Early detection of deterioration in COVID-19 patients by continuous ward respiratory rate monitoring: a pilot prospective cohort study.

Background: Tachypnea is among the earliest signs of pulmonary decompensation. Contactless continuous respiratory rate monitoring might be useful in isolated COVID-19 patients admitted in wards. We therefore aimed to determine whether continuous monitoring of respiratory patterns in hospitalized patients with COVID-19 predicts subsequent need for increased respiratory support. Methods: Single-center pilot prospective cohort study in COVID-19 patients who were cared for in routine wards. COVID-19 patients who had at least one escalation of pulmonary management were matched to three non-escalated patients. Contactless respiratory monitoring was instituted after patients enrolled, and continued for 15 days unless hospital discharge, initiation of invasive mechanical ventilation, or death occurred. Clinicians were blinded to respiratory rate data from the continuous monitor. The exposures were respiratory features over rolling periods of 30 min, 24 h, and 72 h before respiratory care escalation. The primary outcome was a subsequent escalation in ventilatory support beyond a Venturi mask. Results: Among 125 included patients, 13 exhibited at least one escalation and were each matched to three non-escalated patients. A total of 28 escalation events were matched to 84 non-escalation episodes. The 30-min mean respiratory rate in escalated patients was 23 breaths per minute (bpm) ranging from 13 to 40 bpm, similar to the 22 bpm in non-escalated patients, although with less variability (range 14 to 31 bpm). However, higher respiratory rate variability, especially skewness over 1 day, was associated with higher incidence of escalation events. Our overall model, based on continuous data, had a moderate accuracy with an AUC 0.81 (95%CI: 0.73, 0.88) and a good specificity 0.93 (95%CI: 0.87, 0.99). Conclusion: Our pilot observational study suggests that respiratory rate variability as detected with continuous monitoring is associated with subsequent care escalation during the following 24 h. Continuous respiratory monitoring thus appears to be a valuable increment over intermittent monitoring. Strengths and limitations: Our study was the initial evaluation of Circadia contactless respiratory monitoring in COVID-19 patients who are at special risk of pulmonary deterioration. The major limitation is that the analysis was largely post hoc and thus needs to be confirmed in an out-of-sample population.

Safety and Feasibility of Transbronchial Cryobiopsy in Mechanically Ventilated Patients

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Elevated plasma levels of epithelial and endothelial cell markers in COVID-19 survivors with reduced lung diffusing capacity six months after hospital discharge.

BACKGROUND: Some COVID-19 survivors present lung function abnormalities during follow-up, particularly reduced carbon monoxide lung diffusing capacity (DLCO). To investigate risk factors and underlying pathophysiology, we compared the clinical characteristics and levels of circulating pulmonary epithelial and endothelial markers in COVID-19 survivors with normal or reduced DLCO 6 months after discharge. METHODS: Prospective, observational study. Clinical characteristics during hospitalization, and spirometry, DLCO and plasma levels of epithelial (surfactant protein (SP) A (SP-A), SP-D, Club cell secretory protein-16 (CC16) and secretory leukocyte protease inhibitor (SLPI)), and endothelial (soluble intercellular adhesion molecule 1 (sICAM-1), soluble E-selectin and Angiopoietin-2) 6 months after hospital discharge were determined in 215 COVID-19 survivors. RESULTS: DLCO was < 80% ref. in 125 (58%) of patients, who were older, more frequently smokers, had hypertension, suffered more severe COVID-19 during hospitalization and refer persistent dyspnoea 6 months after discharge. Multivariate regression analysis showed that age ≥ 60 years and severity score of the acute episode ≥ 6 were independent risk factors of reduced DLCO 6 months after discharge. Levels of epithelial (SP-A, SP-D and SLPI) and endothelial (sICAM-1 and angiopoietin-2) markers were higher in patients with reduced DLCO, particularly in those with DLCO ≤ 50% ref. Circulating SP-A levels were associated with the occurrence of acute respiratory distress syndrome (ARDS), organizing pneumonia and pulmonary embolisms during hospitalization. CONCLUSIONS: Reduced DLCO is common in COVID-19 survivors 6 months after hospital discharge, especially in those older than 60 years with very severe acute disease. In these individuals, elevated levels of epithelial and endothelial markers suggest persistent lung damage.

Anticoagulation strategies and risk of bleeding events in critically ill COVID-19 patients.

OBJECTIVE: To evaluate the rate of thrombosis, bleeding and mortality comparing anticoagulant doses in critically ill COVID-19 patients. DESIGN: Retrospective observational and analytical cohort study. SETTING: COVID-19 patients admitted to the intensive care unit of a tertiary hospital between March and April 2020. PATIENTS: 201 critically ill COVID-19 patients were included. Patients were categorized into three groups according to the highest anticoagulant dose received during hospitalization: prophylactic, intermediate and therapeutic. INTERVENTIONS: The incidence of venous thromboembolism (VTE), bleeding and mortality was compared between groups. We performed two logistic multivariable regressions to test the association between VTE and bleeding and the anticoagulant regimen. MAIN VARIABLES OF INTEREST: VTE, bleeding and mortality. RESULTS: 78 patients received prophylactic, 94 intermediate and 29 therapeutic doses. No differences in VTE and mortality were found, while bleeding events were more frequent in the therapeutic (31%) and intermediate (15%) dose group than in the prophylactic group (5%) (p<0.001 and p<0.05 respectively). The anticoagulant dose was the strongest determinant for bleeding (odds ratio 2.4, 95% confidence interval 1.26-4.58, p=0.008) but had no impact on VTE. CONCLUSIONS: Intermediate and therapeutic doses appear to have a higher risk of bleeding without a decrease of VTE events and mortality in critically ill COVID-19 patients.

Role of respiratory intermediate care units during the SARS-CoV-2 pandemic.

RATIONALE: The SARS-CoV2 pandemic increased exponentially the need for both Intensive (ICU) and Intermediate Care Units (RICU). The latter are of particular importance because they can play a dual role in critical and post-critical care of COVID-19 patients. Here, we describe the setup of 2 new RICUs in our institution to face the SARS-CoV-2 pandemic and discuss the clinical characteristics and outcomes of the patients attended. METHODS: Retrospective analysis of the characteristics and outcomes of COVID-19 patients admitted to 2 new RICUs built specifically in our institution to face the first wave of the SARS-CoV-2 pandemic, from April 1 until May 30, 2020. RESULTS: During this period, 106 COVID-19 patients were admitted to these 2 RICUs, 65 of them (61%) transferred from an ICU (step-down) and 41 (39%) from the ward or emergency room (step-up). Most of them (72%) were male and mean age was 66 ± 12 years. 31% of them required support with oxygen therapy via high-flow nasal cannula (HFNC) and 14% non-invasive ventilation (NIV). 42 of the 65 patients stepping down (65%) had a previous tracheostomy performed and most of them (74%) were successfully decannulated during their stay in the RICU. Length of stay was 7 [4-11] days. 90-day mortality was 19% being significantly higher in stepping up patients than in those transferred from the ICU (25 vs. 10% respectively; p < 0.001). CONCLUSIONS: RICUs are a valuable hospital resource to respond to the challenges of the SARS-CoV-2 pandemic both to treat deteriorating and recovering COVID-19 patients.

Lung Function sequelae in COVID-19 Patients 3 Months After Hospital Discharge / Secuelas en la función pulmonar de los pacientes con COVID-19 tres meses después del alta hospitalaria

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Low birth weight as a potential risk factor for severe COVID-19 in adults.

The identification of factors predisposing to severe COVID-19 in young adults remains partially characterized. Low birth weight (LBW) alters cardiovascular and lung development and predisposes to adult disease. We hypothesized that LBW is a risk factor for severe COVID-19 in non-elderly subjects. We analyzed a prospective cohort of 397 patients (18-70 years) with laboratory-confirmed SARS-CoV-2 infection attended in a tertiary hospital, where 15% required admission to Intensive Care Unit (ICU). Perinatal and current potentially predictive variables were obtained from all patients and LBW was defined as birth weight ≤ 2.500 g. Age (adjusted OR (aOR) 1.04 [1-1.07], P = 0.012), male sex (aOR 3.39 [1.72-6.67], P < 0.001), hypertension (aOR 3.37 [1.69-6.72], P = 0.001), and LBW (aOR 3.61 [1.55-8.43], P = 0.003) independently predicted admission to ICU. The area under the receiver-operating characteristics curve (AUC) of this model was 0.79 [95% CI, 0.74-0.85], with positive and negative predictive values of 29.1% and 97.6% respectively. Results were reproduced in an independent cohort, from a web-based survey in 1822 subjects who self-reported laboratory-positive SARS-CoV-2 infection, where 46 patients (2.5%) needed ICU admission (AUC 0.74 [95% CI 0.68-0.81]). LBW seems to be an independent risk factor for severe COVID-19 in non-elderly adults and might improve the performance of risk stratification algorithms.

Once-daily 1 g ceftriaxone optimizes exposure in patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration.

PURPOSE: Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC). METHODS: In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®. RESULTS: We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration. CONCLUSION: Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.

Severe acute kidney injury in critically ill COVID-19 patients.

BACKGROUND: Acute kidney injury (AKI) is frequent in Coronavirus Infection Disease 2019 (COVID-19) patients. Factors associated with AKI in COVID-19 intensive care unit (ICU) patients and their outcomes have not been previously explored. METHODS: Prospective observational study of COVID-19 patients admitted to the ICUs of the Hospital Clínic of Barcelona (Spain), from March 25th to April 21st, 2020, who developed AKI stage 2 or higher (AKIN classification). The primary goal was to describe the characteristics of moderate-severe AKI of COVID-19 patients in an ICU context. As a secondary goal, we aimed to find independent predictors of AKI progression, Renal Replacement Therapy (RRT) requirement and mortality among these patients. RESULTS: During the study period, 52 out of 237 ICU patients, developed AKIN stage 2 or higher and were included in the study. A Sequential Organ Failure Assessment (SOFA) score at AKI diagnosis of 8 or higher was associated with RRT, OR 5.2, p 0.032. At the time of AKI diagnosis, patients had a worse liver profile and higher inflammation markers than at admission. Fifty per cent of the patients presented AKI progression from AKIN 2 to 3 and 28.85% required RRT. The use of corticosteroids in 69.2% of patients was associated with a reduced requirement of RRT, OR 0.13 (CI 95% 0.02-0.89), p 0.037. AKI was associated with high mortality (50%) and a longer hospital stay, median 35 vs 18 days (p 0.024). CONCLUSIONS: The prevalence of moderate/severe AKI in COVID-19 patients admitted to the ICU is high and has a strong correlation with mortality and length of hospital stay.

Administración intrapleural secuencial de agentes fibrinolíticos y dornasa alfa en el empiema. Protocolo de uso clínico en base a su estabilidad fisicoquímica / Sequential intrapleural administration of fibrinolytic drugs and dornase alfa for empyema management. Treatment protocol based on its physicochemical stability

Objetivo: La administración intrapleural de fibrinolíticos y dornasa alfa ha demostrado en estudios aleatorizados ser capaz de disminuir la necesidad de desbridamiento quirúrgico del empiema y los días de estancia media hospitalaria. Sin embargo, su aplicación en práctica clínica es limitada, probablemente debido a la falta de protocolos que simplifiquen su administración. El presente estudio tiene como objetivo analizar la estabilidad fisicoquímica de la administración simultánea de uroquinasa y dornasa alfa para el posterior desarrollo de un protocolo de uso en práctica clínica. Método: Ensayo de estabilidad in vitro de uroquinasa, dornasa alfa y la mezcla de ambos. Se evaluó su estabilidad como (i) ausencia de partículas, (ii) variación de color y (iii) cambios de pH a tiempos 0,30 minutos, 1, 2 y 4 horas a 37°C. Cada muestra se preparó y analizó por triplicado. Resultados: Las soluciones individuales de uroquinasa y dornasa alfa mostraron cambios ligeros del pH, sin cambios en su color ni presencia de partículas en suspensión. La mezcla de uroquinasa y dornasa alfa no fue estable transcurridas 2 horas, mostrando turbidez por la floculación y separación de fases con formación de precipitado a las 4 horas. Se desarrolló un protocolo de uso clínico basado en la administración secuencial de uroquinasa y dornasa alfa, ya que no fue posible garantizar la estabilidad fisicoquímica de la administración simultánea de ambos fármacos. Conclusiones: Los datos de estabilidad fisicoquímica no permiten asegurar la administración simultánea de ambos fármacos de manera segura y eficaz, por lo que se propone un protocolo de administración secuencial

Objective: Intrapleural administration of fibrinolytics and dornase alfa has been shown in randomized studies to be able to reduce both the need for surgical debridement of empyema and the average hospital stay. However, its application in clinical practice is limited, probably due to the lack of protocols that simplify its administration. The present study aims to analyze the physicochemical stability of the simultaneous urokinase and dornase alfa administration for the subsequent development of a clinical practice use protocol. Method: In vitro stability test of urokinase, dornase alfa and a combination of both. Its stability was evaluated as (i) absence of particles, (ii) color variation and (iii) pH changes at times 0,30 minutes, 1,2 and 4 hours at 37°C. Each sample was prepared and analyzed in triplicate. Results: Individual solutions of urokinase and dornase alfa showed slight changes in pH, finding no changes in either color or presence of suspended particles. The urokinase and dornase alfa combination was not stable after 2 hours, when turbidity emerged due to flocculation and phase separation. After 4 hours, precipitate formation was found. A protocol for clinical use was developed based on urokinase and dornase alfa sequential administration, since it was not possible to guarantee the physicochemical stability of the simultaneous administration of both drugs. Conclusions: The physicochemical stability data obtained does not allow to ensure a simultaneous administration of both drugs in a safe and effective way, thus a sequential administration protocol is proposed

Sequential intrapleural administration of fibrinolytic drugs and dornase alfa for empyema management. Treatment protocol based on its physicochemical stability.

OBJECTIVE: Intrapleural administration of fibrinolytics and dornase alfa has been shown in randomized studies to be able to reduce both the  need for surgical debridement of empyema and the average  hospital stay. However, its application in clinical practice is limited,  probably due to the lack of protocols that simplify its administration. The  present study aims to analyze the physicochemical stability of the  simultaneous urokinase and dornase alfa administration for the  subsequent development of a clinical practice use protocol. METHOD: In vitro stability test of urokinase, dornase alfa and a  combination of both. Its stability was evaluated as (i) absence of  particles, (ii) color variation and (iii) pH changes at times 0, 30 minutes,  1, 2 and 4 hours at 37 °C. Each sample was prepared and  analyzed in triplicate. RESULTS: Individual solutions of urokinase and dornase alfa showed slight changes in pH, finding no changes in either color or  presence of suspended particles. The urokinase and dornase alfa  combination was not stable after 2 hours, when turbidity emerged due  to flocculation and phase separation. After 4 hours, precipitate  formation was found. A pro tocol for clinical use was developed based on  urokinase and dornase alfa sequential administration, since it was  not possible to guarantee the physicochemical stability of the simultaneous administration of both drugs. CONCLUSIONS: The physicochemical stability data obtained does not allow to ensure a simultaneous administration of both drugs in a  safe and effective way, thus a sequential administration protocol is  proposed.

Objetivo: La administración intrapleural de fibrinolíticos y dornasa alfa ha demostrado en estudios aleatorizados ser capaz de disminuir la  necesidad de desbridamiento quirúrgico del empiema y los días de  estancia media hospitalaria. Sin embargo, su aplicación en práctica  clínica es limitada, probablemente debido a la falta de protocolos que  simplifiquen su administración. El presente estudio tiene como objetivo  analizar la estabilidad fisicoquímica de la administración simultánea de  uroquinasa y dornasa alfa para el posterior desarrollo de un protocolo de  uso en práctica clínica.Método: Ensayo de estabilidad in vitro de uroquinasa, dornasa alfa y la  mezcla de ambos. Se evaluó su estabilidad como (i) ausencia de partículas, (ii) variación de color y (iii) cambios de pH a tiempos 0,  30 minutos, 1, 2 y 4 horas a 37 °C. Cada muestra se preparó y analizó  por triplicado.Resultados: Las soluciones individuales de uroquinasa y dornasa alfa mostraron cambios ligeros del pH, sin cambios en su color ni  presencia de partículas en suspensión. La mezcla de uroquinasa y  dornasa alfa no fue estable transcurridas 2 horas, mostrando turbidez  por la floculación y sepa ración de fases con formación de precipitado a  las 4 horas. Se desarrolló un protocolo de uso clínico basado en la  administración secuencial de uroquinasa y dornasa alfa, ya que no fue  posible garantizar la estabilidad fisicoquímica de la administración  simultánea de ambos fármacos.Conclusiones: Los datos de estabilidad fisicoquímica no permiten  asegurar la administración simultánea de ambos fármacos de manera  segura y eficaz, por lo que se propone un protocolo de administración  secuencial.

Distribution, temporal stability and association with all-cause mortality of the 2017 GOLD groups in the ECLIPSE cohort.

BACKGROUND: In 2017, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposed a new classification of patients with chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS: We contrasted the distribution of COPD patients according to GOLD 2017 and 2011 classifications, the temporal stability of the 2017 groups during 3 years follow-up and their association with all-cause mortality in the ECLIPSE cohort. RESULTS: We found that GOLD 2017: (1) switched a substantial proportion of GOLD 2011C and D patients to A and B groups at recruitment; (2) about half of A, B and D patients remained in the same group at the end of follow-up, whereas 74% of C patients (the smallest group of all) changed, either because exacerbation rate decreased or dyspnea increased; and, (3) all-cause mortality by group was not significantly different between GOLD 2011 and 2017. Of note, mortality in B (16%) and D patients (18%) was similar, both with similar severity of airflow limitation, the best individual mortality risk factor. CONCLUSIONS: These results illustrate the cross-sectional and longitudinal effects of excluding FEV1 from GOLD 2017, and highlight both the clinical relevance of symptom assessment in the management of COPD and the prognostic capacity of FEV1.