 385 (45.2%) patients. Acute respiratory distress syndrome (ARDS) severity was lowest in hyperoxemic patients. Hyperoxemic patients were ventilated with higher positive end-expiratory pressure (PEEP), while rescue therapies for hypoxemia were applied more often in normoxemic patients. Neither in the unmatched nor in the matched analysis were there differences between hyperoxemic and normoxemic patients with regard to any of the clinical outcomes. CONCLUSION: In this cohort of invasively ventilated COVID-19 patients, hyperoxemia occurred often and so did excessive oxygen use. The main differences between hyperoxemic and normoxemic patients were ARDS severity and use of PEEP. Clinical outcomes were not different between hyperoxemic and normoxemic patients.

Intensive care admissions following rapid response team reviews in patients with COVID-19 in Australia

Objectives: To evaluate the epidemiology of rapid response team (RRT) reviews that led to intensive care unit (ICU) admissions, and to evaluate the frequency of in-hospital cardiac arrests (IHCAs) among ICU patients with confirmed coronavirus disease 2019 (COVID-19) in Australia. Design: Multicentre, retrospective cohort study. Setting: 48 public and private ICUs in Australia. Participants: All adults (aged ≥ 16 years) with confirmed COVID-19 admitted to participating ICUs between 25 January and 31 October 2020, as part of SPRINT-SARI (Short PeRiod IncideNce sTudy of Severe Acute Respiratory Infection) Australia, which were linked with ICUs contributing to the Australian and New Zealand Intensive Care Society Adult Patient Database (ANZICS APD). Main outcome measures and results: Of the 413 critically ill patients with COVID-19 who were analysed, 48.2% (199/413) were admitted from the ward and 30.5% (126/413) were admitted to the ICU following an RRT review. Patients admitted following an RRT review had higher Acute Physiology and Chronic Health Evaluation (APACHE) scores, fewer days from symptom onset to hospitalisation (median, 5.4 [interquartile range (IQR), 3.2–7.6] v 7.1 days [IQR, 4.1–9.8];P < 0.001) and longer hospitalisations (median, 18 [IQR, 11–33] v 13 days [IQR, 7–24];P < 0.001) compared with those not admitted via an RRT review. Admissions following RRT review comprised 60.3% (120/199) of all ward-based admissions. Overall, IHCA occurred in 1.9% (8/413) of ICU patients with COVID-19, and most IHCAs (6/8, 75%) occurred during ICU admission. There were no differences in IHCA rates or in ICU or hospital mortality rates based on whether a patient had a prior RRT review or not. Conclusions: This study found that RRT reviews were a common way for deteriorating ward patients with COVID-19 to be admitted to the ICU, and that IHCA was rare among ICU patients with COVID-19. © 2022, College of Intensive Care Medicine. All rights reserved.

The effect of age on ventilation management and clinical outcomes in critically ill COVID-19 patients-insights from the PRoVENT-COVID study

Introduction: We analyzed the association of age with ventilation practice and outcomes in critically ill COVID-19 patients requiring invasive ventilation. Methods: Posthoc analysis of the PRoVENT-COVID study, an observational study performed in 22 ICUs in the first 3 months of the national outbreak in the Netherlands. The coprimary endpoint was a set of ventilator parameters, including tidal volume normalized for predicted bodyweight, positive end-expiratory pressure, driving pressure, and respiratory system compliance in the first 4 days of invasive ventilation. Secondary endpoints were other ventilation parameters, the use of rescue therapies, pulmonary and extrapulmonary complications in the first 28 days in the ICU, hospital- and ICU stay, and mortality. Results: 1122 patients were divided into four groups based on age quartiles. No meaningful differences were found in ventilation parameters and in the use of rescue therapies for refractory hypoxemia in the first 4 days of invasive ventilation. Older patients received more often a tracheostomy, developed more frequently acute kidney injury and myocardial infarction, stayed longer in hospital and ICU, and had a higher mortality. Conclusions: In this cohort of invasively ventilated critically ill COVID-19 patients, age had no effect on ventilator management. Higher age was associated with more complications, longer length of stay in ICU and hospital and a higher mortality.

Six-month outcomes following venovenous ECMO for severe COVID-19 and viral pneumonitis: 2019-2020 Australian experience

Objective: To compare the characteristics, treatments and 6-month functional outcomes of patients with coronavirus disease 2019 (COVID-19) versus non-COVID-19 viral pneumonitis supported by venovenous extracorporeal membrane oxygenation (VV-ECMO). Design: Prospective, observational cohort study in seven intensive care units (ICUs) across Australia. Participants: Patients admitted to participating ICUs with laboratory-confirmed COVID-19 or viral pneumonitis requiring VV-ECMO. Results: From 30 March 2019 to 31 December 2020, 13 patients were initiated on VV-ECMO for COVID-19 and 23 were initiated for non-COVID-19 viral pneumonitis. Patients with COVID-19 were older and had a longer duration from intubation to ECMO initiation, but had similar illness severity and APACHE IV scores at the time of initiation. Overall disability, health-related quality of life, and mortality were similar, but ICU and hospital length of stay were significantly longer in patients with COVID-19. Conclusions: Six-month functional outcomes and mortality were similar between COVID-19 and viral pneumonitis patients treated with VV-ECMO. However, length of stay was longer in COVID-19 patients, which may have resource implications.

ISARIC-4C Mortality Score overestimates risk of death due to COVID-19 in Australian ICU patients: a validation cohort study

Objective: To assess the performance of the UK International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) Coronavirus Clinical Characterisation Consortium (4C) Mortality Score for predicting mortality in Australian patients with coronavirus disease 2019 (COVID-19) requiring intensive care unit (ICU) admission. Design: Multicentre, prospective, observational cohort study. Setting: 78 Australian ICUs participating in the SPRINT-SARI (Short Period Incidence Study of Severe Acute Respiratory Infection) Australia study of COVID-19. Participants: Patients aged 16 years or older admitted to participating Australian ICUs with polymerase chain reaction (PCR)confirmed COVID-19 between 27 February and 10 October 2020. Main outcome measures: ISARIC-4C Mortality Score, calculated at the time of ICU admission. The primary outcome was observed versus predicted in-hospital mortality (by 4C Mortality and APACHE II). Results: 461 patients admitted to a participating ICU were included. 149 (32%) had complete data to calculate a 4C Mortality Score without imputation. Overall, 61/461 patients (13.2%) died, 16.9% lower than the comparable ISARIC-4C cohort in the United Kingdom. In patients with complete data, the median (interquartile range [IQR]) 4C Mortality Score was 10.0 (IQR, 8.0-13.0) and the observed mortality was 16.1% (24/149) versus 22.9% median predicted risk of death. The 4C Mortality Score discriminatory performance measured by the area under the receiver operating characteristic curve (AUROC) was 0.79 (95% CI, 0.68-0.90), similar to its performance in the original ISARIC-4C UK cohort (0.77) and not superior to APACHE II (AUROC, 0.81;95% CI, 0.75-0.87). Conclusions: When calculated at the time of ICU admission, the 4C Mortality Score consistently overestimated the risk of death for Australian ICU patients with COVID-19. The 4C Mortality Score may need to be individually recalibrated for use outside the UK and in different hospital settings. Crit Care Resusc 2021;23 (4): 403-13

Comparison of baseline characteristics, treatment and clinical outcomes of critically ill COVID-19 patients admitted in the first and second waves in Australia

Objective: To report longitudinal differences in baseline characteristics, treatment, and outcomes in patients with coronavirus disease 2019 (COVID-19) admitted to intensive care units (ICUs) between the first and second waves of COVID-19 in Australia. Design, setting and participants: SPRINT-SARI Australia is a multicentre, inception cohort study enrolling adult patients with COVID-19 admitted to participating ICUs. The first wave of COVID-19 was from 27 February to 30 June 2020, and the second wave was from 1 July to 22 October 2020. Results: A total of 461 patients were recruited in 53 ICUs across Australia;a higher number were admitted to the ICU during the second wave compared with the first: 255 (55.3%) versus 206 (44.7%). Patients admitted to the ICU in the second wave were younger (58.0 v 64.0 years;P = 0.001) and less commonly male (68.9% v 60.0%;P = 0.045), although Acute Physiology and Chronic Health Evaluation (APACHE) II scores were similar (14 v 14;P = 0.998). High flow oxygen use (75.2% v 43.4%;P < 0.001) and non-invasive ventilation (16.5% v 7.1%;P = 0.002) were more common in the second wave, as was steroid use (95.0% v 30.3%;P < 0.001). ICU length of stay was shorter (6.0 v 8.4 days;P = 0.003). In-hospital mortality was similar (12.2% v 14.6%;P = 0.452), but observed mortality decreased over time and patients were more likely to be discharged alive earlier in their ICU admission (hazard ratio, 1.43;95% CI, 1.13–1.79;P = 0.002). Conclusion: During the second wave of COVID-19 in Australia, ICU length of stay and observed mortality decreased over time. Multiple factors were associated with this, including changes in clinical management, the adoption of new evidence-based treatments, and changes in patient demographic characteristics but not illness severity. © 2021, College of Intensive Care Medicine. All rights reserved.